Post on 17-May-2015
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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