DENDRIMER

Presented by: Chinchole Pravin Sonu

(M.PHARM 2nd SEM)DEPARTMENT OF PHARMACEUTICS & QUALITY

ASSURANCE

R. C. Patel Institute of Pharmaceutical Education and Research, shirpur.

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CONTENT INTRODUCTION

NEED OF DENDRIMERS

METHODS OF SYNTHESIS

MECHANISMS OF DRUG DELIVERY

GENERATION

TYPES OF DENDRIMERS

PROPERTIES OF DENDRIMERS

CHARACTERIZATION OF DENDRIMERS

APPLICATIONS

REFERENCES2

The word “dendrimer” originated from two Greek words,

dendron :- meaning tree,

meros:- meaning part or segment.

Dendrimers are a new class of polymeric materials. They are

highly branched, monodisperse , artificial macromolecules.

Dendrimers may be defined as synthetic three-dimensional

hyper branched, globular macromolecule, which is characterized

by its highly branched 3D structure that provides a high degree of

surface functionality.

Dendrimers also refered as the “Polymers of the 21st century”.

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HISTORY In 1978, Vogtle and co-workers was first introduced

chemistry of Dendrimer . In 1980, Donald Tomalia and co-workers discovered, these

hyper branched molecules were called dendrimers. In 1985, Vogtle synthesized the first family of dendrimers

the first “cascade molecules”. At the same time, Newkome’s group independently reported

synthesis of similar macromolecules. They called them arborols from the Latin word ‘arbor’ also

meaning a tree. The term cascade molecule is also used, but ‘dendrimer’ is

the well established one.

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Dendrimers possess three distinguished components, namely

(i) An initiator core. (ii) Interior layers:- composed of repeating units, radically attached to the interior core(generations). (iii) Exterior layers :- attached to the outermost interior

generations (terminal functionality).

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NEED OF DENDRIMERS:-Nano-particle drug-delivery systems are most popular one.

However reticuloendothelial system (RES) uptake, drug

leakage, immunogenicity, haemolytic toxicity, cytotoxicity,

restrict the use of these nanostructures. These are overcome by surface engineering the dendrimer

such as Polyester dendrimer, Glyco-dendrimers, PEGylated dendrimers etc.

The bioactive agents can be easily encapsulated into the interior of the dendrimers.

or Chemically attached i.e. physically adsorbed on to the

dendrimer surface.6

• Traditional method dendrimer synthesis are: Michael reaction Williamson ether synthesis. Modern techniques are : solid-phase synthesis, organosilicon chemistry, organo-phosphorus chemistry.

MANUFACTURE COUNTRY DENDRIMERS TRADE MARK NAME

CORE MOLECULE

Dendritech TM

U.S.A. PAMAM dendrimers

Starburst dendrimers

Ethylenediamine (EDA) core

DSM Netherlands

PPI dendrimers

Astramol TM

Butylenediamine (BDA) core

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METHODS OF SYNTHESIS:-

1) Divergent method.

2) Convergent method.

3) Hypercores & branched monomers method.

4) Double Exponential And Mixed Growth.

5) Other accelerated growth technique.

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Core surface activation Dendrimermolecule

Dendrimers starts from the central core and extends toward the surface

i.e. diverging into space.

Two step process:

Activation of functional surface groups

Addition of branching monomers units.

Divergent approach is successful for the production of large quantities

of dendrimers. It causes some difficulties in the purification of the final product.

1) Divergent method

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Surface unit Monomers Core molecule Dendrimer

2) Convergent method

Dendrimer starting from the end groups and progressing inwards.

When the growing wedges are enough large, attached to a suitable core

to give a complete Dendrimer.

The convergent methodology also suffers from low yields in the

synthesis of large structures.

Advantages:

1.Relatively easy to purify the desired product.

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3) Hypercores & Branched Monomers TechniqueFrechet group continued their efforts on research of

hypercore & branchad monomers.

This method involves the pre assembly of oligomeric species, which can then be linked together to give dendrimer.

These monomers allow the to design synthetic strategies that are more convergent in classical synthetic sense of world.

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4) ‘Double Exponential’ And ‘Mixed’ Growth Double exponential growth, similar to a rapid growth

technique for linear polymers, involves an AB2 monomer with orthogonal protecting groups for the A and B functionalities.

This approach allows the preparation of monomers for both convergent and divergent growth from a single starting material.

These two products are reacted together to give an orthogonally protected trimer, which may be used to repeat the growth process again.

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This is two step approach designed by frechet. In this approach two different monomers are used so as to

avoid the need of an activation step between growth steps.

The two monomeric units are AB2 &CD2.where A&D reacts to form bond under required conditions while B&C are stable, where B&C reacts to form bond while A&D remain stable.

In this technique the hindrance likely to be experienced is that difficulty of finding a set of reactions,which conform to above criteria.

5) Other Accelerated Growth Techniques

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The first synthesized dendrimer was Polyamidoamines(PAMAMs)

They are also known as starbust dendrimers.

Ammonia is used as the core molecule & In the presence of methanol, it reacts

with methylacrylate and then ethylenediamine is added By repeating .

The Michael addition & amidation reaction step by step, high generation

dendrimers can be obtained .

Due to their multivalent and monodisperse character, dendrimers have wide

interest in the field of chemistry and biology, especially in applications like drug

delivery, gene therapy and chemotherapy.

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Mechanisms of Drug Delivery Simple encapsulation:-It directly encapsulates guest

molecules into macromolecule interior.

Electrostatic interaction:-Surface functional groups enhances solubility of hydrophobic drugs by electrostatic interaction e.g. Ibuprofen, ketoprofen, indomethacin.

Covalent conjugation:-The drug is covalently bound to dendrimers & its cleavage occurs via chemical or enzymatic cleavage of hydrolytically labile bonds. It allows tissue targeting & controlled delivery as drug-dendrimer conjugate diffuse slower than the free.

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GENERATION:- The number of focal points when going from the core towards the

dendrimer surface is the generation number.

That is a dendrimer having five focal points when going from the centre to the periphery is denoted as the 5th generation dendrimer.

Here, we abbreviate this term to simply a G5-dendrimer, e.g. a 5th

generation polypropylene imine is abbreviated to a “G5-PPI- dendrimer.”

Intermediates during the dendrimer synthesis are sometimes denoted

half-generations, a well-known example is the carboxylic acid-terminated PAMAM dendrimers.

Diameter of dendrimer with an ethylenediamine core increases from 1.1 to 12.4 nm.

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PAMAM dendrimers of low generation,G0-G3, have ellipsoidal shapes.

PAMAM dendrimers of high generations,G4-G10, with well defined cavities have roughly spherical shapes.

TYPES OF DENDRIMERS

1) PAMAM Dendrimers2 ) PAMAMOS Dendrimers3 ) PPI Dendrimers4) TECTO Dendrimers5) MULTILINGUAL Dendrimers6 ) CHIRAL Dendrimers7 ) HYBRID Dendrimers linear polymers8) AMPHIPHILIC Dendrimers 9) MICELLAR Dendrimers 10) MULTIPLE ANTIGEN PEPTIDE Dendrimers11) FRECHET-TYPE Dendrimers

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Properties Of Dendrimers

Sr. No

Property Dendrimers Linear Polymers

1 Structure Compact, Globular Not compact

2 Synthesis Careful & stepwise growth

Single step polycondensation

3 Structural control Very high Low

4 Architecture Regular Irregular

5 Shape Spherical Random coil

6 Aqueous solubility

High Low

7 Nonpolar solubility

High Low

8 Viscosity Non linear relationship with molecular weight

Linear relation with molecular weight

9 Reactivity High Low

10 Compressibility Low High

11 Polydispersity Monodisperse Polydisperse 19

CHARACTERIZATION OF DENDRIMERS POLYMERS :-

1. Spectroscopy and Spectrometry Methods

2. Scattering Techniques

3. Electrical Techniques

4. Size Exclusion Chromatography

5. Microscopy

6. Physical Properties & Rheology

7. Miscellaneous

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APPLICATIONS

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REFERENCES“Advances in Controlled & Novel Drug Delivery”, 1st

edition 2001,by Jain N.K,CBS Publications, New Delhi,361-

376.

“Encyclopedia of Pharmaceutical Technology”, vol-18,by

James swarbrick, Marcel dekker inc,55-89.

“ Journal of Pharmaceutical sciences”, vol-97,No-1. January

2008,by American Pharmacists Association,123-143.22

“Journal of Pharmaceutical sciences”, vol-98,No-1. January

2009,by American Pharmacists Association,1-26.

http://en.wikipedia.org/wiki/dendrimer.

http://www.actabp.pl/pdf/1_2001/199-208.pdf.

http://www.pharmainfo.net/reviews/dendrimer-overview.

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