DENDRIMERS

The term “dendrimer” is derived from the Greek words “dendron” means tree or branches and “meros” means part.

It was introduced in 1984 by Donald A. Tomalia.

INTRODUCTION

Highly branched macromolecule

Capable of encapsulatingHigh loading capacityBackbone of Carbons or

NitrogensMonodisperse and

controllableHighly stable Low immunogenicity and

toxicity

What is a Dendrimer

The structure is highly defined and organized.

Dendrimers posses 3 distinguishing architectural components:

1) Initiator core. 2) Interior layers. 3) Terminal functionalities.

STRUCTURE

They start from a core molecule with at least 3 chemically reactive arms.

To these arms, branches are attached. - Repeated many time

•Branches extend from core to periphery.

•Large dendrimers adopt a globular shape, in which all bonds converge to a focal point

•“Star Burst Effect”.

Monodispersive.

Exact same molecular weight and structure.

Peculiar behaviour of intrinsic viscosity

PROPERTIES

The terminal groups affect solubility and viscosity

The outer surface area of the molecule increases with the number of generations

There are void space within the molecule.

These unique geometries give the molecule special properties such as ability to entrap foreign molecules (drugs).

Two common delivery systems

1. Liposome 2. Polymers

Poor stability Difficulty in targeting Toxicity Reduces circulation time

COMPARISONS

ENTANG L EMENTS

Dendrimers Linear Polymers

less entanglements more entanglement

.

Architecture

Dendrimers Linear Polymers

Dendritic architecture Linear architecture

has been shown as has not been shown

elegant, uniform, as elegant and can be

spherical and as visualized as

“green peas” “ cooked spaghetti”.

e.g. e.g Polyether linear

Polyether dendrimer. polymer

S ize / Po lyd ispers i ty

Dendrimers L inear PolymersHave certain size, Does not have

monodisperse certain size and are , . usually poly disperse.

Solubility

Dendrimers Linear PolymersMore solubility in Less soluble than organic solvent in analogous

dendrimercomparison to the in organic solventanalogous linear e.g. phenylene

linear polymer e.g. analogue.1, 3, 5 phenylene based dendrimer.

SYMMETRY

Dendrimers Hyper branched Polymers

Monodispersible regular P olydispersible , neither

and highly symmetrical. regular nor symmetrical.

SYNTHESIS

Obtained by careful , Obtained in a single step

stepwise growth of by poly condensation of

successive an A2B monomer.

generations.

SYNTHESIS

There are two defined methods of dendrimer synthesis:

-Divergent -Convergent growth approach.  In the divergent method the molecule is

assembled from the core to the periphery.

In the divergent method, the surface groups initially are non-reactive or protected species which are converted to reactive species for the next stage of the reaction.

In the convergent approach the opposite holds, as the reactive species must be on the focal point of dendritic wedge.

DIVERGENT APPROACH

This type of synthesis involves two steps:

( 1 ) The activation of functional surface groups.

( 2 ) Addition of branching monomer units.

Divergent Synthesis

ADVANTAGE

The advantage of this method is the ability to modify the surface of the dendrimer molecule.

In successive generation growth, side reactions and incomplete additions become more apparent. This is due to steric hindrance.

The overall yield is considerably small

The outer generation has only one kind of functional group.

Disadvantages

Convergent Growth Method•The difficulty of many reactions that have to be performed on one molecule is overcome by starting the synthesis at the periphery and ending at the core.

•In this method, growth begins at what will become the periphery of the final macromolecule and proceed inward, the final reaction being attachment to a polyfunctional core.

It involves the attachment of the outermost functional group to an inner generation and the attachment of the inner generation to the core.

The structural units before the final attachment to the core is called the wedge.

Usually 3 to 4 wedges attach to the core. Each wedge can have different functional groups at periphery.

Convergent Synthesis

Advantage of this method over “divergent growth” approach :-

control over surface functionality.

Ease for purification.

LIMITATIONS

More susceptible to steric inhibition at the focal point group.

This effectively limits the size of the

macromolecules that may be prepared in conventional fashion.

.

Comparison Between Divergent And Convergent Growth

Convergent approach affords better control to obtain a better dendrites architecture than the divergent approach.

Divergent approach is for large scale production.

Both involve stepwise processes that are tedious and time consuming.

DENDRIMERS AS DRUG CARRIER S

The well-defined structure, compact globular shape, size monodispersity and controllable ‘surface’ functionalities of dendrimer makes them excellent candidates for evaluation as drug carriers.

They can be used as drug delivery agents in 2 ways

(1) Drugs molecules can be physically entrapped inside

  the dentritic structure.

(2) Drug molecules can be covalently attached onto

  surface or other functionalities to afford dendrimer

drug conjugates.

The internal ‘cavity’ of the dendritic structure can be used for the entrapment drugs.

( I ) FIRST STRATEGY: - First strategy for the encapsulation of the guest

molecules in dendrimers is physical encapsulation.

PHYSICAL ENTRAPMENT

Held by Van der Waals or dipole moments

Carrier compounds do not have to be solublized

Encapsulation

1. Targeted delivery would be difficult to achieve because drug release occurred by dialysis.

2. Difficult to make universal for all drugs, because encapsulation by the dendrimer varied significantly depending on drug and the dendrimer structure.

Disadvantages

The second strategy for the encapsulation of guest molecules in dendrimers is based on multiple non- covalent chemical interactions, such as hydrogen bonding between guest molecules and dendritic structure.

Sustained release is possible.

( II ) Second Strategy

The third and the most easily implemented startegy for the encapsulation of drug molecules in dendrimers is making use of hydrophobic interactions

  Newkome et al. prepared dendritic

macromolecules with a hydrophobic interiors and hydrophilic chain ends.

These molecules were said to behave as unimolecular micelles capable of solubilizing various hydrophobic compounds in aqueous solution.

 

( III ) Third Strategy

e.g.:- Poly (aryl ether) dendrimers bearing carboxylic groups as chain ends are able to enhance the water solubility of the hydrophobic compound such as pyrene and anthracene.

 

Higher generation dendrimers have a greater number of end groups that can be functionalized

Longer retention time in blood – PEG Targeting – ability to attach to certain tissues or active sites

Imaging – Fluorescence, MRI, or X-rayDrug CarrierTherapeutic – used to detect disease while in body

Functionalized Dendrimers

Functionalized Dendrimer

NuclearDisassembly

Proteins

+

SelfAssembly

mRNA

EndosomalEscape

CytoplasmicDegradation

Endocytosis

mRNA

Transcription

LysosomalDegradation

NuclearTransport

NuclearTransport

Ribosome

NuclearDisassembly

DNA

CytoplasmicDisassembly

PolyplexReducible polycationSS SS SS

SHHS

SHHS

SH HS

NuclearDisassembly

Proteins

+

SelfAssembly

mRNA

EndosomalEscape

CytoplasmicDegradation

Endocytosis

mRNA

Transcription

LysosomalDegradation

NuclearTransport

NuclearTransport

Ribosome

NuclearDisassembly

DNA

CytoplasmicDisassembly

PolyplexReducible polycationSS SS SSSS SS SS

SHHS

SHHS SHHS

SH HSSH HS

Applications in gene delivery

Dendrimers as Cancer Therapy

Cell deathmonitorReporter

Therapeuticagent

Cancerdetector

Watermolecule

Nanodevces

A single dendrimer can carry a molecule that recognizes cancer cells,

A therapeutic agent to kill those cells,

A molecule that recognizes the signals of cell death

YOU

T HANK