Drug delivery across BBB

Recent advances in delivering drug across blood brain barrier.

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Aman Kumar Naik
Integrated M.Sc.
Drug Delivery across the
Blood–Brain Barrier(BBB)

2. (junctional adhesion molecule-1, occludin, and claudins) with cy-
toplasmic accessory proteins (zonula occludens-1 and -2, cingulin,
AF-6, and 7H6). They are linked to the actin cytoskeleton[9],
thereby forming the most intimate cell to cell connection. The TJ
are further strengthened and maintained by the interaction or
communication of astrocytes and pericytes with brain endothelia
cells[10];
3) the expression of various transporters including GLUT1 glucose
carrier, amino acid carrier LAT1, transferring receptors, insulin re-
ceptors, lipoprotein receptors and ATP family of efflux trans-
porters such as p-glycoprotein (P-gp) and multidrug resistance-
related proteins MRPs[3,11]. Some of these aid the transport
into the brain while others prevent the entry of many molecules;
4) the synergistic inductive functions and upregulating of BBB features
by astrocytes, astrocytic perivascular endfeet, pericytes, perivascular
macrophages and neurons, as suggested by the strong evidence
from cell culture studies[12–14];
5) the lack of lymphatic drainage, and absence of major histocompat-
ibility complex (MHC) antigens in CNS with immune reactivity in-
ducible on temporary demand in order to provide maximum
protection to neuronal function[15]. The BBB has a strict limit
for the passage of immune cells, especially lymphocytes[16]and
its immune barrier is made by the association between BBB endo-
thelia cells and perivascular macrophages and mast cells[17]. Ad-
ditionally, this immune barrier is reinforced by local microglial
cells[18].
All these characteristics lead to BBB to possess multiple functions
as a physical barrier (TJ), a transport barrier (P-gp), a metabolic or en-
zymatic barrier (specialised enzyme systems[11,19]and an immuno-
logical barrier.
3. Transport routes across the blood–brain barrier
It has been well established that there are several transport routes
by which solute molecules move across the BBB[11,20]. Diffusion of
substances into the brain can be divided into paracellular and trans-
cellular. As illustrated inFig. 2.a, small water-soluble molecules sim-
ply diffuse through the TJ but not to any great extent. Small lipid
soluble substances like alcohol and steroid hormones penetrate trans-
cellularly by dissolving in their lipid plasma membrane (Fig. 2.b).
However, for almost all other substances, including essential mate-
rials such as glucose and amino acids, transport proteins (carriers),
specific receptor-mediated or vesicular mechanisms (adsorptive
transcytosis) are required to pass the BBB.
In the case of transport proteins or known as carrier-mediated
transport (Fig. 2.c), there is binding of a solute such as glucose or
amino acids to a protein transporter on one side of the membrane
that triggers a conformational change in the protein, resulting in the
transport of the substance to the other side of the membrane, from
high to low concentration. If compounds need to be moved against
a concentration gradient, ATP may provide the energy to facilitate
the process. Efflux pumps or transporters (Fig. 2.d) are responsible
for extruding drugs from the brain and this mechanism is a major ob-
stacle for the accumulation of a wide range of biologically active mol-
ecules in the brain, with the ATP binding cassette (ABC) transporter
P-gp and multidrug resistant protein (MRP) being the principle efflux
mechanism of these agents[21]. Inhibition of P-gp in pre-clinical
studies has enhanced the penetration of paclitaxel into the brain, in-
dicating the feasibility of achieving improved drug delivery to the
brain by suppression of P-gp[22].
Receptor-mediated transcytosis (RMT) (Fig. 2.e) provides a means
for selective uptake of macromolecules. Endothelial cells have recep-
tors for the uptake of many different types of ligands, including
growth factors, enzymes and plasma proteins. For example, insulin
moleculesfirst bind to receptors that collect in specialized areas of
the plasma membrane known as coated pits. When bound to ligand
these pits invaginate into the cytoplasm and then pinch free of the
plasma membrane to form coated vesicles. After acidification of the
endosome, the ligand will dissociate from the receptor and cross the
other side of membrane. RMT has been extensively studied for brain
targeting[23]. Those well-characterised systems include transferring
receptor (TfR), insulin receptor, lipoprotein receptors, scavenger re-
ceptors class B type I, diphtheria toxin receptor and glutathione trans-
porter[3].
Adsorptive-mediated transcytosis (AMT), also known as the pino-
cytosis route (Fig. 2.f), is triggered by an electrostatic interaction be-
tween a positively charged substance, usually the charged moiety of
a peptide, and the negatively charged plasma membrane surface
(i.e. heparin sulphate proteoglycans). Adsorptive-mediated transport
has a lower affinity but higher capacity than RMT. The development
of many new drug delivery technologies focuses on AMT[24]. AMT-
Fig. 1.Schematic representation of the blood–brain barrier (BBB) and other components of a neurovascular unit (NVU).
Reproduced with permission from reference[11].
642 Y. Chen, L. Liu / Advanced Drug Delivery Reviews 64 (2012) 640–665
Schematic representation of the blood–brain barrier (BBB)
© 2006 Nature Publishing Group

*Wolfson Centre for Age-
Related Diseases, King’s
College London, UK.
‡
Institute of Clinical
Neuroscience, The
Sahlgrenska Academy at
Göteborg University,
Göteborg, Sweden.
Correspondence to N.J.A.
e-mail: [email protected]
doi:10.1038/nrn1824
Neurovascular unit
A functional unit composed of
groups of neurons and their
associated astrocytes,
interacting with smooth muscle
cells and endothelial cells on
the microvessels (arterioles)
responsible for their blood
supply, and capable of
regulating the local blood flow.
Gliovascular unit
A proposed functional unit
composed of single astrocytic
glial cells and the neurons they
surround, interacting with local
segments of blood vessels, and
capable of regulating blood
flow at the arteriolar level and
BBB functions at the capillary
level.
Astrocyte–endothelial interactions
at the blood–brain barrier
N. Joan Abbott*, Lars Rönnbäck
‡
and Elisabeth Hansson
‡
Abstract | The blood–brain barrier, which is formed by the endothelial cells that line
cerebral microvessels, has an important role in maintaining a precisely regulated
microenvironment for reliable neuronal signalling. At present, there is great interest in
the association of brain microvessels, astrocytes and neurons to form functional
‘neurovascular units’, and recent studies have highlighted the importance of brain
endothelial cells in this modular organization. Here, we explore specific interactions
between the brain endothelium, astrocytes and neurons that may regulate
blood–brain barrier function. An understanding of how these interactions are disturbed
in pathological conditions could lead to the development of new protective and
restorative therapies.
Neuroscience has traditionally focused on the neurons
of the central and peripheral nervous systems, and,
increasingly, on their interactions with the glial cells
that support their function. It is now becoming clear
that neurons, glia and microvessels are organized into
well-structured neurovascular units, which are involved
in the regulation of cerebral blood flow
1
. Within
this organization, further modular structure can be
detected; in particular, the proposed gliovascular units,
in which individual astrocytic glia support the function
of particular neuronal populations and territories, and
communicate with associated segments of the micro-
vasculature
2,3
. Several recent studies have highlighted
the importance of the brain endothelial cells that
form the blood–brain barrier (BBB) in this modular
organization, and the physiology and pharmacology
of the signalling between glia and endothelium that is
involved in regulating the BBB. Here, we describe the
properties of the brain endothelium that contribute to
its barrier function, and how cell–cell interactions lead
to induction of the specialized features of the BBB and
associated cell types. We review work showing that the
BBB is a dynamic system, and discuss the ways in which
BBB permeability and transport can be modulated. We
then consider the important role of astrocytes and the
BBB in brain ion and volume regulation. Finally, we
discuss some of the pathologies that involve BBB dys-
function, and the development of protective strategies
for the brain endothelium that may reduce secondary
neural damage in both acute and chronic neurological
conditions.
Barriers of the CNS
The cerebral ventricles and subarachnoid space contain
cerebrospinal fluid (CSF), which is secreted by choroid
plexuses in the lateral, third and fourth ventricles
4
. Three
barrier layers limit and regulate molecular exchange at the
interfaces between the blood and the neural tissue or its
fluid spaces (FIG. 1): the BBB formed by the cerebro vascular
endothelial cells between blood and brain interstitial
fluid (ISF), the choroid plexus epithelium between blood
and ventricular CSF, and the arachnoid epithelium
between blood and subarachnoid CSF
5
. Individual neu-
rons are rarely more than 8–20 µm from a brain capillary
6
,
although they may be millimetres or centimetres from a
CSF compartment. Hence, of the various CNS barriers,
the BBB exerts the greatest control over the immediate
microenvironment of brain cells.
The blood–brain barrier
The BBB is a selective barrier formed by the endothelial
cells that line cerebral microvessels
7–10
(FIG. 2). It acts as a
‘physical barrier’ because complex tight junctions between
adjacent endothelial cells force most molecular traffic
to take a transcellular route across the BBB, rather than
moving paracellularly through the junctions, as in most
endothelia
11,12
(FIG. 3). Small gaseous molecules such as O
2

and CO
2
can diffuse freely through the lipid membranes,
and this is also a route of entry for small lipophilic agents,
including drugs such as barbiturates and ethanol. The
presence of specific transport systems on the luminal
and abluminal membranes regulates the transcellular
traffic of small hydrophilic molecules, which provides
REVIEWS
NATURE REVIEWS | NEUROSCIENCE VOLUME 7 | JANUARY 2006 | 41
© 2006 Nature Publishing Group

*Wolfson Centre for Age-
Related Diseases, King’s
College London, UK.
‡
Institute of Clinical
Neuroscience, The
Sahlgrenska Academy at
Göteborg University,
Göteborg, Sweden.
Correspondence to N.J.A.
e-mail: [email protected]
doi:10.1038/nrn1824
Neurovascular unit
A functional unit composed of
groups of neurons and their
associated astrocytes,
interacting with smooth muscle
cells and endothelial cells on
the microvessels (arterioles)
responsible for their blood
supply, and capable of
regulating the local blood flow.
Gliovascular unit
A proposed functional unit
composed of single astrocytic
glial cells and the neurons they
surround, interacting with local
segments of blood vessels, and
capable of regulating blood
flow at the arteriolar level and
BBB functions at the capillary
level.
Astrocyte–endothelial interactions
at the blood–brain barrier
N. Joan Abbott*, Lars Rönnbäck
‡
and Elisabeth Hansson
‡
Abstract | The blood–brain barrier, which is formed by the endothelial cells that line
cerebral microvessels, has an important role in maintaining a precisely regulated
microenvironment for reliable neuronal signalling. At present, there is great interest in
the association of brain microvessels, astrocytes and neurons to form functional
‘neurovascular units’, and recent studies have highlighted the importance of brain
endothelial cells in this modular organization. Here, we explore specific interactions
between the brain endothelium, astrocytes and neurons that may regulate
blood–brain barrier function. An understanding of how these interactions are disturbed
in pathological conditions could lead to the development of new protective and
restorative therapies.
Neuroscience has traditionally focused on the neurons
of the central and peripheral nervous systems, and,
increasingly, on their interactions with the glial cells
that support their function. It is now becoming clear
that neurons, glia and microvessels are organized into
well-structured neurovascular units, which are involved
in the regulation of cerebral blood flow
1
. Within
this organization, further modular structure can be
detected; in particular, the proposed gliovascular units,
in which individual astrocytic glia support the function
of particular neuronal populations and territories, and
communicate with associated segments of the micro-
vasculature
2,3
. Several recent studies have highlighted
the importance of the brain endothelial cells that
form the blood–brain barrier (BBB) in this modular
organization, and the physiology and pharmacology
of the signalling between glia and endothelium that is
involved in regulating the BBB. Here, we describe the
properties of the brain endothelium that contribute to
its barrier function, and how cell–cell interactions lead
to induction of the specialized features of the BBB and
associated cell types. We review work showing that the
BBB is a dynamic system, and discuss the ways in which
BBB permeability and transport can be modulated. We
then consider the important role of astrocytes and the
BBB in brain ion and volume regulation. Finally, we
discuss some of the pathologies that involve BBB dys-
function, and the development of protective strategies
for the brain endothelium that may reduce secondary
neural damage in both acute and chronic neurological
conditions.
Barriers of the CNS
The cerebral ventricles and subarachnoid space contain
cerebrospinal fluid (CSF), which is secreted by choroid
plexuses in the lateral, third and fourth ventricles
4
. Three
barrier layers limit and regulate molecular exchange at the
interfaces between the blood and the neural tissue or its
fluid spaces (FIG. 1): the BBB formed by the cerebro vascular
endothelial cells between blood and brain interstitial
fluid (ISF), the choroid plexus epithelium between blood
and ventricular CSF, and the arachnoid epithelium
between blood and subarachnoid CSF
5
. Individual neu-
rons are rarely more than 8–20 µm from a brain capillary
6
,
although they may be millimetres or centimetres from a
CSF compartment. Hence, of the various CNS barriers,
the BBB exerts the greatest control over the immediate
microenvironment of brain cells.
The blood–brain barrier
The BBB is a selective barrier formed by the endothelial
cells that line cerebral microvessels
7–10
(FIG. 2). It acts as a
‘physical barrier’ because complex tight junctions between
adjacent endothelial cells force most molecular traffic
to take a transcellular route across the BBB, rather than
moving paracellularly through the junctions, as in most
endothelia
11,12
(FIG. 3). Small gaseous molecules such as O
2

and CO
2
can diffuse freely through the lipid membranes,
and this is also a route of entry for small lipophilic agents,
including drugs such as barbiturates and ethanol. The
presence of specific transport systems on the luminal
and abluminal membranes regulates the transcellular
traffic of small hydrophilic molecules, which provides
REVIEWS
NATURE REVIEWS | NEUROSCIENCE VOLUME 7 | JANUARY 2006 | 41
© 2006 Nature Publishing Group

*Wolfson Centre for Age-
Related Diseases, King’s
College London, UK.
‡
Institute of Clinical
Neuroscience, The
Sahlgrenska Academy at
Göteborg University,
Göteborg, Sweden.
Correspondence to N.J.A.
e-mail: [email protected]
doi:10.1038/nrn1824
Neurovascular unit
A functional unit composed of
groups of neurons and their
associated astrocytes,
interacting with smooth muscle
cells and endothelial cells on
the microvessels (arterioles)
responsible for their blood
supply, and capable of
regulating the local blood flow.
Gliovascular unit
A proposed functional unit
composed of single astrocytic
glial cells and the neurons they
surround, interacting with local
segments of blood vessels, and
capable of regulating blood
flow at the arteriolar level and
BBB functions at the capillary
level.
Astrocyte–endothelial interactions
at the blood–brain barrier
N. Joan Abbott*, Lars Rönnbäck
‡
and Elisabeth Hansson
‡
Abstract | The blood–brain barrier, which is formed by the endothelial cells that line
cerebral microvessels, has an important role in maintaining a precisely regulated
microenvironment for reliable neuronal signalling. At present, there is great interest in
the association of brain microvessels, astrocytes and neurons to form functional
‘neurovascular units’, and recent studies have highlighted the importance of brain
endothelial cells in this modular organization. Here, we explore specific interactions
between the brain endothelium, astrocytes and neurons that may regulate
blood–brain barrier function. An understanding of how these interactions are disturbed
in pathological conditions could lead to the development of new protective and
restorative therapies.
Neuroscience has traditionally focused on the neurons
of the central and peripheral nervous systems, and,
increasingly, on their interactions with the glial cells
that support their function. It is now becoming clear
that neurons, glia and microvessels are organized into
well-structured neurovascular units, which are involved
in the regulation of cerebral blood flow
1
. Within
this organization, further modular structure can be
detected; in particular, the proposed gliovascular units,
in which individual astrocytic glia support the function
of particular neuronal populations and territories, and
communicate with associated segments of the micro-
vasculature
2,3
. Several recent studies have highlighted
the importance of the brain endothelial cells that
form the blood–brain barrier (BBB) in this modular
organization, and the physiology and pharmacology
of the signalling between glia and endothelium that is
involved in regulating the BBB. Here, we describe the
properties of the brain endothelium that contribute to
its barrier function, and how cell–cell interactions lead
to induction of the specialized features of the BBB and
associated cell types. We review work showing that the
BBB is a dynamic system, and discuss the ways in which
BBB permeability and transport can be modulated. We
then consider the important role of astrocytes and the
BBB in brain ion and volume regulation. Finally, we
discuss some of the pathologies that involve BBB dys-
function, and the development of protective strategies
for the brain endothelium that may reduce secondary
neural damage in both acute and chronic neurological
conditions.
Barriers of the CNS
The cerebral ventricles and subarachnoid space contain
cerebrospinal fluid (CSF), which is secreted by choroid
plexuses in the lateral, third and fourth ventricles
4
. Three
barrier layers limit and regulate molecular exchange at the
interfaces between the blood and the neural tissue or its
fluid spaces (FIG. 1): the BBB formed by the cerebro vascular
endothelial cells between blood and brain interstitial
fluid (ISF), the choroid plexus epithelium between blood
and ventricular CSF, and the arachnoid epithelium
between blood and subarachnoid CSF
5
. Individual neu-
rons are rarely more than 8–20 µm from a brain capillary
6
,
although they may be millimetres or centimetres from a
CSF compartment. Hence, of the various CNS barriers,
the BBB exerts the greatest control over the immediate
microenvironment of brain cells.
The blood–brain barrier
The BBB is a selective barrier formed by the endothelial
cells that line cerebral microvessels
7–10
(FIG. 2). It acts as a
‘physical barrier’ because complex tight junctions between
adjacent endothelial cells force most molecular traffic
to take a transcellular route across the BBB, rather than
moving paracellularly through the junctions, as in most
endothelia
11,12
(FIG. 3). Small gaseous molecules such as O
2

and CO
2
can diffuse freely through the lipid membranes,
and this is also a route of entry for small lipophilic agents,
including drugs such as barbiturates and ethanol. The
presence of specific transport systems on the luminal
and abluminal membranes regulates the transcellular
traffic of small hydrophilic molecules, which provides
REVIEWS
NATURE REVIEWS | NEUROSCIENCE VOLUME 7 | JANUARY 2006 | 41
© 2006 Nature Publishing Group

*Wolfson Centre for Age-
Related Diseases, King’s
College London, UK.
‡
Institute of Clinical
Neuroscience, The
Sahlgrenska Academy at
Göteborg University,
Göteborg, Sweden.
Correspondence to N.J.A.
e-mail: [email protected]
doi:10.1038/nrn1824
Neurovascular unit
A functional unit composed of
groups of neurons and their
associated astrocytes,
interacting with smooth muscle
cells and endothelial cells on
the microvessels (arterioles)
responsible for their blood
supply, and capable of
regulating the local blood flow.
Gliovascular unit
A proposed functional unit
composed of single astrocytic
glial cells and the neurons they
surround, interacting with local
segments of blood vessels, and
capable of regulating blood
flow at the arteriolar level and
BBB functions at the capillary
level.
Astrocyte–endothelial interactions
at the blood–brain barrier
N. Joan Abbott*, Lars Rönnbäck
‡
and Elisabeth Hansson
‡
Abstract | The blood–brain barrier, which is formed by the endothelial cells that line
cerebral microvessels, has an important role in maintaining a precisely regulated
microenvironment for reliable neuronal signalling. At present, there is great interest in
the association of brain microvessels, astrocytes and neurons to form functional
‘neurovascular units’, and recent studies have highlighted the importance of brain
endothelial cells in this modular organization. Here, we explore specific interactions
between the brain endothelium, astrocytes and neurons that may regulate
blood–brain barrier function. An understanding of how these interactions are disturbed
in pathological conditions could lead to the development of new protective and
restorative therapies.
Neuroscience has traditionally focused on the neurons
of the central and peripheral nervous systems, and,
increasingly, on their interactions with the glial cells
that support their function. It is now becoming clear
that neurons, glia and microvessels are organized into
well-structured neurovascular units, which are involved
in the regulation of cerebral blood flow
1
. Within
this organization, further modular structure can be
detected; in particular, the proposed gliovascular units,
in which individual astrocytic glia support the function
of particular neuronal populations and territories, and
communicate with associated segments of the micro-
vasculature
2,3
. Several recent studies have highlighted
the importance of the brain endothelial cells that
form the blood–brain barrier (BBB) in this modular
organization, and the physiology and pharmacology
of the signalling between glia and endothelium that is
involved in regulating the BBB. Here, we describe the
properties of the brain endothelium that contribute to
its barrier function, and how cell–cell interactions lead
to induction of the specialized features of the BBB and
associated cell types. We review work showing that the
BBB is a dynamic system, and discuss the ways in which
BBB permeability and transport can be modulated. We
then consider the important role of astrocytes and the
BBB in brain ion and volume regulation. Finally, we
discuss some of the pathologies that involve BBB dys-
function, and the development of protective strategies
for the brain endothelium that may reduce secondary
neural damage in both acute and chronic neurological
conditions.
Barriers of the CNS
The cerebral ventricles and subarachnoid space contain
cerebrospinal fluid (CSF), which is secreted by choroid
plexuses in the lateral, third and fourth ventricles
4
. Three
barrier layers limit and regulate molecular exchange at the
interfaces between the blood and the neural tissue or its
fluid spaces (FIG. 1): the BBB formed by the cerebro vascular
endothelial cells between blood and brain interstitial
fluid (ISF), the choroid plexus epithelium between blood
and ventricular CSF, and the arachnoid epithelium
between blood and subarachnoid CSF
5
. Individual neu-
rons are rarely more than 8–20 µm from a brain capillary
6
,
although they may be millimetres or centimetres from a
CSF compartment. Hence, of the various CNS barriers,
the BBB exerts the greatest control over the immediate
microenvironment of brain cells.
The blood–brain barrier
The BBB is a selective barrier formed by the endothelial
cells that line cerebral microvessels
7–10
(FIG. 2). It acts as a
‘physical barrier’ because complex tight junctions between
adjacent endothelial cells force most molecular traffic
to take a transcellular route across the BBB, rather than
moving paracellularly through the junctions, as in most
endothelia
11,12
(FIG. 3). Small gaseous molecules such as O
2

and CO
2
can diffuse freely through the lipid membranes,
and this is also a route of entry for small lipophilic agents,
including drugs such as barbiturates and ethanol. The
presence of specific transport systems on the luminal
and abluminal membranes regulates the transcellular
traffic of small hydrophilic molecules, which provides
REVIEWS
NATURE REVIEWS | NEUROSCIENCE VOLUME 7 | JANUARY 2006 | 41
© 2006 Nature Publishing Group

*Wolfson Centre for Age-
Related Diseases, King’s
College London, UK.
‡
Institute of Clinical
Neuroscience, The
Sahlgrenska Academy at
Göteborg University,
Göteborg, Sweden.
Correspondence to N.J.A.
e-mail: [email protected]
doi:10.1038/nrn1824
Neurovascular unit
A functional unit composed of
groups of neurons and their
associated astrocytes,
interacting with smooth muscle
cells and endothelial cells on
the microvessels (arterioles)
responsible for their blood
supply, and capable of
regulating the local blood flow.
Gliovascular unit
A proposed functional unit
composed of single astrocytic
glial cells and the neurons they
surround, interacting with local
segments of blood vessels, and
capable of regulating blood
flow at the arteriolar level and
BBB functions at the capillary
level.
Astrocyte–endothelial interactions
at the blood–brain barrier
N. Joan Abbott*, Lars Rönnbäck
‡
and Elisabeth Hansson
‡
Abstract | The blood–brain barrier, which is formed by the endothelial cells that line
cerebral microvessels, has an important role in maintaining a precisely regulated
microenvironment for reliable neuronal signalling. At present, there is great interest in
the association of brain microvessels, astrocytes and neurons to form functional
‘neurovascular units’, and recent studies have highlighted the importance of brain
endothelial cells in this modular organization. Here, we explore specific interactions
between the brain endothelium, astrocytes and neurons that may regulate
blood–brain barrier function. An understanding of how these interactions are disturbed
in pathological conditions could lead to the development of new protective and
restorative therapies.
Neuroscience has traditionally focused on the neurons
of the central and peripheral nervous systems, and,
increasingly, on their interactions with the glial cells
that support their function. It is now becoming clear
that neurons, glia and microvessels are organized into
well-structured neurovascular units, which are involved
in the regulation of cerebral blood flow
1
. Within
this organization, further modular structure can be
detected; in particular, the proposed gliovascular units,
in which individual astrocytic glia support the function
of particular neuronal populations and territories, and
communicate with associated segments of the micro-
vasculature
2,3
. Several recent studies have highlighted
the importance of the brain endothelial cells that
form the blood–brain barrier (BBB) in this modular
organization, and the physiology and pharmacology
of the signalling between glia and endothelium that is
involved in regulating the BBB. Here, we describe the
properties of the brain endothelium that contribute to
its barrier function, and how cell–cell interactions lead
to induction of the specialized features of the BBB and
associated cell types. We review work showing that the
BBB is a dynamic system, and discuss the ways in which
BBB permeability and transport can be modulated. We
then consider the important role of astrocytes and the
BBB in brain ion and volume regulation. Finally, we
discuss some of the pathologies that involve BBB dys-
function, and the development of protective strategies
for the brain endothelium that may reduce secondary
neural damage in both acute and chronic neurological
conditions.
Barriers of the CNS
The cerebral ventricles and subarachnoid space contain
cerebrospinal fluid (CSF), which is secreted by choroid
plexuses in the lateral, third and fourth ventricles
4
. Three
barrier layers limit and regulate molecular exchange at the
interfaces between the blood and the neural tissue or its
fluid spaces (FIG. 1): the BBB formed by the cerebro vascular
endothelial cells between blood and brain interstitial
fluid (ISF), the choroid plexus epithelium between blood
and ventricular CSF, and the arachnoid epithelium
between blood and subarachnoid CSF
5
. Individual neu-
rons are rarely more than 8–20 µm from a brain capillary
6
,
although they may be millimetres or centimetres from a
CSF compartment. Hence, of the various CNS barriers,
the BBB exerts the greatest control over the immediate
microenvironment of brain cells.
The blood–brain barrier
The BBB is a selective barrier formed by the endothelial
cells that line cerebral microvessels
7–10
(FIG. 2). It acts as a
‘physical barrier’ because complex tight junctions between
adjacent endothelial cells force most molecular traffic
to take a transcellular route across the BBB, rather than
moving paracellularly through the junctions, as in most
endothelia
11,12
(FIG. 3). Small gaseous molecules such as O
2

and CO
2
can diffuse freely through the lipid membranes,
and this is also a route of entry for small lipophilic agents,
including drugs such as barbiturates and ethanol. The
presence of specific transport systems on the luminal
and abluminal membranes regulates the transcellular
traffic of small hydrophilic molecules, which provides
REVIEWS
NATURE REVIEWS | NEUROSCIENCE VOLUME 7 | JANUARY 2006 | 41

3. based drug delivery typically involves either cationic proteins or cell-
penetrating peptide such as Tat-derived peptides and Syn-B vectors.
Last, but not least, cell-mediated transcytosis (Fig. 2.g) is a more
recently identified route of drug transport across the BBB[25], al-
though it is a well established mechanism for some pathogens such
asCryptococcus neoformansand HIV entry into the brain, known as“
Trojan horse”model[26,27]. This transport route relies on immune
cells such as monocytes or macrophages to cross the intact BBB. Un-
like aforementioned transport pathways which normally permit
only solute molecules with specific properties, cell-mediated transcy-
tosis is unique in that it can be used virtually for any type of mole-
cules or materials as well as particulate carrier systems[28].
Due to the unique properties of the TJs, paracellular transport of
hydrophilic drugs is virtually absent and transcellular transport by
passive diffusion is only available to molecules which fulfil certain cri-
teria[4,29,30]such as: 1) molecular weight is less than 500 Da;
2) compounds are unionised; 3) log P value of the drug is close to
2; 4) cumulative number of hydrogen bonds is not more than 10. Un-
fortunately only a small percentage of drugsfit these criteria[2]. For
other therapeutic molecules, their transport across the BBB will
then have to rely on either the integrity of the BBB or the drug or
drug carrier properties and their interaction with or affinity for recep-
tors expressed at the BBB, as well as other biological or immunologi-
cal processes occurring at the BBB. In other words, the BBB properties
and related biological processes, and their roles in trafficking various
types of molecules are fundamental to the success of drug transport
across the BBB. This is the reason for the need to gain a thorough un-
derstanding of the biological and pathological properties and process-
es of the BBB.
4. Biological and pathological properties of BBB for drug transport
Recent progress in the study of the molecular biology of the BBB
has led to a greater understanding of the barrier functions under nor-
mal physiological and pathological conditions, as well as when the
BBB is subjected to external stimuli. More importantly, this knowl-
edge empowers researchers to develop new strategies for therapeutic
molecules to target and transport across the BBB for treatment of
various CNS associated diseases. This section is focused on the physi-
cal barrier and properties of the BBB undergoing pathological changes
which may present potential opportunities for drug transport.
4.1. Physical barrier
The physical barrier of the BBB is a result of the formation of an
elaborated junctional complex by TJ and adherens junctions (AJ) be-
tween adjacent endothelial cells[31].
4.1.1. Tight junctions
TJ are located on the apical region of endothelia cells and structur-
ally formed by an intricate complex network made of a series of par-
allel, interconnected, transmembrane and cytoplasmatic strands of
proteins[32,31]. The high level of integrity of TJ is reflected by the
high electrical resistance of the BBB (1500–2000Ωcm
2
), which de-
pends on a proper extracellular Ca
2+
ion concentration. There are ex-
tensive reviews on the TJ elsewhere[31–33]. Here the focus of this
review is placed on some key molecules involved in the formation
and maintenance of TJ and the regulation of the permeability of TJ.
Among the identified molecules associated with TJ, the transmem-
brane proteins claudins and occludin are most well studied. Claudins
form dimmers and bind homotypically to other claudin molecules in
an adjacent brain capillary endothelia cell[34,35]thus forming the
primary seal of the TJ [31]. On the other hand, occludin is not essential
for the formation of TJ, as indicted in the knockout and knockdown
experiments[9]and its main function appears to be for TJ regulation
and as an additional support structure[10,36]. Of claudins, Claudin-5
has been shown to be involved in size-selective loosening the perme-
ability of BBB in mice[37]with permeability of molecules of size less
than 800 Da affected. However, similar effects were not observed
with barrier function of non-BBB endothelium, such as human umbil-
ical vein endothelial cells (HUVEC)[38]. In another experiment, treat-
ment of claudin-5 by cyclic AMP (cAMP) lead to enhancement of
claudin-5 activity along cell borders, rapid reduction in transendothe-
lial electrical resistance (TER), and loosening of the claudin-5-based
endothelial barrier against mannitol, but not inulin[39]. These sug-
gest that manipulation of claudin-5, or potentially other TJ proteins
Fig. 2.Transport routes across the blood–brain barrier. Pathways“a”to“f”are commonly for solute molecules; and the route“g”involves monocytes, macrophages and other im-
mune cells and can be used for any drugs or drugs incorporated liposomes or nanoparticles.
Adapted from reference[11].
643Y. Chen, L. Liu / Advanced Drug Delivery Reviews 64 (2012) 640–665
Transport routes across the blood–brain barrier
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr

4. Tight junction opening
Biological stimuli
Zonula occludens toxin (Zot)
vasoactive compounds and
inflammatory stimuli such as
histamine, bradykinin and VEGF
H2 receptors NO and cyclic GMP production
Tight junction opening
Chemical stimuli
Arterial injection of hyperosmolar solution
(e.g., mannitol, arabinose) Shrinkage of endothelial cells Opening gaps between cells
Sodium dodecyl sulphate (SDS)
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr

5. Physical stimuli
* FUS = Focused Ultrasound
Magnetic resonance monitoring of focused
ultrasound/magnetic nanoparticle targeting delivery
of therapeutic agents to the brain
Hao-Li Liu
a,b,1
, Mu-Yi Hua
c,1
, Hung-Wei Yang
c,1
, Chiung-Yin Huang
d
, Po-Chun Chu
a
, Jia-Shin Wu
a
, I-Chou Tseng
d
,
Jiun-Jie Wang
e
, Tzu-Chen Yen
b,f
, Pin-Yuan Chen
d,g,2,3
, and Kuo-Chen Wei
d,2,3
Departments of
a
Electrical Engineering,
c
Chemical and Material Engineering, and
e
Medical Image and Radiological Sciences and
g
Graduate Institute of Clinical
Medical Sciences, Chang-Gung University, Taoyuan 333, Taiwan;
b
Molecular Imaging Center and
f
Department of Nuclear Medicine, Chang-Gung Memorial
Hospital, Taoyuan 333, Taiwan; and
d
Department of Neurosurgery, Chang-Gung University College of Medicine and Memorial Hospital, Taoyuan 333, Taiwan
Edited by Ralph Weissleider, Harvard Medical School, Boston, MA, and accepted by the Editorial Board July 13, 2010 (received for review March 16, 2010)
The superparamagnetic properties of magnetic nanoparticles
(MNPs) allow them to be guided by an externally positioned magnet
and also provide contrast for MRI. However, their therapeutic use in
treating CNS pathologies in vivo is limited by insufficient local
accumulation and retention resulting from their inability to traverse
biological barriers. The combined use of focused ultrasound and
magnetic targeting synergistically delivers therapeutic MNPs across
the blood–brain barrier to enter the brain both passively and ac-
tively. Therapeutic MNPs were characterized and evaluated both
in vitro and in vivo, and MRI was used to monitor and quantify their
distribution in vivo. The technique could be used in normal brains or
in those with tumors, and significantly increased the deposition of
therapeutic MNPs in brains with intact or compromised blood–brain
barriers. Synergistic targeting and image monitoring are powerful
techniques for the delivery of macromolecular chemotherapeutic
agents into the CNS under the guidance of MRI.
blood–brain barrier|brain drug delivery|focused ultrasound|magnetic
nanoparticles|magnetic targeting
W
ithin the CNS, the blood–brain barrier (BBB) excludes
larger (>400 Da) molecules from entering the brain pa-
renchyma, protecting it from toxic foreign substances (1). How-
ever, it also prohibits delivery of many potentially effective
diagnostic or therapeutic agents and restricts the enhanced per-
meability and retention (EPR) of therapeutic nanoparticles.
Many factors affect EPR, including the pH, polarity, and size of
the delivered substance. Even when pathologic processes com-
promise the integrity or function of the BBB, EPR can be limited
by microenvironmental characteristics such as hypovascularity,
fibrosis, or necrosis (2–4).
In the presence of microbubbles and with use of a low-energy
burst tone, focused ultrasound (FUS) can increase the perme-
ability of the BBB (5). This noninvasive procedure disrupts the
BBB locally rather than systemically, minimizing off-target
effects. Furthermore, the disruption is reversible within several
hours, providing a window of opportunity to achieve local delivery
of chemotherapeutic agents in brains with intact or compromised
BBBs. However, drug delivery in such cases is passive, relying on
the free diffusion of the agents across the barrier.
Advances in nanotechnology and molecular biology have allowed
development of novel nanomedical platforms (6–8). Such
approaches allow simultaneous diagnostic imaging and drug de-
livery monitoring in vivo in real time (9, 10). Magnetic nanoparticles
(MNPs) have intrinsic magnetic properties that enable their use as
contrast agents in MRI (8, 11). Because MNPs are also sensitive to
external magnetic forces, magnetic targeting (MT) actively enhan-
ces their deposition at the target site, increasing the therapeutic
dose delivered beyond that obtainable by passive diffusion (12).
This study combines FUS and MT of nanoparticles as a syn-
ergistic delivery system for chemotherapeutic agents concurrent
with MRI monitoring for treating CNS diseases. FUS creates the
opportunity to deliver therapeutic MNPs by passive local EPR,
and externally applied magnetic forces actively increase the local
MNP concentration. When combined, these techniques permit
the delivery of large molecules into the brain (Fig. 1). Further-
more, the deposition of the therapeutic MNPs can be monitored
and quantified in vivo by MRI.
Results
Characterization of Therapeutic MNPs.The saturated magnetiza-
tion, mean hydrodynamic size, and particle size of the com-
mercially available MNP Resovist and the newly synthesized
MNPs generated for this study are summarized inTable S1. As
measured by transmission EM (TEM), MNP-3 had a mean di-
ameter of 12.3 nm (Fig. 2A). This was significantly smaller than
the hydrodynamic sizes measured by dynamic light scattering (64
nm for Resovist, 74–83 nm for MNPs-1–3;Fig. S1AandTable
S1), although such differences could be attributable to solvent
effects. The measured zeta potentials of all of the synthesized
MNPs were similar to that of Resovist (approximately 45 mV).
Magnetization of MNPs is crucial for their utility in MT, and
crystallinity significantly affects this parameter. During synthesis,
the crystallinity of the MNPs was manipulated by controlling the
reaction conditions. MNP-3 exhibited the best crystallinity among
the MNPs tested (Fig. S1C) and also displayed the highest degree
of magnetization (Fig. S1B).
Administration of the MNPs into biological tissues profoundly
alters the spin–spin relaxation rate (R2), and thus can serve as an
indicator of the MRI contrast agent. The R2, and hence the de-
tection sensitivity, of MNP-3 was twice that of Resovist by MRI
(Fig. 2EandFandTable S1).
The polymer poly[aniline-co-N-(1-one-butyric acid)] aniline
(SPAnH) was used to encapsulate iron oxide (Fe
3O
4). This pro-
cess decreases the aggregation typical of MNPs and improves
their stability in aqueous solutions. Fourier transform IR (FT-IR)
spectroscopy indicated that the surface of the Fe3O4particles was
covered with a layer of the SPAnH polymer, and that the out-
Author contributions: H.-L.L., M.-Y.H., H.-W.Y., P.-Y.C., and K.-C.W. designed research;
H.-L.L., M.-Y.H., H.-W.Y., C.-Y.H., P.-C.C., J.-S.W., I.-C.T., J.-J.W., T.-C.Y., and P.-Y.C. per-
formed research; H.-L.L., M.-Y.H., and H.-W.Y. contributed new reagents/analytic tools;
H.-L.L., M.-Y.H., H.-W.Y., C.-Y.H., P.-C.C., J.-S.W., I.-C.T., J.-J.W., T.-C.Y., P.-Y.C., and K.-C.W.
analyzed data; and H.-L.L., M.-Y.H., H.-W.Y., and K.-C.W. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. R.W. is a guest editor invited by the Editorial
Board.
Freely available online through the PNAS open access option.
1
H.-L.L., M.-Y.H., and H.-W.Y. contributed equally to this work.
2
P.-Y.C. and K.-C.W. contributed equally to this work.
3
To whom correspondence may be addressed. E-mail: [email protected] or
[email protected].
This article contains supporting information online atwww.pnas.org/lookup/suppl/doi:10.
1073/pnas.1003388107/-/DCSupplemental.
www.pnas.org/cgi/doi/10.1073/pnas.1003388107 PNAS |August 24, 2010|vol. 107|no. 34|15205–15210
MEDICAL SCIENCES
Magnetic resonance monitoring of focused
ultrasound/magnetic nanoparticle targeting delivery
of therapeutic agents to the brain
Hao-Li Liu
a,b,1
, Mu-Yi Hua
c,1
, Hung-Wei Yang
c,1
, Chiung-Yin Huang
d
, Po-Chun Chu
a
, Jia-Shin Wu
a
, I-Chou Tseng
d
,
Jiun-Jie Wang
e
, Tzu-Chen Yen
b,f
, Pin-Yuan Chen
d,g,2,3
, and Kuo-Chen Wei
d,2,3
Departments of
a
Electrical Engineering,
c
Chemical and Material Engineering, and
e
Medical Image and Radiological Sciences and
g
Graduate Institute of Clinical
Medical Sciences, Chang-Gung University, Taoyuan 333, Taiwan;
b
Molecular Imaging Center and
f
Department of Nuclear Medicine, Chang-Gung Memorial
Hospital, Taoyuan 333, Taiwan; and
d
Department of Neurosurgery, Chang-Gung University College of Medicine and Memorial Hospital, Taoyuan 333, Taiwan
Edited by Ralph Weissleider, Harvard Medical School, Boston, MA, and accepted by the Editorial Board July 13, 2010 (received for review March 16, 2010)
The superparamagnetic properties of magnetic nanoparticles
(MNPs) allow them to be guided by an externally positioned magnet
and also provide contrast for MRI. However, their therapeutic use in
treating CNS pathologies in vivo is limited by insufficient local
accumulation and retention resulting from their inability to traverse
biological barriers. The combined use of focused ultrasound and
magnetic targeting synergistically delivers therapeutic MNPs across
the blood–brain barrier to enter the brain both passively and ac-
tively. Therapeutic MNPs were characterized and evaluated both
in vitro and in vivo, and MRI was used to monitor and quantify their
distribution in vivo. The technique could be used in normal brains or
in those with tumors, and significantly increased the deposition of
therapeutic MNPs in brains with intact or compromised blood–brain
barriers. Synergistic targeting and image monitoring are powerful
techniques for the delivery of macromolecular chemotherapeutic
agents into the CNS under the guidance of MRI.
blood–brain barrier|brain drug delivery|focused ultrasound|magnetic
nanoparticles|magnetic targeting
W
ithin the CNS, the blood–brain barrier (BBB) excludes
larger (>400 Da) molecules from entering the brain pa-
renchyma, protecting it from toxic foreign substances (1). How-
ever, it also prohibits delivery of many potentially effective
diagnostic or therapeutic agents and restricts the enhanced per-
meability and retention (EPR) of therapeutic nanoparticles.
Many factors affect EPR, including the pH, polarity, and size of
the delivered substance. Even when pathologic processes com-
promise the integrity or function of the BBB, EPR can be limited
by microenvironmental characteristics such as hypovascularity,
fibrosis, or necrosis (2–4).
In the presence of microbubbles and with use of a low-energy
burst tone, focused ultrasound (FUS) can increase the perme-
ability of the BBB (5). This noninvasive procedure disrupts the
BBB locally rather than systemically, minimizing off-target
effects. Furthermore, the disruption is reversible within several
hours, providing a window of opportunity to achieve local delivery
of chemotherapeutic agents in brains with intact or compromised
BBBs. However, drug delivery in such cases is passive, relying on
the free diffusion of the agents across the barrier.
Advances in nanotechnology and molecular biology have allowed
development of novel nanomedical platforms (6–8). Such
approaches allow simultaneous diagnostic imaging and drug de-
livery monitoring in vivo in real time (9, 10). Magnetic nanoparticles
(MNPs) have intrinsic magnetic properties that enable their use as
contrast agents in MRI (8, 11). Because MNPs are also sensitive to
external magnetic forces, magnetic targeting (MT) actively enhan-
ces their deposition at the target site, increasing the therapeutic
dose delivered beyond that obtainable by passive diffusion (12).
This study combines FUS and MT of nanoparticles as a syn-
ergistic delivery system for chemotherapeutic agents concurrent
with MRI monitoring for treating CNS diseases. FUS creates the
opportunity to deliver therapeutic MNPs by passive local EPR,
and externally applied magnetic forces actively increase the local
MNP concentration. When combined, these techniques permit
the delivery of large molecules into the brain (Fig. 1). Further-
more, the deposition of the therapeutic MNPs can be monitored
and quantified in vivo by MRI.
Results
Characterization of Therapeutic MNPs.The saturated magnetiza-
tion, mean hydrodynamic size, and particle size of the com-
mercially available MNP Resovist and the newly synthesized
MNPs generated for this study are summarized inTable S1. As
measured by transmission EM (TEM), MNP-3 had a mean di-
ameter of 12.3 nm (Fig. 2A). This was significantly smaller than
the hydrodynamic sizes measured by dynamic light scattering (64
nm for Resovist, 74–83 nm for MNPs-1–3;Fig. S1AandTable
S1), although such differences could be attributable to solvent
effects. The measured zeta potentials of all of the synthesized
MNPs were similar to that of Resovist (approximately 45 mV).
Magnetization of MNPs is crucial for their utility in MT, and
crystallinity significantly affects this parameter. During synthesis,
the crystallinity of the MNPs was manipulated by controlling the
reaction conditions. MNP-3 exhibited the best crystallinity among
the MNPs tested (Fig. S1C) and also displayed the highest degree
of magnetization (Fig. S1B).
Administration of the MNPs into biological tissues profoundly
alters the spin–spin relaxation rate (R2), and thus can serve as an
indicator of the MRI contrast agent. The R2, and hence the de-
tection sensitivity, of MNP-3 was twice that of Resovist by MRI
(Fig. 2EandFandTable S1).
The polymer poly[aniline-co-N-(1-one-butyric acid)] aniline
(SPAnH) was used to encapsulate iron oxide (Fe
3O
4). This pro-
cess decreases the aggregation typical of MNPs and improves
their stability in aqueous solutions. Fourier transform IR (FT-IR)
spectroscopy indicated that the surface of the Fe3O4particles was
covered with a layer of the SPAnH polymer, and that the out-
Author contributions: H.-L.L., M.-Y.H., H.-W.Y., P.-Y.C., and K.-C.W. designed research;
H.-L.L., M.-Y.H., H.-W.Y., C.-Y.H., P.-C.C., J.-S.W., I.-C.T., J.-J.W., T.-C.Y., and P.-Y.C. per-
formed research; H.-L.L., M.-Y.H., and H.-W.Y. contributed new reagents/analytic tools;
H.-L.L., M.-Y.H., H.-W.Y., C.-Y.H., P.-C.C., J.-S.W., I.-C.T., J.-J.W., T.-C.Y., P.-Y.C., and K.-C.W.
analyzed data; and H.-L.L., M.-Y.H., H.-W.Y., and K.-C.W. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. R.W. is a guest editor invited by the Editorial
Board.
Freely available online through the PNAS open access option.
1
H.-L.L., M.-Y.H., and H.-W.Y. contributed equally to this work.
2
P.-Y.C. and K.-C.W. contributed equally to this work.
3
To whom correspondence may be addressed. E-mail: [email protected] or
[email protected].
This article contains supporting information online atwww.pnas.org/lookup/suppl/doi:10.
1073/pnas.1003388107/-/DCSupplemental.
www.pnas.org/cgi/doi/10.1073/pnas.1003388107 PNAS |August 24, 2010|vol. 107|no. 34|15205–15210
MEDICAL SCIENCES
Magnetic resonance monitoring of focused
ultrasound/magnetic nanoparticle targeting delivery
of therapeutic agents to the brain
Hao-Li Liu
a,b,1
, Mu-Yi Hua
c,1
, Hung-Wei Yang
c,1
, Chiung-Yin Huang
d
, Po-Chun Chu
a
, Jia-Shin Wu
a
, I-Chou Tseng
d
,
Jiun-Jie Wang
e
, Tzu-Chen Yen
b,f
, Pin-Yuan Chen
d,g,2,3
, and Kuo-Chen Wei
d,2,3
Departments of
a
Electrical Engineering,
c
Chemical and Material Engineering, and
e
Medical Image and Radiological Sciences and
g
Graduate Institute of Clinical
Medical Sciences, Chang-Gung University, Taoyuan 333, Taiwan;
b
Molecular Imaging Center and
f
Department of Nuclear Medicine, Chang-Gung Memorial
Hospital, Taoyuan 333, Taiwan; and
d
Department of Neurosurgery, Chang-Gung University College of Medicine and Memorial Hospital, Taoyuan 333, Taiwan
Edited by Ralph Weissleider, Harvard Medical School, Boston, MA, and accepted by the Editorial Board July 13, 2010 (received for review March 16, 2010)
The superparamagnetic properties of magnetic nanoparticles
(MNPs) allow them to be guided by an externally positioned magnet
and also provide contrast for MRI. However, their therapeutic use in
treating CNS pathologies in vivo is limited by insufficient local
accumulation and retention resulting from their inability to traverse
biological barriers. The combined use of focused ultrasound and
magnetic targeting synergistically delivers therapeutic MNPs across
the blood–brain barrier to enter the brain both passively and ac-
tively. Therapeutic MNPs were characterized and evaluated both
in vitro and in vivo, and MRI was used to monitor and quantify their
distribution in vivo. The technique could be used in normal brains or
in those with tumors, and significantly increased the deposition of
therapeutic MNPs in brains with intact or compromised blood–brain
barriers. Synergistic targeting and image monitoring are powerful
techniques for the delivery of macromolecular chemotherapeutic
agents into the CNS under the guidance of MRI.
blood–brain barrier|brain drug delivery|focused ultrasound|magnetic
nanoparticles|magnetic targeting
W
ithin the CNS, the blood–brain barrier (BBB) excludes
larger (>400 Da) molecules from entering the brain pa-
renchyma, protecting it from toxic foreign substances (1). How-
ever, it also prohibits delivery of many potentially effective
diagnostic or therapeutic agents and restricts the enhanced per-
meability and retention (EPR) of therapeutic nanoparticles.
Many factors affect EPR, including the pH, polarity, and size of
the delivered substance. Even when pathologic processes com-
promise the integrity or function of the BBB, EPR can be limited
by microenvironmental characteristics such as hypovascularity,
fibrosis, or necrosis (2–4).
In the presence of microbubbles and with use of a low-energy
burst tone, focused ultrasound (FUS) can increase the perme-
ability of the BBB (5). This noninvasive procedure disrupts the
BBB locally rather than systemically, minimizing off-target
effects. Furthermore, the disruption is reversible within several
hours, providing a window of opportunity to achieve local delivery
of chemotherapeutic agents in brains with intact or compromised
BBBs. However, drug delivery in such cases is passive, relying on
the free diffusion of the agents across the barrier.
Advances in nanotechnology and molecular biology have allowed
development of novel nanomedical platforms (6–8). Such
approaches allow simultaneous diagnostic imaging and drug de-
livery monitoring in vivo in real time (9, 10). Magnetic nanoparticles
(MNPs) have intrinsic magnetic properties that enable their use as
contrast agents in MRI (8, 11). Because MNPs are also sensitive to
external magnetic forces, magnetic targeting (MT) actively enhan-
ces their deposition at the target site, increasing the therapeutic
dose delivered beyond that obtainable by passive diffusion (12).
This study combines FUS and MT of nanoparticles as a syn-
ergistic delivery system for chemotherapeutic agents concurrent
with MRI monitoring for treating CNS diseases. FUS creates the
opportunity to deliver therapeutic MNPs by passive local EPR,
and externally applied magnetic forces actively increase the local
MNP concentration. When combined, these techniques permit
the delivery of large molecules into the brain (Fig. 1). Further-
more, the deposition of the therapeutic MNPs can be monitored
and quantified in vivo by MRI.
Results
Characterization of Therapeutic MNPs.The saturated magnetiza-
tion, mean hydrodynamic size, and particle size of the com-
mercially available MNP Resovist and the newly synthesized
MNPs generated for this study are summarized inTable S1. As
measured by transmission EM (TEM), MNP-3 had a mean di-
ameter of 12.3 nm (Fig. 2A). This was significantly smaller than
the hydrodynamic sizes measured by dynamic light scattering (64
nm for Resovist, 74–83 nm for MNPs-1–3;Fig. S1AandTable
S1), although such differences could be attributable to solvent
effects. The measured zeta potentials of all of the synthesized
MNPs were similar to that of Resovist (approximately 45 mV).
Magnetization of MNPs is crucial for their utility in MT, and
crystallinity significantly affects this parameter. During synthesis,
the crystallinity of the MNPs was manipulated by controlling the
reaction conditions. MNP-3 exhibited the best crystallinity among
the MNPs tested (Fig. S1C) and also displayed the highest degree
of magnetization (Fig. S1B).
Administration of the MNPs into biological tissues profoundly
alters the spin–spin relaxation rate (R2), and thus can serve as an
indicator of the MRI contrast agent. The R2, and hence the de-
tection sensitivity, of MNP-3 was twice that of Resovist by MRI
(Fig. 2EandFandTable S1).
The polymer poly[aniline-co-N-(1-one-butyric acid)] aniline
(SPAnH) was used to encapsulate iron oxide (Fe
3O
4). This pro-
cess decreases the aggregation typical of MNPs and improves
their stability in aqueous solutions. Fourier transform IR (FT-IR)
spectroscopy indicated that the surface of the Fe3O4particles was
covered with a layer of the SPAnH polymer, and that the out-
Author contributions: H.-L.L., M.-Y.H., H.-W.Y., P.-Y.C., and K.-C.W. designed research;
H.-L.L., M.-Y.H., H.-W.Y., C.-Y.H., P.-C.C., J.-S.W., I.-C.T., J.-J.W., T.-C.Y., and P.-Y.C. per-
formed research; H.-L.L., M.-Y.H., and H.-W.Y. contributed new reagents/analytic tools;
H.-L.L., M.-Y.H., H.-W.Y., C.-Y.H., P.-C.C., J.-S.W., I.-C.T., J.-J.W., T.-C.Y., P.-Y.C., and K.-C.W.
analyzed data; and H.-L.L., M.-Y.H., H.-W.Y., and K.-C.W. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. R.W. is a guest editor invited by the Editorial
Board.
Freely available online through the PNAS open access option.
1
H.-L.L., M.-Y.H., and H.-W.Y. contributed equally to this work.
2
P.-Y.C. and K.-C.W. contributed equally to this work.
3
To whom correspondence may be addressed. E-mail: [email protected] or
[email protected].
This article contains supporting information online atwww.pnas.org/lookup/suppl/doi:10.
1073/pnas.1003388107/-/DCSupplemental.
www.pnas.org/cgi/doi/10.1073/pnas.1003388107 PNAS |August 24, 2010|vol. 107|no. 34|15205–15210
MEDICAL SCIENCES
Magnetic resonance monitoring of focused
ultrasound/magnetic nanoparticle targeting delivery
of therapeutic agents to the brain
Hao-Li Liu
a,b,1
, Mu-Yi Hua
c,1
, Hung-Wei Yang
c,1
, Chiung-Yin Huang
d
, Po-Chun Chu
a
, Jia-Shin Wu
a
, I-Chou Tseng
d
,
Jiun-Jie Wang
e
, Tzu-Chen Yen
b,f
, Pin-Yuan Chen
d,g,2,3
, and Kuo-Chen Wei
d,2,3
Departments of
a
Electrical Engineering,
c
Chemical and Material Engineering, and
e
Medical Image and Radiological Sciences and
g
Graduate Institute of Clinical
Medical Sciences, Chang-Gung University, Taoyuan 333, Taiwan;
b
Molecular Imaging Center and
f
Department of Nuclear Medicine, Chang-Gung Memorial
Hospital, Taoyuan 333, Taiwan; and
d
Department of Neurosurgery, Chang-Gung University College of Medicine and Memorial Hospital, Taoyuan 333, Taiwan
Edited by Ralph Weissleider, Harvard Medical School, Boston, MA, and accepted by the Editorial Board July 13, 2010 (received for review March 16, 2010)
The superparamagnetic properties of magnetic nanoparticles
(MNPs) allow them to be guided by an externally positioned magnet
and also provide contrast for MRI. However, their therapeutic use in
treating CNS pathologies in vivo is limited by insufficient local
accumulation and retention resulting from their inability to traverse
biological barriers. The combined use of focused ultrasound and
magnetic targeting synergistically delivers therapeutic MNPs across
the blood–brain barrier to enter the brain both passively and ac-
tively. Therapeutic MNPs were characterized and evaluated both
in vitro and in vivo, and MRI was used to monitor and quantify their
distribution in vivo. The technique could be used in normal brains or
in those with tumors, and significantly increased the deposition of
therapeutic MNPs in brains with intact or compromised blood–brain
barriers. Synergistic targeting and image monitoring are powerful
techniques for the delivery of macromolecular chemotherapeutic
agents into the CNS under the guidance of MRI.
blood–brain barrier|brain drug delivery|focused ultrasound|magnetic
nanoparticles|magnetic targeting
W
ithin the CNS, the blood–brain barrier (BBB) excludes
larger (>400 Da) molecules from entering the brain pa-
renchyma, protecting it from toxic foreign substances (1). How-
ever, it also prohibits delivery of many potentially effective
diagnostic or therapeutic agents and restricts the enhanced per-
meability and retention (EPR) of therapeutic nanoparticles.
Many factors affect EPR, including the pH, polarity, and size of
the delivered substance. Even when pathologic processes com-
promise the integrity or function of the BBB, EPR can be limited
by microenvironmental characteristics such as hypovascularity,
fibrosis, or necrosis (2–4).
In the presence of microbubbles and with use of a low-energy
burst tone, focused ultrasound (FUS) can increase the perme-
ability of the BBB (5). This noninvasive procedure disrupts the
BBB locally rather than systemically, minimizing off-target
effects. Furthermore, the disruption is reversible within several
hours, providing a window of opportunity to achieve local delivery
of chemotherapeutic agents in brains with intact or compromised
BBBs. However, drug delivery in such cases is passive, relying on
the free diffusion of the agents across the barrier.
Advances in nanotechnology and molecular biology have allowed
development of novel nanomedical platforms (6–8). Such
approaches allow simultaneous diagnostic imaging and drug de-
livery monitoring in vivo in real time (9, 10). Magnetic nanoparticles
(MNPs) have intrinsic magnetic properties that enable their use as
contrast agents in MRI (8, 11). Because MNPs are also sensitive to
external magnetic forces, magnetic targeting (MT) actively enhan-
ces their deposition at the target site, increasing the therapeutic
dose delivered beyond that obtainable by passive diffusion (12).
This study combines FUS and MT of nanoparticles as a syn-
ergistic delivery system for chemotherapeutic agents concurrent
with MRI monitoring for treating CNS diseases. FUS creates the
opportunity to deliver therapeutic MNPs by passive local EPR,
and externally applied magnetic forces actively increase the local
MNP concentration. When combined, these techniques permit
the delivery of large molecules into the brain (Fig. 1). Further-
more, the deposition of the therapeutic MNPs can be monitored
and quantified in vivo by MRI.
Results
Characterization of Therapeutic MNPs.The saturated magnetiza-
tion, mean hydrodynamic size, and particle size of the com-
mercially available MNP Resovist and the newly synthesized
MNPs generated for this study are summarized inTable S1. As
measured by transmission EM (TEM), MNP-3 had a mean di-
ameter of 12.3 nm (Fig. 2A). This was significantly smaller than
the hydrodynamic sizes measured by dynamic light scattering (64
nm for Resovist, 74–83 nm for MNPs-1–3;Fig. S1AandTable
S1), although such differences could be attributable to solvent
effects. The measured zeta potentials of all of the synthesized
MNPs were similar to that of Resovist (approximately 45 mV).
Magnetization of MNPs is crucial for their utility in MT, and
crystallinity significantly affects this parameter. During synthesis,
the crystallinity of the MNPs was manipulated by controlling the
reaction conditions. MNP-3 exhibited the best crystallinity among
the MNPs tested (Fig. S1C) and also displayed the highest degree
of magnetization (Fig. S1B).
Administration of the MNPs into biological tissues profoundly
alters the spin–spin relaxation rate (R2), and thus can serve as an
indicator of the MRI contrast agent. The R2, and hence the de-
tection sensitivity, of MNP-3 was twice that of Resovist by MRI
(Fig. 2EandFandTable S1).
The polymer poly[aniline-co-N-(1-one-butyric acid)] aniline
(SPAnH) was used to encapsulate iron oxide (Fe
3O
4). This pro-
cess decreases the aggregation typical of MNPs and improves
their stability in aqueous solutions. Fourier transform IR (FT-IR)
spectroscopy indicated that the surface of the Fe3O4particles was
covered with a layer of the SPAnH polymer, and that the out-
Author contributions: H.-L.L., M.-Y.H., H.-W.Y., P.-Y.C., and K.-C.W. designed research;
H.-L.L., M.-Y.H., H.-W.Y., C.-Y.H., P.-C.C., J.-S.W., I.-C.T., J.-J.W., T.-C.Y., and P.-Y.C. per-
formed research; H.-L.L., M.-Y.H., and H.-W.Y. contributed new reagents/analytic tools;
H.-L.L., M.-Y.H., H.-W.Y., C.-Y.H., P.-C.C., J.-S.W., I.-C.T., J.-J.W., T.-C.Y., P.-Y.C., and K.-C.W.
analyzed data; and H.-L.L., M.-Y.H., H.-W.Y., and K.-C.W. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. R.W. is a guest editor invited by the Editorial
Board.
Freely available online through the PNAS open access option.
1
H.-L.L., M.-Y.H., and H.-W.Y. contributed equally to this work.
2
P.-Y.C. and K.-C.W. contributed equally to this work.
3
To whom correspondence may be addressed. E-mail: [email protected] or
[email protected].
This article contains supporting information online atwww.pnas.org/lookup/suppl/doi:10.
1073/pnas.1003388107/-/DCSupplemental.
www.pnas.org/cgi/doi/10.1073/pnas.1003388107 PNAS |August 24, 2010|vol. 107|no. 34|15205–15210
MEDICAL SCIENCES
Electromagnetic field (EMF) Pulse
Protein kinase C signalling
Translocation of tight junction's
Protein ZO-1
Tight Junction Opening
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addrModern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr

6. Transport system-mediated drug delivery
Nanocarriers for brain drug delivery
mdpi.com
•Nontoxic, biodegradable and biocompatible
•Particle size less than 100 nm
•Stable in blood (no aggregation and dissociation)
•Non-immunogenic
•BBB-targeted moiety
•Applicable to carry small molecules, proteins, peptides or nucleic acids
Nano carriers May be Liposomes, Micelles, Polymeric Gels, Amphiphilic Gels
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr

7. Transport vectors
Drugs
Molecular structure mimicking the endogenous nutrients
Prodrugs
BBB
Drugs
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addrModern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Dopamine
Levodopa
Dopaminelevodopa
Decarboxylase
CNS
Type 1 l-type
Amino-acid transporter
Levodopa contains the carboxyl and α-amino groups

8. Adsorptive-mediated transcytosis
journals.cambridge.org/
Cell-penetrating peptides (CPPs)
The application of CPPs is based on the premises that biologically
active cargo can be attached to CPPs and translocated into cells. The
link between the CPPs and cargo is most commonly a covalent bond
and seldom in non-covalent bond. A large variety of cargo mole-
cules/materials have been effectively delivered into cells via CPPs, in-
cluding small molecules, proteins, peptides, fragments of DNA,
liposomes and nanoparticles[204]. Some can enter brain capillary en-
dothelia cells or are even translocated into the brain tissues. Some ex-
amples are highlighted here.
Adenot and colleagues studied brain uptake of a number of free
and SynB3 vectorized chemotherapeutic agents using both in situ
brain perfusion and in vitro BBB/cell model[203]. They reported
that SynB3's conjugation with various poorly brain-penetrating
drugs enhanced their brain penetration by a factor of 30 for doxorubi-
cin, 7 for benzylpenicillin, 22 for paclitaxel, 18 for dalargin and 50 for
morphine-6-glucuronide with no effect on tight junction integrity.
Brain uptake of the enkaphalin analogue, dalargin, a hexapeptide,
was enhanced significantly when conjugated to SynB and injected in-
travenously in mice[208]. This study signalled the potential for deliv-
ery of peptides or drugs for treatment of brain cancer, through the
targeting of brain tissue after systemic delivery.
TAT is a HIV-1 trans-activating transcriptor with 101 amino acids.
The protein consists offive domains; probably the best-studied region
of TAT is located in domain 4, which contains a highly basic region
(with two lysines and six arginines in nine residues) involved in nuclear
and nucleolar localization[209]. While all CPPs listed inTable 3above
have been used mainly for small cargoes such as peptides and oligonu-
cleotides, Schwarze et al.[210]synthesized full-length fusion proteins
that contained a NH2-terminal 11-amino acid protein transduction do-
main (PTD) from the HIV TAT protein. Transduction of the proteins
evaluated was non-cell-specific, and was seen to occur even across
the BBB. Further proof of this mode of peptide delivery was attained
by Cao et al.[211]who fused the antiapoptotic protein Bcl-xL to TAT
and injected the construct intraperitoneally into mice that were affect-
ed by stroke. The Bcl-xL protein is expressed in adult neurons of the CNS
and is believed to have an important role in the prevention of neuronal
apoptosis that would normally occur during brain development, or re-
sults from varying stimuli leading to pathology, including cerebral
ischemia. Protein transduction with this entity occurred in a rapid,
concentration-dependent fashion, with entry into cells thought to
occur via the lipid bilayer component of the cellular membrane. A
study by Kilic et al.[212]using the same model showed that brain tissue
was progressively transduced with TAT proteins within 3–4 h after in-
travenous delivery. TAT-Bcl-xL treatment reduced infarct volume and
neurological deficits after long ischemic insults lasting 90 min, when
applied both before and after ischemia.
Studies have also shown that even relatively large particles could be
delivered into various cells by TAT vector. A biocompatible 45 nm
nanoparticle with an iron core, a dextran coating, and covalently linked
TAT peptides was efficiently taken up by human hematopoietic CD34
+
cells[213]. Even cytoplasmatic uptake of liposomes with a diameter of
200 nm has been documented[214].
Taking the TAT-mediated nanoparticles delivery approach a step
further, one of the most exciting demonstrations of the effectiveness
of TAT-shuttled nanocarriers across the BBB was accomplished by
TAT-conjugated CdS:Mn/ZnS quantum dots (Qdots)[215]. Histologi-
cal data clearly showed that TAT-Qdots migrated beyond endothelial
cells and reached the brain parenchyma. TAT-mediated intracellular
delivery of large molecules and nanoparticles was proved to proceed
via the energy-dependent macropinocytosis with subsequent en-
hanced escape from endosome into the cell cytoplasm[207]. Recent-
ly, Liu et al. produced compelling evidence that TAT facilitates human
brain endothelia cell uptake of nanoparticles self-assembled from
TAT-PEG-b-cholesterol in vitro and more importantly, the nanoparti-
cles with TAT were able to cross the BBB and translocate around the
cell nucleus of neurons[216]. This study demonstrates the effective-
ness of TAT in promoting the transport of nanoparticles across the
BBB. It confirms that nanocarriers conjugated with TAT could be a
promising carrier system for transporting drug across the BBB for
the treatment of brain disorders.
In a more recent study by Wang et al., cationic nanoparticles fabri-
cated from cholesterol-CG3R6TAT via self-assembly showed strong anti-
microbial activity[217]. Biodistribution studies of FITC-loaded
nanoparticles in rabbits and efficacy studies in aC. neoformansmeningi-
tis rabbit model revealed that these nanoparticles crossed the BBB and
produced antimicrobial activity against the pathological strains in the
brain tissue with a similar efficacy as amphotericin B, suggesting a ther-
apeutic dose was delivered by TAT containing nanoparticles. Further-
more, these nanoparticles avoided causing the side-effects associated
with amphotericin. This study holds importance for TAT-containing
nanoparticles as it has proven that it is possible to deliver a therapeutic
dose, together with functional agents, via TAT-nanoparticles into the
brain for treatment of brain infections and tracking of nanoparticles in
vivo, a step closer to the development of a clinically applicable nanocar-
riers for treatment as well as monitoring meningitis and other brain-
related disorders.
Recent evidence showed that TAT can also enhance the delivery of
liposomes into the brain. Qin et al. prepared liposomes using
cholesterol-PEG2000-TAT (TAT-LIP) and compared them to liposomes
fabricated from cholesterol-PEG2000polymer (LLIP) and conventional
cholesterol formulation (LIP) in vitro and in vivo[218]. TAT-LIP accu-
mulated most in the brain (including various regions of the brain)
within 24 hr after administration via tail vein, although all were not
selectively targeted to the brain. All liposomes showed a uniform dis-
tribution across the brain. The study also suggested adsorptive trans-
cytosis could be one of the mechanisms for TAT-LIP transport across
the BBB and the positive charge of the TAT-LIP played an important
role in enhancing this transport[218].
In addition to CPPs, cationic protein can also enter the brain via an
adsorptive-mediated mechanism and Poduslo and Curran demon-
strated that polyamine modification of proteins (insulin, albumin
and IgG) can dramatically increase the permeability of proteins at
the BBB with 1.7–2.0 fold increase for insulin, 54–165 folds for albu-
min and 111–349 fold for IgG in normal adult rats[219]. It is, howev-
er, unknown, if this chemical modification may lead to toxicity or
immunogenicity problems. In a study reported by Lu et al., cationic
bovine serum albumin (CBSA) conjugated PEG-PLA nanoparticles
(CBSA-NP) was compared to native PLA bovine serum albumin conju-
gated nanoparticles (BSA-NP) and CBSA unconjugated PEGylated
nanoparticles (NP) in brain transcytosis across the BBB coculture
and brain delivery in mice using afluorescent probe[220]. This
study confirmed that AMT is the mechanism of brain delivery of
CBSA-NP. Increasing the surface density of CBSA conjugated per
nanoparticle promoted the transcytosis ability of nanoparticles
Table 3
Principle features of the selected cell penetrating peptides (CPPs).
Peptide name Sequence Net
charge
Cell lytic
activity
MAP KLALKLALKALKAALKLA + 5 Yes
pAntp
43–68 RQIKIWFQNRRMKWKK + 8 No
Transportan GWTLNSAGYLLGKINLKALAALAKKIL + 4 Yes
SBP MGLGLHLLVLAAALQGAWSQPKKKRKV + 6 –
FBP GALFLGWLGAAGSTMGAWSQPKKKRKV + 6 –
TAT48–60 GRKKRRQRRRPPQ + 8 No
SynB1 RGGRLSYSRRRFSTSTGR + 6 No
SynB3 RRLSYSRRRF + 6 No
MAP: model amphipathic peptide; Antp: Antennapedia; SBP: sequence signal-based
peptide; FBP, fusion sequence-based peptide; TAT, HIV-1 trans-activating transcriptor.
The peptide residues in this table are expressed with one-letter-code: K—lysine; L—
leucine; A—alanine; R—arginines; Q—glutamine; I—isoleucine; W—tryptophan; F—
phenylalanine; N—asparagine; M—methionine; G—glycines; S—serine; T—threonine. Data
was collected from references[204,206,221,222,312–314].
654 Y. Chen, L. Liu / Advanced Drug Delivery Reviews 64 (2012) 640–665
The major dogma has
been that CPPs enter cells
by a receptor and energy-
independent process but
the exact mechanisms are
not yet fully understood
SynB1, SynB1
TAT derived CPPs Lipid raft-mediated macropinocytosis
Endosomal transport
All are having Net Positive Charge but Internalization differed in each case.

9. Endogenous receptor-mediated transcytosis
Receptor-ligand binding
Endocytosis at the luminal (blood) side
Movement through the endothelia cytoplasm
Exocytosis of the drug or ligand-attached
drug or cargo at the abluminal (brain) side
mdpi.com
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addrModern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr

10. 1810Wu et al.
(21). Therefore, the presence of any unconjugated 83-14 mAb
in the formulation comprised of the 8314-SA complex would
compete with binding of 8314-SA conjugate to BBB insulin re-
ceptor, and this would inhibit brain uptake of the conjugated
peptide radiopharmaceutical. In parallel to the production of
8314-SA conjugate, bio-Ab
1–40
must be iodinated and purified.
Ab
1–40
is a relatively hydrophobic peptide, and subsequent
biotinylation and iodination further increases the hydropho-
bicity of this molecule, which makes it difficult to release
125
I-
bio-Ab
1–40
from reverse phase surfaces (our unpublished ob-
servations). However, this problem is obviated and the percent
recovery of
125
I-bio-Ab
1–40
after iodination is high using HILC
(Fig. 2). Similar results were demonstrated previously after
monobiotinylation and iodination of a vasoactive intestinal
peptide analog (30).
The multifunctionality of the amyloid imaging agent is re-
tained after attachment of
125
I-bio-Ab
1–40
to the 8314-SA con-
jugate. The three domains are depicted in Fig. 11, and include
the amyloid-binding domain, a linker domain, and a BBB
transport domain. The mAb and avidin domains are joined by
a thiol-ether linkage (-S- in Fig. 11), a much more stable bond
than the disulfide (-S-S-) linkage used in previous formulations
(30). In this case (Fig. 11), the peptide is attached to the target-
ing vector by a noncleavable bond that confers metabolic sta-
bility and is used because Ab
1–40
still binds to the target amy-
loid despite attachment to the delivery system (Fig. 6). High
affinity binding of
125
I-bio-Ab
1–40
/8314-SA to the BBB insulin
receptor is demonstrated both in vitro with isolated brain cap-
illaries (Figs. 4 and 5) and in vivo in rhesus monkeys (Fig. 8).
The avid binding in vivo is consistent with previous studies
showing that endogenous insulin exerts minimal inhibition of
83-14 mAb binding to the BBB insulin receptor (21). The bi-
otin-binding property of the 8314-SA conjugate is contained
within the linker domain (Fig. 11), and is demonstrated with
HPLC experiments in Fig. 3 and radioreceptor assays in Figs. 4
and 5. The amyloid-binding domain is comprised of radiola-
beled Ab
1–40
, and the retention of the amyloid-binding proper-
ties of the peptide pharmaceutical after conjugation to the
BBB delivery system is demonstrated with the emulsion auto-
radiography experiments using Alzheimer’s disease tissue sec-
tions (Fig. 6). These results are similar to previously reported
emulsion and film autoradiography experiments demonstrat-
ing binding of
125
I-bio-Ab
1–40
to amyloid plaques of sections of
Alzheimer’s disease brain after conjugation of the peptide phar-
maceutical to a conjugate of SA and the OX26 mAb (16),
which is a murine mAb to the rat transferrin receptor (31). In
these previous experiments, the biotin linkage was attached to
the e-amino group of an internal lysine residue (16). In con-
trast, these experiments use an Ab
1–40
analog in which the bi-
otin moiety is attached to the amino terminus. Previous inves-
tigations have demonstrated that attachment of biotin to the
amino terminus of Ab
1–40
does not impair deposition of this
peptide onto preexisting Ab amyloid plaques (32).
Pharmacokinetic studies demonstrate that
125
I-bio-Ab
1–40
is
removed rapidly from the bloodstream and is subjected to
rapid metabolic degradation, as indicated by the decrease in
plasma TCA precipitability (Fig. 6). Although
125
I-Ab
1–40
is
. 90% bound by human albumin (33), this binding is rela-
tively weak in vivo and does not inhibit the rapid clearance
of
125
I-bio-Ab
1–40
in vivo (Fig. 7). The TCA-soluble Iodine-125
radioactivity in plasma at 1–3 h after i.v. injection of the peptide
may arise from proteolysis of the peptide with release of iodo-
tyrosine. An alternative pathway is surface deiodination of the
intact peptide, possibly by ectoenzymes on the endothelial sur-
face of organ capillary beds. Evidence for this pathway is the
observation that the systemic clearance (C1, Table I) for the
125
I-bio-Ab
1–40
/OX26-SA conjugate, 2.6 ml/min/kg, is approxi-
mately fourfold greater than the systemic clearance of the un-
conjugated
125
I-83-14 mAb in rhesus monkeys, 0.39–1.00 ml/
min/kg (21). The rapid conversion of plasma radioactivity into
TCA-soluble metabolites shown in Fig. 7 indicates that radio-
iodination may not be the optimal formulation for peptide ra-
diopharmaceuticals used in the future, and that alternative ra-
diolabeling procedures might be considered. For example,
chelating agents may be attached to e-amino groups of internal
lysines of the Ab
1–40
peptide, which would allow for radiolabel-
ing with Indium-111 or Technetium-99m (34).
Despite the relatively rapid rate of plasma clearance of
conjugated bio-Ab
1–40
from plasma (Fig. 7) and the relative re-
duction in plasma AUC (Table I), there is still robust brain up-
take of peptide radiopharmaceutical after attachment to 8314-SA
conjugate (Figs. 8 and 9). There is a twofold greater enrich-
ment in brain uptake of bio-Ab
1–40
conjugated to 8314-SA vec-
tor in gray matter versus white matter (Figs. 8 and 9), consis-
tent with previous observations showing a greater abundance
of insulin receptor in gray matter versus white matter (21).
This greater abundance of receptor is due to the approxi-
mately three- to fourfold greater vascular density in gray mat-
ter versus white matter, as demonstrated in previous morpho-
metric studies in rhesus monkey brain (21).
There is no measurable brain uptake of unconjugated bio-
Ab
1–40
by the brain (Figs. 8 and 9), consistent with previous
studies in rats indicating lack of significant transport of Ab
1–40
through the BBB in vivo (16). Earlier experiments reported a
brain V
D of unconjugated Ab
1–40
after internal carotid artery
perfusion that exceeded the brain plasma volume measured
with labeled sucrose (16, 35). However, these results are con-
sistent with nonspecific absorption of Ab
1–40
to the brain vas-
culature (16). The nonspecific absorption of
125
I-bio-Ab
1–40
is
further demonstrated with isolated brain capillaries in vitro, as
shown by the experiments in Fig. 5, where the brain capillary
Figure 11.Scheme depicting the multifunctionality and three do-
mains of the peptide radiopharmaceutical conjugated to the BBB de-
livery system. The imaging agent is comprised of amyloid-binding do-
main, a linker domain, and a BBB transport domain, the last
constituted by the mAb to the HIR. The HIR is localized in human
brain capillary endothelium (reference 21), which forms the BBB in
vivo.

1804

Wu et al.

J. Clin. Invest.
© The American Society for Clinical Investigation, Inc.
0021-9738/97/10/1804/09 $2.00
Volume 100, Number 7, October 1997, 1804–1812
http://www.jci.org

Drug Targeting of a Peptide Radiopharmaceutical through the Primate Blood–Brain
Barrier In Vivo with a Monoclonal Antibody to the Human Insulin Receptor

Dafang Wu, Jing Yang, and William M. Pardridge

Department of Medicine, UCLA School of Medicine, Los Angeles, California 90095-1682

Abstract

Peptide radiopharmaceuticals are potential imaging agents
for brain disorders, should these agents be enabled to un-
dergo transport through the blood–brain barrier (BBB) in

vivo. Radiolabeled A

b

1–40

images brain amyloid in tissue
sections of Alzheimer’s disease autopsy brain, but this pep-
tide radiopharmaceutical cannot be used to image brain
amyloid in vivo owing to negligible transport through the
BBB. In these studies,

125

I-A

b

1–40

was monobiotinylated
(bio) and conjugated to a BBB drug delivery and brain tar-
geting system comprised of a complex of the 83-14 mono-
clonal antibody (mAb) to the human insulin receptor, which
is tagged with streptavidin (SA). A marked increase in
rhesus monkey brain uptake of the

125

I-bio-A

b

1–40

was ob-
served after conjugation to the 8314-SA delivery system at
3 h after intravenous injection. In contrast, no measurable
brain uptake of

125

I-bio-A

b

1–40

was observed in the absence
of a BBB drug delivery system. The peptide radiopharma-
ceutical was degraded in brain with export of the iodide ra-
dioactivity, and by 48 h after intravenous injection, 90% of
the radioactivity was cleared from the brain. In conclusion,
these studies describe a methodology for BBB drug delivery
and brain targeting of peptide radiopharmaceuticals that
could be used for imaging amyloid or other brain disorders.

(

J. Clin. Invest.

1997. 100:1804–1812.) Key words: Alzhei-

mer’s disease

•

amyloid

•

monoclonal antibody

•

insulin re-
ceptor

•

avidin

Introduction

Peptide radiopharmaceuticals have potential for diagnostic im-
aging (1). The somatostatin receptor is overexpressed in cer-
tain neuroendocrine tumors, as well as brain tumors such as

meningiomas or gliomas, and

125

I- or

111

In-labeled octreotide, a
somatostatin peptide analog, has been used to image these tu-
mors (2, 3). Owing to the small size of the peptide radiophar-
maceutical, octreotide readily crosses the porous capillaries
perfusing tumors in the periphery, or certain brain tumors such
as meningiomas, which lack a blood–brain barrier (BBB).

1

However, well-differentiated gliomas, which also overexpress
somatostatin receptors, have an intact BBB; it is not possible
to image these tumors with octreotide (3, 4), since this peptide
does not cross the BBB in vivo (5).
In addition to tumors, it should also be possible to image
other medical disorders with peptide radiopharmaceuticals,
such as amyloid. The deposition of amyloid in brain of Alz-
heimer’s disease correlates with the degree of dementia in this
disorder (6, 7). Extracellular amyloid in Alzheimer’s disease is
comprised of two types: senile (neuritic) plaque and vascular
amyloid (8–12). Both types of amyloid in Alzheimer’s disease
are comprised of a 43–amino acid amyloidotic peptide, desig-

nated A

b

1–43

. There are as well A

b

1–42

forms, produced from
the abnormal proteolysis of a normal cellular protein, the amy-
loid peptide precursor (13).
The A

b

amyloid of tissue sections of Alzheimer’s disease
autopsy brain can be identified with dyes such as Congo Red,
or with antibodies directed against certain epitopes of the
A

b

1–42/43

peptide (14). However, the A

b

amyloid of brain sec-
tions may also be identified in vitro by autoradiography with

125

I-A

b

1–40

, a peptide containing the first 40 amino acids of the
A

b

1–42/43

peptide that deposits with high affinity onto preexist-
ing A

b

amyloid (15). Therefore, radiolabeled A

b

1–40

is a po-
tential peptide radiopharmaceutical that could be used for
neurodiagnostic quantitation of the A

b

amyloid burden in
Alzheimer’s disease brain of living subjects using standard ex-
ternal detection methodologies, such as single photon emission
computed tomography or positron emission tomography.
However,

125

I-A

b

1–40

does not cross the BBB in rats unless a
vector-mediated BBB drug delivery system is used (16). A

b

amyloid does not deposit in the brain of aged rats, but does
form in the brain of New World primates, such as the aged
(15–20 yr) squirrel monkey, as vascular amyloid, and is pro-
duced in the brain of Old World primates, such as the aged
(27–30 yr) rhesus monkey, in neuritic plaque form (17–20).
These studies use

125

I-A

b

1–40

adapted to a BBB drug deliv-
ery system that enables the peptide to enter the brain from
blood to a high degree, allowing for imaging of the distribution
of the peptide radiopharmaceutical in the brain after systemic
(intravenous, i.v.) injection. The goal of these studies is four-
fold: first, to prepare radiolabeled peptide pharmaceutical con-
jugated to the BBB delivery system; second, to demonstrate
that the deposition of

125

I-A

b

1–40

on amyloid plaques in sec-

Address correspondence to William M. Pardridge, M.D., Department
of Medicine, UCLA School of Medicine, Los Angeles, CA 90095-
1682. Phone: [phone]; FAX: [phone]; E-mail: wpardrid@
med1.medsch.ucla.edu

Received for publication 30 April 1997 and accepted in revised
form 7 August 1997.

1.

Abbreviations used in this paper:

A

b

1–40

, first 40 amino acids of

b

-peptide of Alzheimer’s disease; AUC, area under the plasma con-
centration curve; BBB, blood–brain barrier; bio, biotinylated; HILC,
hydrophilic interaction liquid chromatography; HIR, human insulin
receptor; OX26, murine mAb to rat transferrin receptor; PS, perme-
ability–surface area product; RHB, Ringer-Hepes buffer; SA, strept-
avidin; TEAP, triethylamine phosphate; V

D

, volume of distribution.

11/17/2015Drug targeting of a peptide radiopharmaceutical through the primate blood-brain barrier in vivo with a monoclonal antibody to the human insulin receptor.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC508366/ 1/4
J Clin Invest. 1997 Oct 1; 100(7): 1804–1812.
doi:  10.1172/JCI119708
PMCID: PMC508366
Drug targeting of a peptide radiopharmaceutical through the primate blood­brain
barrier in vivo with a monoclonal antibody to the human insulin receptor.
D Wu, J Yang, and W M Pardridge
Department of Medicine, UCLA School of Medicine, Los Angeles, California 90095­1682, USA.
Copyright notice
This article has been cited by other articles in PMC.
Abstract
Peptide radiopharmaceuticals are potential imaging agents for brain disorders, should these agents be enabled to
undergo transport through the blood­brain barrier (BBB) in vivo. Radiolabeled Abeta1­40 images brain amyloid
in tissue sections of Alzheimer's disease autopsy brain, but this peptide radiopharmaceutical cannot be used to
image brain amyloid in vivo owing to negligible transport through the BBB. In these studies, 125I­Abeta1­40
was monobiotinylated (bio) and conjugated to a BBB drug delivery and brain targeting system comprised of a
complex of the 83­14 monoclonal antibody (mAb) to the human insulin receptor, which is tagged with
streptavidin (SA). A marked increase in rhesus monkey brain uptake of the 125I­bio­Abeta1­40 was observed
after conjugation to the 8314­SA delivery system at 3 h after intravenous injection. In contrast, no measurable
brain uptake of 125I­bio­Abeta1­40 was observed in the absence of a BBB drug delivery system. The peptide
radiopharmaceutical was degraded in brain with export of the iodide radioactivity, and by 48 h after intravenous
injection, 90% of the radioactivity was cleared from the brain. In conclusion, these studies describe a
methodology for BBB drug delivery and brain targeting of peptide radiopharmaceuticals that could be used for
imaging amyloid or other brain disorders.
Full Text
The Full Text of this article is available as a PDF (354K).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
Fischman AJ, Babich JW, Strauss HW. A ticket to ride: peptide radiopharmaceuticals. J Nucl Med. 1993
Dec;34(12):2253–2263. [PubMed]
Krenning EP, Kwekkeboom DJ, Reubi JC, Van Hagen PM, van Eijck CH, Oei HY, Lamberts SW. 111In­
octreotide scintigraphy in oncology. Metabolism. 1992 Sep;41(9 Suppl 2):83–86. [PubMed]
Reubi JC, Kvols L, Krenning E, Lamberts SW. Distribution of somatostatin receptors in normal and tumor
tissue. Metabolism. 1990 Sep;39(9 Suppl 2):78–81. [PubMed]
Haldemann AR, Rösler H, Barth A, Waser B, Geiger L, Godoy N, Markwalder RV, Seiler RW, Sulzer M,
Reubi JC. Somatostatin receptor scintigraphy in central nervous system tumors: role of blood­brain barrier
permeability. J Nucl Med. 1995 Mar;36(3):403–410. [PubMed]
Pardridge WM, Triguero D, Yang J, Cancilla PA. Comparison of in vitro and in vivo models of drug
transcytosis through the blood­brain barrier. J Pharmacol Exp Ther. 1990 May;253(2):884–891. [PubMed]
Tomlinson BE, Blessed G, Roth M. Observations on the brains of demented old people. J Neurol Sci. 1970
Sep;11(3):205–242. [PubMed]
Cummings BJ, Cotman CW. Image analysis of beta­amyloid load in Alzheimer's disease and relation to
dementia severity. Lancet. 1995 Dec 9;346(8989):1524–1528. [PubMed]
Insulin receptor
Amyloid-β- peptide
125
I-Abeta1–40
conjugated to 83–14 monoclonal antibody (mAb)
Insulin receptor
Diagnostic probe for AD Receptor mediated Endocytosis
11/17/2015Drug targeting of a peptide radiopharmaceutical through the primate blood-brain barrier in vivo with a monoclonal antibody to the human insulin receptor.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC508366/ 1/4
J Clin Invest. 1997 Oct 1; 100(7): 1804–1812.
doi:  10.1172/JCI119708
PMCID: PMC508366
Drug targeting of a peptide radiopharmaceutical through the primate blood­brain
barrier in vivo with a monoclonal antibody to the human insulin receptor.
D Wu, J Yang, and W M Pardridge
Department of Medicine, UCLA School of Medicine, Los Angeles, California 90095­1682, USA.
Copyright notice
This article has been cited by other articles in PMC.
Abstract
Peptide radiopharmaceuticals are potential imaging agents for brain disorders, should these agents be enabled to
undergo transport through the blood­brain barrier (BBB) in vivo. Radiolabeled Abeta1­40 images brain amyloid
in tissue sections of Alzheimer's disease autopsy brain, but this peptide radiopharmaceutical cannot be used to
image brain amyloid in vivo owing to negligible transport through the BBB. In these studies, 125I­Abeta1­40
was monobiotinylated (bio) and conjugated to a BBB drug delivery and brain targeting system comprised of a
complex of the 83­14 monoclonal antibody (mAb) to the human insulin receptor, which is tagged with
streptavidin (SA). A marked increase in rhesus monkey brain uptake of the 125I­bio­Abeta1­40 was observed
after conjugation to the 8314­SA delivery system at 3 h after intravenous injection. In contrast, no measurable
brain uptake of 125I­bio­Abeta1­40 was observed in the absence of a BBB drug delivery system. The peptide
radiopharmaceutical was degraded in brain with export of the iodide radioactivity, and by 48 h after intravenous
injection, 90% of the radioactivity was cleared from the brain. In conclusion, these studies describe a
methodology for BBB drug delivery and brain targeting of peptide radiopharmaceuticals that could be used for
imaging amyloid or other brain disorders.
Full Text
The Full Text of this article is available as a PDF (354K).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
Fischman AJ, Babich JW, Strauss HW. A ticket to ride: peptide radiopharmaceuticals. J Nucl Med. 1993
Dec;34(12):2253–2263. [PubMed]
Krenning EP, Kwekkeboom DJ, Reubi JC, Van Hagen PM, van Eijck CH, Oei HY, Lamberts SW. 111In­
octreotide scintigraphy in oncology. Metabolism. 1992 Sep;41(9 Suppl 2):83–86. [PubMed]
Reubi JC, Kvols L, Krenning E, Lamberts SW. Distribution of somatostatin receptors in normal and tumor
tissue. Metabolism. 1990 Sep;39(9 Suppl 2):78–81. [PubMed]
Haldemann AR, Rösler H, Barth A, Waser B, Geiger L, Godoy N, Markwalder RV, Seiler RW, Sulzer M,
Reubi JC. Somatostatin receptor scintigraphy in central nervous system tumors: role of blood­brain barrier
permeability. J Nucl Med. 1995 Mar;36(3):403–410. [PubMed]
Pardridge WM, Triguero D, Yang J, Cancilla PA. Comparison of in vitro and in vivo models of drug
transcytosis through the blood­brain barrier. J Pharmacol Exp Ther. 1990 May;253(2):884–891. [PubMed]
Tomlinson BE, Blessed G, Roth M. Observations on the brains of demented old people. J Neurol Sci. 1970
Sep;11(3):205–242. [PubMed]
Cummings BJ, Cotman CW. Image analysis of beta­amyloid load in Alzheimer's disease and relation to
dementia severity. Lancet. 1995 Dec 9;346(8989):1524–1528. [PubMed]
Low-density lipoprotein receptor related proteins 1 and 2 (LRP1 and LRP2 receptors)
ApoE (Apolipoprotein E)
Tissue plasminogen activator (tPA)
Plasminogen activator inhibitor 1(PAI-1)
Amyloid precursor protein (APP)
Lactoferrin
Melanotransferrin
α2 macroglobulin (α2 M)
Receptor associated protein (RAP)
HIV-1 TAT protein
Heparin cofactor II
Heat shock protein 96 (HSP-96)
Engineered angiopeps
Binds to
Specific LRP1 and LRP2 receptors in BBB Receptor-mediated transcytosis

11. Diphtheria toxin receptor (DTR)
Transferrin receptor
Expert Review
Blood–Brain Barrier Transport of Therapeutics via Receptor-Mediation
Angela R. Jones
1
and Eric V. Shusta
1,2
Received March 29, 2007; accepted May 3, 2007; published online July 10, 2007
Abstract.Drug delivery to the brain is hindered by the presence of the blood–brain barrier (BBB).
Although the BBB restricts the passage of many substances, it is actually selectively permeable to
nutrients necessary for healthy brain function. To accomplish the task of nutrient transport, the brain
endothelium is endowed with a diverse collection of molecular transport systems. One such class of
transport system, known as a receptor-mediated transcytosis (RMT), employs the vesicular trafficking
machinery of the endothelium to transport substrates between blood and brain. If appropriately
targeted, RMT systems can also be used to shuttle a wide range of therapeutics into the brain in a
noninvasive manner. Over the last decade, there have been significant developments in the arena of
RMT-based brain drug transport, and this review will focus on those approaches that have been
validated in anin vivosetting.
KEY WORDS: antibody; blood–brain barrier; brain drug delivery; transcytosis.
INTRODUCTION
The blood–brain barrier (BBB) provides the brain with
nutrients, prevents the introduction of harmful blood-borne
substances, and restricts the movement of ions and fluid to
ensure an optimal environment for brain function. As a
consequence of its barrier properties, the BBB also prevents
the movement of drugs from the blood into the brain, and
therefore acts as an obstacle for the systemic delivery of
neurotherapeutics. Unless a therapeutic molecule is lipid-
soluble with a molecular weight of 400–600 Da or less, brain
penetration is limited (1). Furthermore, efflux transport
systems may target the drugs that meet these criteria and
export them from the brain. As a result, the BBB excludes
many small-molecule pharmaceuticals, and nearly all bio-
pharmaceuticals such as gene and protein medicines fail to
penetrate into the brain tissue to an appreciable extent (1).
Thus, although the surface area of the human brain
microvasculature available for drug transport (õ20 m
2
) is
more than adequate for treating the entire brain volume, the
barrier properties of the BBB continue to restrict brain drug
delivery via the bloodstream (2).
To date, strategies for the delivery of drugs that do not
have an appreciable BBB permeability have included both
invasive and noninvasive approaches. Direct intracranial
injection, intraventricular administration and BBB disruption
are examples of invasive delivery techniques that have been
reviewed elsewhere (3). Instead, this review will focus on a
rapidly developing class of novel delivery reagents that
function in mediating noninvasive blood-to-brain transport
by taking advantage of endogenous nutrient transport
systems present at the BBB. Nutrients and water-soluble
compounds such as ions, amino acids, vitamins, and proteins
that are necessary for brain function possess specific trans-
port systems embedded in the plasma membranes of the
BBB to allow brain entry. Three main classes of transport
systems function at the BBB. The first, carrier-mediated
transport, relies on molecular carriers present at both the
apical (blood) and basolateral (brain) membranes of the
BBB (Fig.1c). These carriers tend to be highly stereospecific
and function in the selective transport of small molecules
1759 0724-8741/07/0900-1759/0#2007 Springer Science + Business Media, LLC
Pharmaceutical Research, Vol. 24, No. 9, September 2007 (#2007)
DOI: 10.1007/s11095-007-9379-0
1
Department of Chemical and Biological Engineering, University of
Wisconsin-Madison, 1415 Engineering Drive, Madison, Wisconsin
53706, USA.
2
To whom correspondence should be addressed.(e-mail:shusta@
engr.wisc.edu)
ABBREVIATIONS: ADR, adriamycin; AEM, analytical electron
microscopy; AUC, area under the curve; Av, avidin; AZT,
azidothymidine; BBB, blood–brain barrier; BDNF, brain-derived
neurotrophic factor; bFGF, basic fibroblast growth factor; DSPE,
distearoylphosphatidylethanolamine; EGFR, human epidermal
growth factor receptor; FGF-2, fibroblast growth factor-2; GFAP,
glial fibrillary acidic protein; GUS,b-glucuronidase; HB-EGF,
heparin binding epidermal growth factor-like growth factor; HCEC,
human cerebromicrovascular endothelial cells; HD, Huntington_s
disease; HIR, human insulin receptor; HRP, horseradish peroxidase;
IGF-II, insulin-like growth factor II; LDL, low density lipoprotein;
LRP1/2, low density lipoprotein receptor-related protein 1/2; M6P,
mannose 6-phosphate; MAb, monoclonal antibody; MCAO, middle
cerebral artery occlusion; NGF, nerve growth factor; NHS,
N-hydroxysuccinimide; ODN, oligonucleotides; PBCA, poly(butyl
cyanoacrylate); PEG, poly(ethylene glycol); P-GUS, phosphorylated
b-glucuronidase; PNA, peptide nucleic acid; RAP, receptor-
associated protein; RES, reticuloendothelial system; RMT, receptor-
mediated transcytosis; rsCD4, recombinant human soluble CD4; SA/B,
streptavidin/ biotin; SATA,N-succinimidylS-acetylthioacetate; scFv,
single-chain variable fragment; sdAb, single-domain antibodies;
SMCC, Succinimidyl 4-[N-maleimidomethyl]-cyclohexane-1-
carboxylate; SV40, simian virus 40; Tf, transferrin; TfR, transferrin
receptor; TH, tyrosine hydroxylase; tPA, tissue-type plasminogen
activator; VIP, vasoactive intestinal peptide.
Expert Review
Blood–Brain Barrier Transport of Therapeutics via Receptor-Mediation
Angela R. Jones
1
and Eric V. Shusta
1,2
Received March 29, 2007; accepted May 3, 2007; published online July 10, 2007
Abstract.Drug delivery to the brain is hindered by the presence of the blood–brain barrier (BBB).
Although the BBB restricts the passage of many substances, it is actually selectively permeable to
nutrients necessary for healthy brain function. To accomplish the task of nutrient transport, the brain
endothelium is endowed with a diverse collection of molecular transport systems. One such class of
transport system, known as a receptor-mediated transcytosis (RMT), employs the vesicular trafficking
machinery of the endothelium to transport substrates between blood and brain. If appropriately
targeted, RMT systems can also be used to shuttle a wide range of therapeutics into the brain in a
noninvasive manner. Over the last decade, there have been significant developments in the arena of
RMT-based brain drug transport, and this review will focus on those approaches that have been
validated in anin vivosetting.
KEY WORDS: antibody; blood–brain barrier; brain drug delivery; transcytosis.
INTRODUCTION
The blood–brain barrier (BBB) provides the brain with
nutrients, prevents the introduction of harmful blood-borne
substances, and restricts the movement of ions and fluid to
ensure an optimal environment for brain function. As a
consequence of its barrier properties, the BBB also prevents
the movement of drugs from the blood into the brain, and
therefore acts as an obstacle for the systemic delivery of
neurotherapeutics. Unless a therapeutic molecule is lipid-
soluble with a molecular weight of 400–600 Da or less, brain
penetration is limited (1). Furthermore, efflux transport
systems may target the drugs that meet these criteria and
export them from the brain. As a result, the BBB excludes
many small-molecule pharmaceuticals, and nearly all bio-
pharmaceuticals such as gene and protein medicines fail to
penetrate into the brain tissue to an appreciable extent (1).
Thus, although the surface area of the human brain
microvasculature available for drug transport (õ20 m
2
) is
more than adequate for treating the entire brain volume, the
barrier properties of the BBB continue to restrict brain drug
delivery via the bloodstream (2).
To date, strategies for the delivery of drugs that do not
have an appreciable BBB permeability have included both
invasive and noninvasive approaches. Direct intracranial
injection, intraventricular administration and BBB disruption
are examples of invasive delivery techniques that have been
reviewed elsewhere (3). Instead, this review will focus on a
rapidly developing class of novel delivery reagents that
function in mediating noninvasive blood-to-brain transport
by taking advantage of endogenous nutrient transport
systems present at the BBB. Nutrients and water-soluble
compounds such as ions, amino acids, vitamins, and proteins
that are necessary for brain function possess specific trans-
port systems embedded in the plasma membranes of the
BBB to allow brain entry. Three main classes of transport
systems function at the BBB. The first, carrier-mediated
transport, relies on molecular carriers present at both the
apical (blood) and basolateral (brain) membranes of the
BBB (Fig.1c). These carriers tend to be highly stereospecific
and function in the selective transport of small molecules
1759 0724-8741/07/0900-1759/0#2007 Springer Science + Business Media, LLC
Pharmaceutical Research, Vol. 24, No. 9, September 2007 (#2007)
DOI: 10.1007/s11095-007-9379-0
1
Department of Chemical and Biological Engineering, University of
Wisconsin-Madison, 1415 Engineering Drive, Madison, Wisconsin
53706, USA.
2
To whom correspondence should be addressed.(e-mail:shusta@
engr.wisc.edu)
ABBREVIATIONS: ADR, adriamycin; AEM, analytical electron
microscopy; AUC, area under the curve; Av, avidin; AZT,
azidothymidine; BBB, blood–brain barrier; BDNF, brain-derived
neurotrophic factor; bFGF, basic fibroblast growth factor; DSPE,
distearoylphosphatidylethanolamine; EGFR, human epidermal
growth factor receptor; FGF-2, fibroblast growth factor-2; GFAP,
glial fibrillary acidic protein; GUS,b-glucuronidase; HB-EGF,
heparin binding epidermal growth factor-like growth factor; HCEC,
human cerebromicrovascular endothelial cells; HD, Huntington_s
disease; HIR, human insulin receptor; HRP, horseradish peroxidase;
IGF-II, insulin-like growth factor II; LDL, low density lipoprotein;
LRP1/2, low density lipoprotein receptor-related protein 1/2; M6P,
mannose 6-phosphate; MAb, monoclonal antibody; MCAO, middle
cerebral artery occlusion; NGF, nerve growth factor; NHS,
N-hydroxysuccinimide; ODN, oligonucleotides; PBCA, poly(butyl
cyanoacrylate); PEG, poly(ethylene glycol); P-GUS, phosphorylated
b-glucuronidase; PNA, peptide nucleic acid; RAP, receptor-
associated protein; RES, reticuloendothelial system; RMT, receptor-
mediated transcytosis; rsCD4, recombinant human soluble CD4; SA/B,
streptavidin/ biotin; SATA,N-succinimidylS-acetylthioacetate; scFv,
single-chain variable fragment; sdAb, single-domain antibodies;
SMCC, Succinimidyl 4-[N-maleimidomethyl]-cyclohexane-1-
carboxylate; SV40, simian virus 40; Tf, transferrin; TfR, transferrin
receptor; TH, tyrosine hydroxylase; tPA, tissue-type plasminogen
activator; VIP, vasoactive intestinal peptide.
* Here TfR is BBB specific
CNS diseases such as AD,
Parkinson's disease,
multiple sclerosis(MS),
ischemia, encephalitis,
epilepsy, tumour and
lysosomal storage disease
Inflammation In BBB Upregulation of DTR
Diphtheria toxin
Mutated
Cross reacting material (CRM 197)
Target
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr
Modern methods for delivery of drugs across the blood–brain barrier☆
Yan Chen
a,
⁎, Lihong Liu
b,1
a
School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia
b
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore
abstractarticle info
Article history:
Received 6 August 2011
Accepted 21 November 2011
Available online 28 November 2011
Keywords:
Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions
The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the
brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are es-
sential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable,
highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better under-
stood, particularly under different pathological conditions. This review will discuss the barrier issue from a
biological and pathological perspective to provide a better insight to the challenges and opportunities asso-
ciated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed.
Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, andfinally
cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective ther-
apy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take
into account BBB biology as well as the unique features associated with the pathological condition to be
treated.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
2. Physiology and biology of the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
3. Transport routes across the blood–brain barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
4. Biological and pathological properties of BBB for drug transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
4.1. Physical barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Advanced Drug Delivery Reviews 64 (2012) 640–665
Abbreviations:a
2M, alpha-2 macroglobulin; Aβ, amyloidβ; ABC, ATP binding cassette; AD, Alzheimer's disease; AIDS, autoimmunodeficiency syndrome; AJ, adherens junction;
AMT, adsorptive-mediated transport; AMP, adenosine monophosphate; ANG1005, angiopep 2 conjugated with 3 molecules of paclitaxel; Antp, Antennapedia; APP, amyloid beta
precursor protein; ApoE, Apolipoprotein E; ATP, adenosine triphosphate; AUC, area under curve; BBB, blood–brain barrier; BCSFB, blood–cerebrospinalfluid barrier; BSA-NP, bovine
serum albumin conjugated nanoparticles; cAMP, cyclic AMP; CBSA, cationic bovine serum albumin; CBSA-NP, CBSA conjugated PEG-PLA nanoparticles; CED, convection enhanced
diffusion; CHP, hydrophobic cholesterol groups; CMC, critical micelle concentration; CMT, carrier-mediated transport; CNS, central nervous system; CPP, cell penetrating peptide;
CRM, cross reacting material; CSF, cerebrospinalfluid; DT, diphtheria toxin; DT
R, diphtheria toxin receptor; EAE, experimental autoimmune encephalomyelitis; EO, ethylene oxide;
EC, endothelial cell; EMF, electromagneticfields; FBP, fusion sequence-based peptide; g7, similopioid peptide; GMP, guanosine monophosphate; HB-EGF, heparin binding epider-
mal growth factor; HIRMAb, human insulin receptor monoclonal antibody; HIV, human immunodeficiency virus; HLB, hydrophobic–hydrophilic balance; HSA, human serum albu-
min; HSP-96, heat shock protein 96; HUVEC, human umbilical vein endothelial cells; ICH, intercerebral haemorrhage; ICV, intracerebroventricular; IgG, immunoglobulin G; IL,
interleukin; INF, interferon; JAM, junction adhesion molecules; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor; Lf, lactoferrin; LMV, large multilamellar
vesicles; LPA, lysophosphatidic acid; LRP, lipoprotein receptor protein; LUV, large unilamellar vesicles; MAP, model amphipathic peptide; MAPK,mitogen activated protein kinase;
MCP, monocyte chemotactic protein; MHC, major histocompatibility complex; MLCK, myosin light chain kinase; MP, mononuclear phagocytes; MRP, multidrug resistant pro-
tein; MS, multiple sclerosis; NOS, nitric oxide syntheses; NP, nanoparticles; NVU, neurovascular unit; P97, melanotransferrin; PAI-1, plasminogen activator inhibitor 1;
PHDCA, poly(hexadecylcyanoacrylate); PBCA, poly(butylcyanoacrylate); PEG, polyethylene glycol; PEG-PCL, PEG-polycaprolactone; PEG-G-CSF,PEGylated-recombinant
methionyl human granulocyted colony stimulating factor; PEG-PLA, polyethylene glycol-polylactic acid; P-gp, P-glycoprotein; PKA, protein kinase A; PKC, protein kinase C;
PKG, protein kinase G; PLGA, poly(D,L-lactide-co-glycolide); PO, propylene oxide; PTD, protein transduction domain; PTK, protein tyrosine kinase; Qdots, quantum dots; RAP,
receptor associated protein; RES, reticuloendothelial system; REV, reverse phase evaporation vesicles; RMT, receptor-mediated transport; R123,rhodamine123;SA,sialic
acid residue; SBP, sequence signal-based peptide; SUV, small unilamellar vesicles; TAT, HIV-1 trans-activating transcriptor; TEM, transmissionelectron microscopy; TER, transendothelial
electrical resistance; TfR, transferrin receptor; TJ, tight junction; TNF, tumour necrosis factors; tPA, tissue plasminogen activator; VE, vascular endothelial; VEGF, vascular endothelial
growth factor; ZO, zonula occludens.
☆This review is part of theAdvanced Drug Delivery Reviewstheme issue on“Delivery of Therapeutics to the Central Nervous System”.
⁎Corresponding author at: School of Pharmacy, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia. Tel.: [phone]; fax.[phone].
E-mail address:[email protected](Y. Chen).
1
L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.
0169-409X/$–see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2011.11.010
Contents lists available atSciVerse ScienceDirect
Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr

12. Inhibition of efflux Pumps
11/17/2015 PubMed Central, FIG. 1.: NeuroRx. 2005 Jan; 2(1): 86–98. doi:  10.1602/neurorx.2.1.86
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC539326/figure/f1/ 1/1
<< PrevFIG. 1.Next >>PMC full text:NeuroRx. 2005 Jan; 2(1): 86–98.
doi:  10.1602/neurorx.2.1.86
Copyright/License ► Request permission to reuse
FIG. 1.
Localization of selected drug efflux proteins on brain capillary endothelial cells that form the blood­brain
barrier. Only transporters that are localized on the apical (luminal) side of the brain capillary endothelium
would be in a position to restrict brain uptake of xenobiotics. Note that the exact localization in endothelial
cells has not been demonstrated as yet for all transporters shown in the figure, but for some of the
transporters the localization (apical vs basolateral) was derived from studies on polarized epithelial cell
lines.
6
Blood-Brain Barrier Active Efflux Transporters: ATP-Binding
Cassette Gene Family
Wolfgang Lo¨scherand Heidrun Potschka
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover,
Hannover D-30559, Germany
Summary:The blood-brain barrier (BBB) contributes to brain
homeostasis by protecting the brain from potentially harmful
endogenous and exogenous substances. BBB active drug efflux
transporters of the ATP-binding cassette (ABC) gene family
are increasingly recognized as important determinants of drug
distribution to, and elimination from, the CNS. The ABC efflux
transporter P-glycoprotein (Pgp) has been demonstrated as a
key element of the BBB that can actively transport a huge
variety of lipophilic drugs out of the brain capillary endothelial
cells that form the BBB. In addition to Pgp, other ABC efflux
transporters such as members of the multidrug resistance pro-
tein (MRP) family and breast cancer resistance protein (BCRP)
seem to contribute to BBB function. Consequences of ABC
efflux transporters in the BBB include minimizing or avoiding
neurotoxic adverse effects of drugs that otherwise would pen-
etrate into the brain. However, ABC efflux transporters may
also limit the central distribution of drugs that are beneficial to
treat CNS diseases. Furthermore, neurological disorders such
as epilepsy may be associated with overexpression of ABC
efflux transporters at the BBB, resulting in pharmacoresistance
to therapeutic medication. Therefore, modulation of ABC ef-
flux transporters at the BBB forms a novel strategy to enhance
the penetration of drugs into the brain and may yield new
therapeutic options for drug-resistant CNS diseases.Key
Words:P-glycoprotein, multidrug resistance proteins, epi-
lepsy, antiepileptic drugs, depression, AIDS.
INTRODUCTION
ATP-binding cassette (ABC) transporters are multido-
main integral membrane proteins that use the energy of
ATP hydrolysis to translocate solutes across cellular
membranes in all mammalian species.
1
ABC transporters
form one of the largest of all protein families and are
central to many important biomedical phenomena, in-
cluding resistance of cancers and pathogenic microbes to
drugs.
2
Elucidation of the structure and function of ABC
transporters is essential to the rational design of agents to
control their function.
ABC transporters are increasingly recognized to be
important for drug disposition and response.
3–7
P-glyco-
protein (Pgp), the encoded product of the human multi-
drug resistance (MDR1) (ABCB1) gene, is of particular
clinical relevance in that this transporter has a broad
substrate specificity, including a variety of structurally
divergent drugs in clinical use today.
7–9
Moreover, ex-
pression of this efflux transporter in certain tissue com-
partments such as the gastrointestinal tract and brain
capillary endothelial cells limits oral absorption and CNS
entry of many drugs.
7
The use of Pgp-expressing cell
lines, the generation of Pgp knockout mice as well as
studies using Pgp inhibitors in animals, contributed to a
better understanding on the role of active transport pro-
cesses for drug disposition.
8
In addition to Pgp, the ABC
transporters of the multidrug resistance protein (MRP;
ABCC) family and the breast cancer resistance protein
(BCRP; ABCG2) have a role in drug disposition.
6,9
The
family of mammalian ABC transporters, however, is far
more extensive, and functionally highly diverse.
1
In this
review, we limit ourselves to the following ABC trans-
porters: Pgp, MRPs 1-6, and BCRP, i.e., ABC transport-
ers that are expressed at the blood-brain barrier (BBB)
and, particularly Pgp, are involved in the regulation of
brain uptake and extrusion of drugs.
6,7,9,10
WHICH ABC TRANSPORTERS ARE
EXPRESSED AT THE BBB?
Drug uptake into the brain is dependent on a variety of
factors, including the physical barrier presented by the
Address correspondence and reprint requests to Dr. W. Lo¨scher,
Department of Pharmacology, Toxicology and Pharmacy, University of
Veterinary Medicine Hannover, Foundation, Bu¨nteweg 17, D-30559
Hannover, Germany. E-mail: [email protected].
NeuroRx
!
: The Journal of the American Society for Experimental NeuroTherapeutics
Vol. 2, 86 –98, January 2005 © The American Society for Experimental NeuroTherapeutics, Inc.86
Advanced Drug Delivery Reviews 55 (2003) 151–164
www.elsevier.com / locate / drugdeliv

P luronic block copolymers as modulators of drug efflux
transporter activity in the blood–brain barrier
*Alexander V. Kabanov , Elena V. Batrakova, Donald W. Miller
Department of Pharmaceutical Sciences,University of Nebraska Medical Center, 986025Nebraska Medical Center,Omaha,NE68198,
USA
Received 6 July 2002; accepted 11 August 2002
Abstract
Drug efflux transporters can influence the absorption, tissue distribution and elimination of many therapeutic agents.
Modulation of drug efflux transporter activity is being explored as a means for improving the pharmacokinetic and
pharmacodynamic properties of various drugs. In this regard, several polymer formulations have been shown to inhibit drug

efflux transporters such as P-glycoprotein (P-gp). The current review will focus on Pluronic block copolymers in particular,

the mechanisms involved in the effects of Pluronic on drug efflux transporters, and the optimal polymer compositions

required for inhibition of drug efflux transporters. Special emphasis will be placed on the potential applications of Pluronic
in enhancing the blood–brain barrier (BBB) penetration of drugs.
2002 Elsevier Science B.V. All rights reserved.
Keywords:Blood–brain barrier; Multidrug resistance (MDR); P-glycoprotein; Multidrug resistant protein (MRP); Block copolymer
Contents
1 . Introduction ............................................................................................................................................................................ 151

2 . Overview of Pluronic block copolymers in pharmaceutics ........................................................................................................ 152

3 . Pluronic block copolymers in drug resistant cancer .................................................................................................................. 152

4 . Effects of Pluronic on P-gp activity in the blood–brain barrier.................................................................................................. 154

5 . Mechanism of Pluronic -induced inhibition of P-gp in brain endothelial cells ............................................................................. 155

5 .1. ATP depletion in the presence of Pluronic block copolymers ............................................................................................ 155

5 .2. Membrane interactions of Pluronic and inhibition of P-gp ATPase activity......................................................................... 156

6 . Optimization of Pluronic compositions for P-gp inhibition in brain endothelial cells .................................................................. 157

7 . Effects of Pluronic on drug transport across BBB: in vitro and in vivo evaluation ...................................................................... 158

8 . Toxicological considerations of Pluronic block copolymers ...................................................................................................... 160
9 . Conclusion.............................................................................................................................................................................. 161
Acknowledgements ...................................................................................................................................................................... 161
References .................................................................................................................................................................................. 161
*Corresponding author. Tel.:[phone]; fax:[phone].
E-mail address:[email protected](A.V. Kabanov).
0169-409X / 02 / $ – see front matter2002 Elsevier Science B.V. All rights reserved.
PII: S0169-409X(02)00176-X
Advanced Drug Delivery Reviews 55 (2003) 151–164
www.elsevier.com / locate / drugdeliv

P luronic block copolymers as modulators of drug efflux
transporter activity in the blood–brain barrier
*Alexander V. Kabanov , Elena V. Batrakova, Donald W. Miller
Department of Pharmaceutical Sciences,University of Nebraska Medical Center, 986025Nebraska Medical Center,Omaha,NE68198,
USA
Received 6 July 2002; accepted 11 August 2002
Abstract
Drug efflux transporters can influence the absorption, tissue distribution and elimination of many therapeutic agents.
Modulation of drug efflux transporter activity is being explored as a means for improving the pharmacokinetic and
pharmacodynamic properties of various drugs. In this regard, several polymer formulations have been shown to inhibit drug

efflux transporters such as P-glycoprotein (P-gp). The current review will focus on Pluronic block copolymers in particular,

the mechanisms involved in the effects of Pluronic on drug efflux transporters, and the optimal polymer compositions

required for inhibition of drug efflux transporters. Special emphasis will be placed on the potential applications of Pluronic
in enhancing the blood–brain barrier (BBB) penetration of drugs.
2002 Elsevier Science B.V. All rights reserved.
Keywords:Blood–brain barrier; Multidrug resistance (MDR); P-glycoprotein; Multidrug resistant protein (MRP); Block copolymer
Contents
1 . Introduction ............................................................................................................................................................................ 151

2 . Overview of Pluronic block copolymers in pharmaceutics ........................................................................................................ 152

3 . Pluronic block copolymers in drug resistant cancer .................................................................................................................. 152

4 . Effects of Pluronic on P-gp activity in the blood–brain barrier.................................................................................................. 154

5 . Mechanism of Pluronic -induced inhibition of P-gp in brain endothelial cells ............................................................................. 155

5 .1. ATP depletion in the presence of Pluronic block copolymers ............................................................................................ 155

5 .2. Membrane interactions of Pluronic and inhibition of P-gp ATPase activity......................................................................... 156

6 . Optimization of Pluronic compositions for P-gp inhibition in brain endothelial cells .................................................................. 157

7 . Effects of Pluronic on drug transport across BBB: in vitro and in vivo evaluation ...................................................................... 158

8 . Toxicological considerations of Pluronic block copolymers ...................................................................................................... 160
9 . Conclusion.............................................................................................................................................................................. 161
Acknowledgements ...................................................................................................................................................................... 161
References .................................................................................................................................................................................. 161
*Corresponding author. Tel.:[phone]; fax:[phone].
E-mail address:[email protected](A.V. Kabanov).
0169-409X / 02 / $ – see front matter2002 Elsevier Science B.V. All rights reserved.
PII: S0169-409X(02)00176-X
Advanced Drug Delivery Reviews 55 (2003) 151–164
www.elsevier.com / locate / drugdeliv

P luronic block copolymers as modulators of drug efflux
transporter activity in the blood–brain barrier
*Alexander V. Kabanov , Elena V. Batrakova, Donald W. Miller
Department of Pharmaceutical Sciences,University of Nebraska Medical Center, 986025Nebraska Medical Center,Omaha,NE68198,
USA
Received 6 July 2002; accepted 11 August 2002
Abstract
Drug efflux transporters can influence the absorption, tissue distribution and elimination of many therapeutic agents.
Modulation of drug efflux transporter activity is being explored as a means for improving the pharmacokinetic and
pharmacodynamic properties of various drugs. In this regard, several polymer formulations have been shown to inhibit drug

efflux transporters such as P-glycoprotein (P-gp). The current review will focus on Pluronic block copolymers in particular,

the mechanisms involved in the effects of Pluronic on drug efflux transporters, and the optimal polymer compositions

required for inhibition of drug efflux transporters. Special emphasis will be placed on the potential applications of Pluronic
in enhancing the blood–brain barrier (BBB) penetration of drugs.
2002 Elsevier Science B.V. All rights reserved.
Keywords:Blood–brain barrier; Multidrug resistance (MDR); P-glycoprotein; Multidrug resistant protein (MRP); Block copolymer
Contents
1 . Introduction ............................................................................................................................................................................ 151

2 . Overview of Pluronic block copolymers in pharmaceutics ........................................................................................................ 152

3 . Pluronic block copolymers in drug resistant cancer .................................................................................................................. 152

4 . Effects of Pluronic on P-gp activity in the blood–brain barrier.................................................................................................. 154

5 . Mechanism of Pluronic -induced inhibition of P-gp in brain endothelial cells ............................................................................. 155

5 .1. ATP depletion in the presence of Pluronic block copolymers ............................................................................................ 155

5 .2. Membrane interactions of Pluronic and inhibition of P-gp ATPase activity......................................................................... 156

6 . Optimization of Pluronic compositions for P-gp inhibition in brain endothelial cells .................................................................. 157

7 . Effects of Pluronic on drug transport across BBB: in vitro and in vivo evaluation ...................................................................... 158

8 . Toxicological considerations of Pluronic block copolymers ...................................................................................................... 160
9 . Conclusion.............................................................................................................................................................................. 161
Acknowledgements ...................................................................................................................................................................... 161
References .................................................................................................................................................................................. 161
*Corresponding author. Tel.:[phone]; fax:[phone].
E-mail address:[email protected](A.V. Kabanov).
0169-409X / 02 / $ – see front matter2002 Elsevier Science B.V. All rights reserved.
PII: S0169-409X(02)00176-X
Advanced Drug Delivery Reviews 55 (2003) 151–164
www.elsevier.com / locate / drugdeliv

P luronic block copolymers as modulators of drug efflux
transporter activity in the blood–brain barrier
*Alexander V. Kabanov , Elena V. Batrakova, Donald W. Miller
Department of Pharmaceutical Sciences,University of Nebraska Medical Center, 986025Nebraska Medical Center,Omaha,NE68198,
USA
Received 6 July 2002; accepted 11 August 2002
Abstract
Drug efflux transporters can influence the absorption, tissue distribution and elimination of many therapeutic agents.
Modulation of drug efflux transporter activity is being explored as a means for improving the pharmacokinetic and
pharmacodynamic properties of various drugs. In this regard, several polymer formulations have been shown to inhibit drug

efflux transporters such as P-glycoprotein (P-gp). The current review will focus on Pluronic block copolymers in particular,

the mechanisms involved in the effects of Pluronic on drug efflux transporters, and the optimal polymer compositions

required for inhibition of drug efflux transporters. Special emphasis will be placed on the potential applications of Pluronic
in enhancing the blood–brain barrier (BBB) penetration of drugs.
2002 Elsevier Science B.V. All rights reserved.
Keywords:Blood–brain barrier; Multidrug resistance (MDR); P-glycoprotein; Multidrug resistant protein (MRP); Block copolymer
Contents
1 . Introduction ............................................................................................................................................................................ 151

2 . Overview of Pluronic block copolymers in pharmaceutics ........................................................................................................ 152

3 . Pluronic block copolymers in drug resistant cancer .................................................................................................................. 152

4 . Effects of Pluronic on P-gp activity in the blood–brain barrier.................................................................................................. 154

5 . Mechanism of Pluronic -induced inhibition of P-gp in brain endothelial cells ............................................................................. 155

5 .1. ATP depletion in the presence of Pluronic block copolymers ............................................................................................ 155

5 .2. Membrane interactions of Pluronic and inhibition of P-gp ATPase activity......................................................................... 156

6 . Optimization of Pluronic compositions for P-gp inhibition in brain endothelial cells .................................................................. 157

7 . Effects of Pluronic on drug transport across BBB: in vitro and in vivo evaluation ...................................................................... 158

8 . Toxicological considerations of Pluronic block copolymers ...................................................................................................... 160
9 . Conclusion.............................................................................................................................................................................. 161
Acknowledgements ...................................................................................................................................................................... 161
References .................................................................................................................................................................................. 161
*Corresponding author. Tel.:[phone]; fax:[phone].
E-mail address:[email protected](A.V. Kabanov).
0169-409X / 02 / $ – see front matter2002 Elsevier Science B.V. All rights reserved.
PII: S0169-409X(02)00176-X

13. Cell-mediated drug transport across the blood–brain barrier
pharmacy.sites.unc.edu/
troy-movie.stasi.co.uk
Macrophages and monocytes/neutrophils are phagocytic and
have a tendency to endocytose colloidal materials, for
example, nano or microparticles, liposomes and subsequent
exo- cytosis to release drug and/or colloidal materials to
external media. A high payload of drug can be incorporated/
loaded into nanocar- riers or microcarriers, then taken up by
Trojan horse cells .

14. !anks A"
for a Pa#ent Ear
kinetophil.tripod.com/ moraxella.deviantart.com/