Dapus 4 PDF
Dapus 4 PDF
Dapus 4 PDF
Review Article
1980’s by Donald.1 These hyperbranched Ideally targeted drug delivery system should
molecules were called dendrimers. The term have following characteristics:
originates from ‘dendron’ meaning a tree in
Greek. At the same time, Newkome’s group.2 Should be biochemically inert (non-toxic)
Should be non-immunogenic.
Tomalia and co-workers, in the beginning the Should be physically and chemically stable
research on dendrimers focused on the synthesis, in vivo and in vitro conditions.
characterization, and properties of perfect Should have restricted drug distribution to
dendrimers of higher generations. For the target cells or tissues or organs and should have
synthesis of dendrimers constructed by step-by- uniform capillary distribution.
step sequences, two fundamentally different Should have Controllable and predictable
strategies, the divergent approach and rate of drug release and also Drug release should
convergent approach, were employed.3 not affect the drug action.
Dendrimer chemistry is a rapidly expanding Should have therapeutic amount of drug
field for both basic and applicative reasons. release.
From a topological viewpoint, dendrimers Should have minimal drug leakage during
contain three different regions: core, branches transit.
and surface. Another important property of Carriers used should be bio-degradable or
dendrimers is the presence of internal cavities readily eliminated from the body without any
where ions or neutral molecules can be hosted. problem.
Such a property can potentially be exploited for The preparation of the delivery system
a variety of purposes, which include catalysis should be easy or reasonably simple,
and drug delivery.4 reproductive and cost effective.5
Types of drug targeting
Targeted drug delivery
These two approaches are used for drug
Target drug delivery system may also be targeting. An ideal targeted drug delivery
referred to as smart drug delivery system.8 Is the approach would not only increase therapeutic
currently used form of drug delivery system efficacy of drug but also decrease the toxicity
where the pharmacologically active drug (or associated with drug to allow lower doses of the
pro-drug in some cases) is targeted or is drug to be used in therapy.6
delivered specifically to the site of action.
Targeted drug delivery extensively used for Active targeting
selective and effective localization of
pharmacologically active moiety at pre- Active targeting means a specific ligand–
determined target in therapeutic concentration, receptor type interaction for intracellular
while restricting its access to non-target normal localization which occurs only after
cellular linings, thus minimizing toxic effects bloodcirculation and extravasations. This active
and maximizing therapeutic index. Targeting of targeting approach can be further classified into
drugs also help us to bypass first pass three different levels of targeting which are,
metabolism so a drug can be administered in a
form such that it reaches the receptor sites in First order targeting refers to restricted
sufficient concentration without disturbing in distribution of the drug carrier systems to the
extraneous tissue cells. Products based on such a capillary bed of a predetermined target site,
delivery system are being prepared by organ or tissue e.g. compartmental targeting in
considering the Specific properties of target lymphatics, peritoneal cavity, plural cavity,
cells, Nature of markers or transport carriers or cerebral ventricles and eyes, joints.
vehicles, which convey drug to specific
Second order targeting refers to selective
receptors and Ligands and physically modulated
delivery of drugs to specific cell types such as
components.5
tumour cells and not to the normal cells e.g.
Passive targeting
immunoglobulins which are fixed by dendrimers The divergent growth reaction of dendrimer can
to a sheet of glass. The result shows if there is be shown in Figure 2.23
any heart (2.5 and 3.5) are weaker.
Anionic dendrimers, bearing a carboxylate
surface, are not cytotoxic over a broad
concentration range.11
Dendrimers are Inert and non-toxic.
It is Biodegradable.
Non-immunogenic.
Able to cross barriers such as intestine,
Figure 2: Divergent method.23
blood-tissue barriers, cell membranes etc.
Able to stay in circulation for the time Convergent method
needed to have a clinical effect.
Able to target to specific structures. Convergent dendrimer growth begins at what
Compatible with guest molecules. will end up being the surface of the dendrimer,
Must protect the drug until it reaches to the and works inwards by graduall- y linking surface
desired site of action and release the drug.12 units together with more. When the growing
wedges are large enough, several are attached to
Types of dendrimers a suitable core to give a complete dendrimer.
convergent growth method has several
Dendrimer can be differentiated on the basis of advantages like relatively easy to purify the
their shape, end functional groups and internal desired product, occurrence of defects in the
cavities which can be classified in Table 1.13-20 final structure is minimised, does not allow the
formation of high generation dendrimer because
Technology of dendrimers stearic problems occur in the reactions of the
production dendrons and the core molecule.21
2. PPI (Poly Divergent Asramol by Its core structure is based on Di amino butane with
Propylene DSM primary amines as end groups and tertiary
Imine ) (Netherlands) propylene amines as center. These are
Dendrimer commercially available up to G-5 and are
extensively used in material science and biology.16
3. Chiral Convergent chiral The chirality of the dendrimers was based
Dendrimer dendrimers upon the building of constitutionally different but
derived from chemically alike branches
pentaerythritol to chiral core.17
4. Multilingual Convergent VivaGel These are the dendrimers which hold multiple
Dendrimers copies of a particular functional group on their
surface.18
5. Tecto Divergent Mercapto These were made up of core dendrimers, which
Dendrimers can be surrounded by other dendrim-ers, which
execute a specific function leading to a smart
therapeutic system used for diagnose the diseased
state and deliver API to the accepted diseased
cell.18
6. Hybrid Divergent Hybrid dendritic These dendrimers have characteristic of both
Dendrimers linear polymer, dendritic and linear polymer.18
Polysilsesquioxa
nes
7. Peptide Convergent Beta Peptide dendrimers are those which hold amino
Dendrimers Casomorphin acid as branching or interior unit.
(human) These are used for the diagnostic purpose and
vaccine delivery.19
8. Frechet-Type Convergent Frechet type These were based on polybenzyl ether hyper
Dendrimers dendron azides, branched skeleton. Carboxylic
TM acid group attached on the surface of dendrimers
Priostar that provides site for further functionalization and
also improve the solubility of dendrimers.19
9. PAMAMOS Convergent SARSOX These are silicon containing commercial
(Poly and dendrimers which are inverted unimolecular
Amidoamine Divergen micelles and contains exterior hydrophobic
Organosilicon) organosilicon (OS) and interiorly hydrophilic,
Dendrimers nucleophilic polyamidoam-ine.19
10. Multiple Convergent vaccine and These are dendron-like molecular assembly
Antigen and diagnostic based upon a polylysine frame. Lysine with its
Peptide Divergent research alkyl amino side-chain performed as a excellent
Dendrimers monomer for the overture of frequent branching
points.20
Hypercores and branched monomer growth bonds. covalent attachment of drugs to the
surface groups of dendrimers through chemical
This method involved the pre-assembly of bonds offers the opportunity for a better control
oligomeric species which can be linked organic over drug release than that can be achieved by
methodologies.25 In this approach two products simple encapsulation/electrostatic complexation
(monomers for both convergent and divergent of drugs into/with the dendrimers. Naturally, a
growth) are reacted together to give an problem may arise as a consequence of coupling
orthogonally protected trimer, which may be large numbers of drugs to the dendrimer surface
used to repeat the growth process again. by covalent conjugation,that is, the insolubility
Strength of double exponential growth is more of the resultant product.This problem often can
subtle than the ability to build large dendrimers be resolved through the concomitant attachment
in relatively few steps.22,11 of short PEG chains.28
Click chemistry
2. Effect of Salt High High concentration of salt have a strong effect on charged PPI
dendrimers. Favours a contracted conformation of
dendrimers, with a high degree of back-folding somewhat
similar to what is observed upon increasing pH or poor
solvation.
3. Effect of Solvent The solvation power of any solvent to solvate the dendrimer
is a very important parameter.
Dendrimers of all generations generally exhibit a larger extent
of back-folding with decreasing solvent quality.
The dendrimer arms induce a higher molecular density on the
dendrimer
surface.
NMR studies performed on PPI dendrimers concluded that a
nonpolar Solvent like benzene, poorly solvates the dendrimers
favouring intramolecular interactions between the dendrimer
segments and back-folding.
Diagnostic application