Brain specific drug targetting stratergies

it tells aboutthe brain specific drug targetting stratergies:-)

1. BRAIN SPECIFIC DRUG
TARGETTING STRATERGIES
PRESENTED BY
KOORISHMA J
RA1412014010001
M.Tech (BIOTECHNOLOGY)

2. •BRAIN CELLS

3. INTRODUCTION
•drugs, when injected intravenously,
fail to reach brain and spinal cord,
• but the same drugs, when injected
into the ventricles, enter the brain
substances easily.
•This indicates that a barrier exists
at the capillary level between the
blood and nerve cells. So, the blood
brain barrier can be defined as the
separation of the circulating blood
and the brain extracellular fluid in
the Central Nervous System (CNS).

4. FUNCTIONS OF BBB
•Maintaining the internal environment of
brain.
Eg: maintaining brain interstitial fluid &
cerebrospinal fluid.
•BBB protects brain from fluctuation.
•Main function of BBB is neroprotection.

5. FACTORS AFFECTING PARTICULAR
SUBSTRATE TO CROSS BBB
Drug related factors at BBB
1.Conc at the BBB & the size
2.Flexibility
3.Conformation
4.Ionization
5.Lipophilicity
6.Hydrogen bonding potential

6. ROUTES FOR THE TRANSPORT OF
MOLECULES ACROSS THE BBB
• Paracellular hydrophilic diffusion
• Transcellular lipophilic diffusion
• Receptor mediated endocytosis
• Carrier mediated transcytosis
• Adsorptive mediated endocytosis
•Efflux pump

7. RECENT ADVANCES IN BRAIN DRUG
DELIVERY RESEARCH
•Nano particles
•Receptor-mediated transport (RMT)
•Transporter-independent mechanisms to circumvent the BBB.
1)Intranasal Delivery.
2)Convection-enhanced drug delivery (CED)
3)Osmotic BBB Disruption (BBBD).
4)Ultrasound-mediated BBB opening
•Imaging in brain drug targeting.
1)Magnetic resonance imaging
2)Imaging delivery techniques.
3)Positron Emission Tomography.
•BBB genomics.
•P-glycoprotein inhibitors

8. Nano particles
Nanotechnology may also
help in the transfer of
drugs across the BBB.
Recently, researchers
have been trying to build
nanoparticles loaded
with liposomes to gain
access through the BBB.

10. RECEPTOR MEDIATED TANSPORT
The BBB expresses RMT systems for the transport of
endogenous peptides, such as insulin or transferrin.
The RMT systems operate in parallel with the
classical carrier-mediated transporters (CMT), which
transport certain small molecule nutrients, vitamins,
and hormones.

11. Transporter-independent mechanisms to
circumvent the BBB
1)Intranasal Delivery. (not effective)
This method allows drugs that do not cross the blood-brain barrier to be
delivered to the olfactory cerebrospinal fluid via transport across the
olfactory region of the nasal epithelium. The surface area of the olfactory
region of the nasal epithelium in rodents is large, about 50%, and is small
in humans, about 5%, therefore intranasal delivery is not expected to
achieve therapeutic drug levels in most brain regions.
2)Convection-enhanced drug delivery (CED)
CED is a method for local/regional micro infusion targeted directly to brain
tissue. A continuous infusion pressure gradient over hours to days results
in distribution of therapeutic agents into the interstitial space. The CED
technique is used primarily for large molecular weight agents that show
minimal leakage across the BBB and/or have significant systemic toxicity,
including viruses, oligonucleotides, nanoparticles, liposome, and targeted
immunotoxins.

12. 3)Osmotic BBB Disruption (BBBD)
Transient osmotic disruption of the blood-brain, blood-CSF, and blood-tumor
barriers can be achieved throughout a vascular circulation by intra arterial
infusion of a hyper osmotic agent, usually mannitol.
Osmotic BBBD reversibly opens the BBB by shrinking the cerebro vascular
endothelial cells with transient opening of the tight junctions between cells.
4)Ultrasound-mediated BBB opening

BBB disruption by MRI-guided focused ultrasound can achieve focal CNS
delivery in animal models. Consistent vascular leak without tissue damage was
achieved by localizing cavitation-generated mechanical stresses to blood vessel
walls by IV injection of preformed gas bubbles just prior to pulsed ultrasound
treatment.

13. Imaging in brain drug targeting
Imaging has made important contributions in drug
discovery and brain drug targeting, particularly in areas
of pharmacokinetics and in quantifying therapeutic
response.

14. •a. Magnetic resonance imaging
Brain structural imaging data provide important metrics regarding the extent of
brain disease and objective surrogate markers for evaluation of therapies. MRI has
played an important role in evaluating new CNS therapies.
b. Imaging delivery techniques.
The distribution of drug within the brain using any of the BBB strategies is
complex and imaging information can be used to optimize individual therapies.
Contrast enhanced MRI has been used to monitor CED drug delivery and revealed
complex distribution patterns resulting from anisotropic diffusion, vascular efflux,
and other factors.
c. Positron Emission Tomography.
PET is non-invasive, has excellent sensitivity and specificity. Advanced PET
techniques have been used to determine pharmacokinetics of brain drugs
pharmacodynamic response following anti-cancer therapy.

15. Other methods
a.BBB genomics. BBB genomics is the application of gene micro-array
technologies. The endothelial cells occupy a very small volume of the
brain, about 0.1%, or 10-3 parts. The sensitivity of gene micro-array is
about 10-4 parts. Therefore, most BBB specific transcripts may not be
detected in whole brain gene microarray.
b.P-glycoprotein inhibitors. Inhibitors of BBB active efflux transporters,
such as Pglycoprotein, have been developed. Such inhibitors may act as
co-drugs to increase the brain penetration of P-glycoprotein substrates.
Eg:paclitaxel by co-administration of the Pglycoprotein inhibitor.

16. applications of targeted brain delivery
1.neurodegeneration / neuroinflammation
(Stroke, Alzheimers, Parkinsons, ALS, MS)-
protein drugs (growth factors, antibodies, enzymes) –
gene / antisense therapy-
small molecules.
2.lysosomal storage diseases-
enzyme replacement therapies-gene therapy
3.brain tumors / metastasis-
anti-cancer drugs-
protein drugs (antibodies, cytokines)-
gene / antisense therapy

17. THANK YOU