Dendrimers : A recent drug delivery system

Dendrimer is a branched drug delivery system which have higher affinity for drug entrapment.

1. DENDRIMERS – A RECENT
DRUG DELIVERY SYSTEM

Under the guidance of
Dr. K. H. Ramteke
(M.Pharm, Ph.D.)
Dept. of Pharmaceutics
PE Society’s
Modern college of pharmacy (for ladies), Moshi, Pune
1
Presented By,
Varsha V. Awasarkar
M Pharm 1
st
semister

2. Contents
•Aim
•Introduction
•Properties
•Types of dendrimers
•Mechanism of drug release
•Synthesis of dendrimers
•Characterization
•Advantages
•Cytotoxicity
•Applications of dendrimers
•Literature survey
•Conclusion
•References
2

3. AIM
•To emphasize on dendrimeric drug delivery
system.
•To focus on current applications of dendrimers.
3

4. INTRODUCTION
•A suitable drug delivery system would protect the drug against degradation
and ensure that drug reaches proper permeability properties and further
provides a combined transportation and protection system against the
natural barriers, as done by the dendrimers. Dendrimers are highly defined
nanoparticles:
– Size: 1 -15 nanometers
– Very versatile surface functionalisation
– Synthetic: Practical and cost effective
– Well tolerated pharmaceutica.
•The term “Dendrimer” arise from two Greek word :
- “Dendron” meaning tree’
-“Meros” meaning part
•The dendrimers are also called as CASCADE MOLECULES or
ARBOROLS.
4

5. CONT….
•Dendrimers are hyper-branched, globular, monodisperse, three dimensional
nanoscale synthetic polymers, having very well defined size, shape and
definite molecular weight.
•Dendrimer is a nanoparticle (10
-9
) and so has advantages over
microparticles or others due to its small size, easy uptake by cells (through
endocytosis).
•They are branched macromolecules have a central core unit having a high
degree of molecular uniformity, narrow molecular weight, distribution,
specific size and shape characteristics, and a highly- functionalized,
terminal surface.
•Dendrimers exhibit characteristics features of both molecular chemistry and
polymer chemistry. Molecular chemistry like properties are due to their step
by step controlled synthesis while it shows polymer chemistry like properties
as it is made up of monomers.
[1]
Components of a Dendrimer Structure:
Generation, Shell, Pincer, End group.
5

6. CONT….
•Goals behind developing the dendrimers:
A) Modify/Improve the pharmacokinetic and pharmacodynamic
properties of a drug so that there is also an accretion in
bioavailability.
B) Achieve the controlled and targeted release of drug restricted to
the area desired.
[2]
•STRUCTURE: Dendrimers are built from a starting atom, such as
nitrogen, to which carbon and other elements are added by a
repeating series of chemical reactions that produce a spherical
branching structure.
•As the process repeats, successive layers are added, and the
sphere can be expanded to the size required by the investigator.
The result is a spherical macromolecular structure whose size is
similar to albumin and hemoglobin, but smaller than such multimers
as the gigantic IgM antibody complex.
6

7. 1.1 STRUCTURE OF DENDRIMERS
7Figure 1: Schematic representation of the dendrimer typical structure.
Structure of Dendrimers possesses 3 distinct units:
A Central core unit.
Generations i.e. branches, which are radically “Meros” meaning part attached to
the central core.
Terminal functional group attached to the outermost series of branches.

8. 1.2 HISTORY
8

9. Table 1: Properties of Dendrimer And Linear
Polymers
[5]
Serial
Number
Property Dendrimers Linear Polymers
1 Structure Compact and Globular Not compact
2 Shape Spherical Random coil
3 Architecture Regular Irregular
4 Synthesis Stepwise growth Single step
polycondensation
5 Crystallanity Non-crystalline and amorphous
Materials Lower glass
temperatures
Semi crystalline/crystalline
Materials -Higher glass
temperatures
6 Aqueous solubility High Low
7 Nonpolar solubility High Low
8 Compressibility Low High
9

10. 3. TYPES OF DENDRIMERS
10

11. PAMAM Dendrimer
•PAMAM [Poly (amido amine)] dendrimers are spheroidal or ellipsoidal in shape.
These are most studied macromolecules and are commercially available.
•The divergent method is used for their synthesis where ammonia or ethylenediamine
is used as starting material.
•The high solubility and reactivity of these are due to presence of a number of
functional end groups and empty internal cavities.
•The conventional macromolecules have low amino group density as compared to
PAMAM dendrimers.
[1]
•Products up to generation 10 (a molecular weight of over 9,30,000 g/mol) have been
obtained (by comparison, the molecular weight of human hemoglobin is
approximately 65,000 g/mol). PAMAM dendrimers are commercially available, usually
as methanol solutions
•Starburst dendrimers is applied as a trademark name for a sub-class of PAMAM
dendrimers based on a tris-aminoethylene-imine core. The name refers to the star
like pattern observed when looking at the structure of the high-generation dendrimers
of this type in two-dimensions.
11

12. 12
Figure 2: 3 dimentional projection of dendrimer core shell architecture for G-Figure 2: 3 dimentional projection of dendrimer core shell architecture for G-
4.5 PAMAM Dendrimers4.5 PAMAM Dendrimers

13. Table 2: Types of dendrimers
[5]
13
Types Definition Synthesis Example Applications
Pamam
Dendrimer
Poly (amidoamine)
dendrimers possess amino
groups on the
Surface.
Divergent Dendritech(USA) Material Science and
Biomedicine
Computer toners
Pamamos
Dendrimer
Inverted unimolecular
micelles consists of
hydrophilic nuclephilic
PAMAM interiors and
hydrophobic
organosilicon(OS) Exteriors.
Convergent
and Divergent
SARSOX Nano-lithography Electronics,
Photonics Chemical catalysis
Precursor for honeycomb like
network preparations.
PPI
dendrimer
Poly-alkyl amines having
primary amines as end
groups and its
Interior consists of
numerous tertiary
trispropylene amines.
Divergent Asramol by DSM
(Netherlands)
Material science and biology
Tecto
dendrimer
Composed of a core
dendrimer with multiple
dendrimers at its periphery
Divergent Stratus® CS Acute
Care TM,
Starburst®,
Mercapto
Diseased cell recognition
Diseased state drug delivery
diagnosis
Reporting location to
outcome of therapy

14. Types Definition Synthesis Example Applications
Amphiphilic
dendrimers
Unsymmetical globular
dendrimers built with two
segregated sites of
chain end.
Divergent SuperFect,
Hydraamphiphiles
And bola-
amphiphiles
Structure-directing agent, Use
as polar part, cell and gene
transfection.
Micellar
dendrimers
Unimolecular micelle
structure of Water soluble
hyperbranched
polyphenylene
Divergent Beclomethazone
dipropionate, NX-
200,
Magnevist®
Biological and medical
applications,Drug delivery,
Imaging agent.
Multiple
antigen
peptide
dendrimers
Dendron-like molecular
construct
based upon a polylysine
skeleton.
Convergent VivaGel Used in vaccines and
diagnostic research. Biological
applications.
Frechettype
dendrimers

Dendrimes having
carboxylic acid groups as
surface groups and
containing poly-benzyl
ether hyperbranced
skeleton.
Convergent Frechet type
dendron azides,
Priostar
Drug carrier, Purifiers, Organic
synthesis, detecting agent,
drug
delivery.
Liquid
crystalline
dendrimers
Consists of mesogenic
monomers
divergent Polycanter liquid
crystals, Mesogen
functionalized
Carbosilane
dendrimers
Science and Engineering.
Metallo
dendrimers
Dendrimers with
incorporated metal
atoms
Convergent Zinc Porphyrin
dendrimers(M=Zn)
Sensing Catalytic applications,
mimic
biomolecules, lightharvesting,
Biomarkers.
14

15. MECHANISM OF DRUG DELIVERY
THROUGH DENDRIMERS
15
Fig. A Dendrimer molecule with
Drug molecules loaded at terminal
surface of branches.
(electrostatic interactions or
covalent conjugate) .
[2]

Fig. A Dendrimer molecule with
terminal drug molecules
encapsulated within branches.
(simple encapsulation) .
[2]

16. SYNTHESIS OF DENDRIMERS
16

17. Divergent Synthesis
•The dendrimer is assembled from a multifunctional core, which is
extended outward by a series of reactions, commonly a Michael
reaction. Each step of the reaction must be driven to full completion
to prevent mistakes in the dendrimer, which can cause trailing
generations (some branches are shorter than the others). Such
impurities can impact the functionality and symmetry of the
dendrimer, but are extremely difficult to purify out because the
relative size difference between perfect and imperfect dendrimers is
very small.
Convergent synthesis
•Dendrimers are built from small molecules that end up at the
surface of the sphere, and reactions proceed inward building inward
and are eventually attached to a core. This method makes it much
easier to remove impurities and shorter branches along the way, so
that the final dendrimer is more monodisperse. However dendrimers
made this way are not as large as those made by divergent
methods, because crowding due to steric effects along the core is
limiting.
17

18. 18
Figure 9: Divergent synthesis of dendrimer
[4]
Figure 10: Convergent synthesis of dendrimer
[4]

19. Double Exponential and Mixed Method:
This is amixture of both divergent and convergent method.
In this method a single starting material is taken from which
two monomers are prepared by divergent and convergent
method. Then these two monomers are reacted together to
give an orthogonally protected trimer. This protecter trimer
may be use to repeat the growth process again.
[1]
Figure 12: Combined Divergent-Convergent Method
[12]
19

20. CHARACTERIZATION OF
DENDRITIC POLYMERS
[4, 1]
•Spectroscopy UV-Visible, IR, NMR.
•Microscopy TEM , AFM, SEC.
•Rheology, physical properties DSC
•Miscellaneous
•Scattering techniques
•Electrical techniques
•Solubility
•Determination of Melting Point
•Elemental Analysis (Nitrogen)
20

21. ADVANTAGES
A)Medication to the affected part inside a patient's body directly
B)Controlled and sustained release of drugs can also be obtained
C) Drugs can be easily made to remain within layers of skin and not
penetrate in systemic circulation
D)Bypassing the gastric medium and hence the eschewing the
variation due to effect of gastric secretions.
E)Increase in therapeutic efficacy, decrease in side effects:
decreased clearance of drug via altered distribution of drug in
organs at site of localization and transportation due to controlled
and sustained release of the drug.
F) Relatively high drug loading.
G)Preservation of drug activity: as drugs can be incorporated into the
systems without any chemical reaction.
21

22. CYTOTOXICITY
Dendrimer having – NH
2
termini shows and generation dependent
cytotoxicity, hemolytic activity. Which are associated with their cationic
nature. The cytotoxicity is a function of surface charge, size and
concentration. The cytotoxicity and hemolytic activity of cationic.
Non-charged dendrimer are non-toxic and bioavailable.
•A) Dendrimers with positively charged surface groups-prone to destabilize
cell membranes and cause cell lysis.
•B) Generation dependent toxicity-higher generation dendrimers being the
most toxic.
•C) Degree of substitution, type of amine functionality is important- primary
amines being more toxic than secondary or tertiary amines.
[2]
22

23. APPLICATIONS OF DENDRIMERS
1. Therapeutic Application:
-Dendrimer in photodynamic therapy
-Dendrimers for Boron Neutron capture therapy

2. Diagnostic Application:
-Dendrimers as MRI contrast agent
-Dendrimers as X-Ray contrast agent
-Dendrimer as molecular probe

3. Pharmaceutical Application:
-Dendrimers in pulmonary drug delivery
-Dendrimers in Transdermal drug delivery
-Dendrimers in ocular drug delivery
-Dendrimers in oral drug delivery
-Dendrimers for controlled release drug delivery
-Dendrimers in targeted drug delivery
-Dendrimers in gene delivery
-Dendrimers as solubility enhancer
-Cellular delivery using Dendrimers carrier
-Dendrimers based product in cosmetics
-Dendrimers based commercial products
23

24. 4.Dendrimers in Gene Delivery
5.Dendrimers as Solubility Enhancer
6.Dendrimers as Cellular Drug Delivery CarrierDendrimers in
Targeted and Controlled Release Drug Delivery
7.Dendrimers in Cosmetics
8.Dendrimers as a light harvesting antennae
[1]
24
CONT….

25. 25

26. Fig. Dendrimers in ocular drug delivery
26

27. Literature survey
Author Aim Method and materials Result
R. Ritawidya,
A. Pujiyanto,
Mujinah
Synthesis and
Characterization of
Poly(Amidoamine)
Dendrimers
Encapsulated
198Au
Nanoparticles.
PAMAM G3.0, bovine serum
albumin (BSA), gold chloride
(HAuCl4.3H2O), methanol,
and Au foil.
Method- Bottom – up
method.
PAMAM G3.0
dendrimer
encapsulated 198Au
nanoparticles were
synthesized which was
used as brachytherapy
agents.
Gregory Spataro,
Francois Malecaze,
Cedric-Olivier Turrin
Designing
dendrimers for
ocular drug
delivery.
tris(2-chloroethyl) amine
hydrochloride 3 as analogue
of benzalkonium chloride,
hydroxybenzaldehyde with
NaOH in ethanol, carteolol.
Divergent Method
New series of PH-
containing dendrimers,
having one quaternary
ammonium salt as core
and carboxylic acid
terminal groups have
been synthesized from
generation 0 (3
carboxylic acid
terminal groups) to
generation 2 (12
carboxylic acid
terminal groups).
26

28. Literature survey
Author Aim Method and materials Result
Anna Luganinia,
Andrea Giulianib,
Giovanna Pirri.
Peptide-derivatized
dendrimers inhibit
human
cytomegalovirus
infection by
blocking virus
binding to cell
surface heparan
sulfate.
Peptide grade reagents,
resins and solvents were
used for SPPS (solid
phase peptide synthesis)
Method- M6 prototype, a
tetrabranched dendrimer
synthesized on a lysine
core which tethers four 10-
mer peptide chains in
lysine and positions
The two peptide
dendrimers, SB105
and SB105 A10, to
directly and almost
completely inhibit
human
cytomegalovirus
(HCMV) replication in
both primary
fibroblasts and
endothelial cells.
Mona A.,
Abdel-Rahman
Et al
Thermoresponsive
dendrimers based
on oligoethylene
glycols: Design,
synthesis and
cytotoxic activity
against MCF-7
breast cancer
cells.
Tetrabromohydroquinone,
Tetrahydrofuran (THF),
lithium aluminum hydride
(LAH) and
dichloromethane (DCM)
Method- Divergent
method
D2 dendrimer gave
the best result; it
showed cytotoxicity
against MCF-7 cell
line with IC50 of 1.07
mg/mL and resistant
fraction equals
1.97%, the other two
dendrimers showed a
modest cytotoxic
profile.
28

29. CONCLUSION

•PAMAM dendrimers are presented as nanocarriers drugs promising for the
coming years, since the multiple properties related to their three-
dimensional structure, as mono dispersity, versatility, biocompatibility and
other characteristics intrinsic which increase the solubility and activity of
these drugs linked these polymers, improving the bioavailability and reduce
the toxicity potential of many drugs.
•The drug can be linked to the dendrimers by covalent bonds, electrostatic
interactions, or by encapsulation, and the choice of the interaction fits the
drug needs.
•As a flexible and excellent carrier, the dendrimers can be carefully designed
for the delivery of biomolecules to the desired target tissue, which allows the
use of lower doses, although effective in therapy.
29

30. REFERENCES
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Tool for Drug Delivery”, Advances in Biological Research ,6
th
edition (4),
IDOSI Publications, page no. 165-169, 2012.

2. I. Mishra et al, “Dendrimer: A novel drug delivery system”, Journal of Drug
Delivery & Therapeutics, 1
st
publication, 2
nd
edition, 2011, page no. 70-74.
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and G. Srikanth, “Dendrimers: A New
Carrier System For Drug Delivery”, International Journal of Pharmaceutical
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st
edition, 2010, page no. 1-10.
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pharmacy”, International journal of research in pharmacy and chemistry,
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30

31. CONT…..
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7. O. Flomenbom, R. Amir et al, “ Some New Aspects of Dendrimer
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8. Donald A. Tomalia, K. Mardel, Scott A. Henderson, R. Esfand, “Dendrimers
— An Enabling Synthetic Science to Controlled Organic Nanostructures”,
page no. 1- 34.
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