DENDRIMER : FOR NOVEL DRUG DELIVERY SYSTEM- A REVIEW ARTICLE

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PROPERTIES OF DENDRIMER
Monodispersity

Dendrimers are the class of dendritic polymers that can be constructed with a well-defined molecular structure, i.e. being mono-disperse, unlike to linear polymers. Monodispersity offers researchers the possibility to work with a tool for welldefined scalable size.

Nanoscale size and shape
These fundamental properties have in fact lead to their commercial use for gene therapy, immunodiagnostics and variety of other biological applications.

Polyvalency
Polyvalency shows the outward presentation of reactive groups on the dendrimer nanostructure exterior. This creates more connections between surfaces and bulk materials for applications such as adhesives, surface coatings, or polymer cross-linking. The product, a topical vaginal microbicide called Vivagel™, prevents infection by HIV and other sexually transmitted diseases during intercourse takes advantage of dendrimers polyvalent properties.

Physicochemical properties of dendrimers
The use of dendrimers as protein mimics has been encouraged scientists to investigate the physicochemical properties of dendrimers in comparison to proteins shows that dendrimers, similar to protein, can adapt “native” (e.g. tighter) or “denaturated” (e.g.extended) conformations dependent on the polarity, ionic strength and pH of the solvent.

Biocompatibility of dendrimers
In order to utilize dendrimers as biological agents, they have to fulfill certain biological demands. The dendrimer should be: nontoxic, non-immunogenic, able to cross biobarriers (biopermeable), able to stay in circulation for the time needed to have a clinical effect and able to target to specific structures. The cytotoxicity of dendrimers has been primarily evaluated in vitro;

however, a few in vivo studies have been published [14,15]. Dendrimers with positively charged surface groups are prone to destabilize cell membranes and cause cell lysis. For example, in vitro cytotoxicity, IC50 measurements (i.e., the concentration where 50% of cell lysis is observed) for poly (amidoamine) PAMAM dendrimers with amino surface revealed significant cytotoxicity on human intestinal adenocarcinoma, Caco-2 cells. Comparative toxicity studies on anionic (carboxylate-terminated) and cationic (amino-terminated) PAMAM dendrimers using Caco-2 cells have shown significantly lower cytotoxicity of the anionic compounds [16]. Furthermore, the cytotoxicity was found to be generation dependent with higher generation dendrimers being the most toxic,[17] Some recent studies have shown that amino-terminated PAMAM dendrimers exhibit lower toxicity than more flexible linear polymers carrying amine groups, perhaps due to lower adherence of the rigid globular dendrimers to cellular surfaces. The degree of substitution as well as the type of amine functionality is important, with primary amines being more toxic than secondary or tertiary amines.Lower-generation PAMAM dendrimers possessing carboxylate surface groups show neither haemato-toxicity nor cytotoxicity at concentrations up to 2 mg/ml [18].

Immunogenicity
Immunogenicity is one of the crucial biological properties of the dendrimers. Studies performed on unmodified aminoterminated PAMAM dendrimers showing no or only weak immunogenicity of the G3–G7 Many dendrimer syntheses rely upon traditional reactions, such as the Michael reaction or the Williamson ether synthesis whilst others involve the use of modern dendrimers. However, later studies showed some immunogenicity of these dendrimers and found that modification of aminoterminated PAMAM dendrimers with polyethylene glycol (PEG) chains reduces immunogenicity and gives longer lifetime in the blood stream in comparison to unmodified dendrimers [19]

Advantages of Dendrimer
.Dendrimers offers various advantages over other polymers:
(1)   Dendrimers have nanoscopic particle size range from 1- 100 nm, which makes them less susceptible for reticulum endothelium uptake.
(2)   They have lower polydispersity index, due to stringent control during synthesis. As the density of branches increases the outer most branches arrange themselves surrounding a lower density core in the form of spheres and outer surface density is more and most of the space remains hollow towards core. This region can be utilized for drug entrapment.
(3)   Multiple functional groups are present on outer surface of dendrimers, which can be used to attach vector devices for targeting to particular site in the body.
(4)   Dendrimers can be modified as stimuli responsive to release drug.
(5)   Dendrimers might show an enhanced permeability and retention effect which allows them to target tumour cells more effectively than small molecules.
(6)   They can be synthesized and designed for specific applications. Due to their feasible     topology, functionality and dimensions, they are ideal drug delivery systems; and also, their size is very close to various important biological polymers and assemblies such as DNA and proteins whichare physiologically ideal.[20,21,22]

TYPES OF Dendrimer
(1) Radially layered poly (amidoamine-organosilicon) dendrimers (PAMAMOS)

In 1990, Dr. Petar Dvornic and his colleagues at Michigan Molecular Institute, discovered this unique first commercial silicon containing dendrimers. Consist of hydrophilic, nucleophilic polyamidoamine (PAMAM) interiors and hydrophobic organosilicon (OS) exteriors. Excellent its networks regularity and ability to complex and encapsulate various guest species offer unprecedented potentials for new applications in nanolithography, electronics, photonics, chemical catalysis etc.and useful precursors for the preparation of honeycomblike networks with nanoscopic PAMAM and OS domains.[23,24]

(2) Poly (amidoamine) dendrimers (PAMAM)
Synthesized by the divergent method, starting from initiator core reagents like ammonia or ethylenediamine. When looking at the structure of the high-generation in two-dimensions, star like pattern observed. They are commercially available as methanol solutions and in generation G 0-10 with 5 different core type and 10 functional surface groups.[25,26]

(3) Poly (Propylene Imine) dendrimers (PPI)
Poly (Propylene Imine) dendrimers (PPI) generally having poly-alkyl amines as end groups, and numerous tertiary tris-propylene amines present in interior portion. It commercially available up to G5, and wide applications in material science as well as in biology.[27]PPI dendrimers are available as AstramolTM.

(4) Chiral dendrimers
The chirality in these dendrimers is based upon the construction of constitutionally different but chemically similar branches to chiral core. Their potential use as chiral hosts for enantiomeric resolutions and as chiral catalysts for asymmetric synthesis.[28]

(5) Liquid crystalline dendrimers
A highly-branched oligomer or polymer of dendritic structure containing mesogenic groups that can display mesophase behaviour. They consist of mesogenic (liq. crystalline) monomers e.g. mesogen functionalized carbosilane dendrimers.

(6)   Tecto dendrimer
Tecto Dendrimer are composed of a core dendrimer,perform varied functions ranging from diseased cellrecognition, diagnosis of disease state drug delivery,reporting location to reporting outcomes of therapy.

(7) Hybrid dendrimers
Hybrid dendrimers are hybrids (block or graft polymers) of dendritic and linear polymers. Obtained by complete monofunctionalization of the peripheral amines of a "zero-generation" polyethyleneimine dendrimer, provide structurally diverse lamellar, columnar, and cubic selforganized lattices that are less readily available from other modified dendritic structures.

(8) Multilingual Dendrimers
Multilingual Dendrimers contains multiple copies of a particular functional group on the surface.

(9) Micellar Dendrimers
Micellar dendrimers are unimolecular water solublhyper branched polyphenylenes micelles.

(10) Amphiphilic Dendrimers
Amphiphilic dendrimers are built with two segregated sites of chain end, one half is electron withdrawing andthe other half is electron donating.

(11) Peptide dendrimers
Multiple Antigen Peptide dendrimers is a dendron-like molecular construct, use in biological applications, e.g. vaccine and diagnostic research. Peptide dendrimers can be used as drug delivery, contrast agents for magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), fluorogenic imaging and sero diagnosis.[29]

(12) Frechet-Type Dendrimers
Frechet-Type Dendrimers have carboxylic acid groups as surface groups, serving as a good anchoring point for further surface functionalisation, and as polar surface groups to increase the solubility of this hydrophobic dendrimer type in polar solvents or aqueous media.[30.31]

SYNTHESIS OF DENDRIMER
(1) Divergent growth method

This method was introduced by Tomalia. In this method growth of dendrimers originates from a core site. The core is reacted with two or more moles of reagent containing at least two protecting branching sites, followed by removal of the protecting groups, lead to the first generation dendrimers. This process is repeated until the dendrimer of the described size is obtained. By this approach the first synthesized dendrimers were polyamidoamines (PAMAMs), also known as starbust dendrimers[32]

Divergent method for the synthesis of dendrimer

(2) Convergent Dendrimer Growth
Convergent dendrimer growth begins at what will end up being the surface of the dendrimer, and works inwards by gradually linking surface units together with more. When the growing wedges are large enough, several are attached to a suitable core to give a complete dendrimer. convergent growth method has several advantages like relatively easy to purify the desired product, occurrence of defects in the final structure is minimised, does not allow the formation of high generation dendrimer because stearic problems occur in the reactions of the dendrons and the core molecule.[33]

Convergent method for  synthesis of dendrimer

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