INTRODUCTION:^[1-4]

The term dendrimer is originated from the Greekword ‘Dendron’ which means tree like and ‘meros’ which means parts or unit. Dendrimers are tree like in structure and appearance. It has a three dimensional structural symmetry. A large number of branches during polymer synthesis lead to formation of macromolecule with many end groups. Out of highly branched polymers, dendrimers are perfectly branched uniform structure and hyper branched polymers are randomly branched.

A generally accepted definition of dendrimer is a monodisperse macromolecule with perfectly branched regular structure and having at least one branched junction at each repeat unit. However it is difficult to place, dendritic polymers, especially Dendron’s and dendrimers, definitely in any branch of chemistry. They are sometimes described in terms of supramolecular chemistry or polymer chemistry, although in some cases they are neither supramolecule nor polymer in reality. However they are treated as macromolecules. A structurally perfect dendrimer has monodispersity, defined molecular size, and defined number of end groups. Nano architecture with shell structure, structural precision, hydrophilic or lypophilic balance by design, accessible molecular surface and good flexibility; which offers researchers possibility to work in that particular area. Using distinct properties of the dendrimer in architecture; photo physical, photochemical, electrochemical or catalytic functions at the core of dendrimers have placed active sites for researchers. Present review will have more focus on recent studies and many important applications of dendrimers in various fields of science.

Fig 1: ‘Dendrimer’, ‘Dendron’

PROPERTIES:^[5,6]

(1) Dendritic polymers that can be constructed with a well-defined molecular structure, i.e. being mono-disperse, unlike to linear polymers.

(2) Nanoscale sizes that have similar dimensions to important bio-building blocks, e.g., proteins, DNA.

(3) When dendrimer surfaces modified with small functional groups or polyethylene glycol (PEG) show non or low-immunogenicity.

(4) Ability to arrange excretion mode from body, as a function of nanoscale diameter.

(5) An interior void space may be used to encapsulate small molecule drugs, metals, or imaging moieties, reduces the drug toxicity and facilitates controlled release.

(6) Numbers of terminal surface groups suitable for bioconjugation of drugs, signaling groups, targeting moieties or biocompatibility groups.

(7) Surfaces that may be designed with functional groups to resist trans-cellular, epithelial or vascular bio permeability.

(8) Dendrimers are monodisperse macromolecules. Size and molecular mass of dendrimers can be specifically controlled during classical polymerization process.

(9) When the molecular mass of dendrimers increases, their intrinsic viscosity goes through a maximum at the fourth generation and then begins to decline.

(10) The presence of many chain-ends is responsible for high solubility and miscibility and for high reactivity.

(11) Dendrimer solubility is strongly influenced by the nature of surface groups.

(12) The dendrimer should be: nontoxic, on-immunogenic, able to cross bio barriers (biopermeable), able to stay in circulation for the time needed to have a clinical effect and able to target to specific structures.

HISTORY OF DENDRIMER:^[7-11]

Dendrimers are an attractive exclusive class of polymers with controlled structure. A dendrimer is both a covalently assemble molecule and also a distinct nanoparticle. The first dendrimers be completed by divergent synthesis advanced by FritzVogtle in 1978, R.G. Denkewalter at Allied Corporation in 1981, Donald Tomalia at DowChemical in 1983 and in 1985, and by George Newkome in 1985. In 1990 a convergent synthetic approach was introduce by Jean Fréchet. A lot of research has already been completed by studying the different properties and application of dendrimers but a lot of researchers still believe it to be in its initial stages.

TYPES OF DENDRIMERS:^[12-17]

(1) Radially layered poly (amidoamineorganosilicon) 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, lectronics, photonics, chemical catalysis etc. and useful precursors for the preparation of honeycomb like networks with nanoscopicPAMAM and OS domains.

(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 ingeneration G 0-10 with 5 different core type and 10 functional surface groups.

(3) Poly (Propylene Imine) dendrimers (PPI):

Poly (Propylene Imine) dendrimers (PPI) generally having poly-alkyl amines as end groups, and numerous tertiary trispropylene amines present in interior portion. It commercially available up to G5, and wide applications in material science as well as in biology.PPI dendrimers are available as Astramol TM.

(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.

(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) Tectodendrimer:

TectoDendrimer are composed of a core dendrimer, perform varied functions ranging from diseased cell recognition, 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 soluble hyper branched polyphenylenes micelles.

SYNTHESIS OF DENDRIMER:^[18-24]

· Divergent growth method

· Convergent growth method

· Hyper cores and branched monomers growth

· Double exponential growth

First two are the Main two methods for synthesis of dendrimers.

a) 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 (PAMAM), also known as starbust Dendrimers.

(b) 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 An advantage of convergent growth over divergent growth is that purification Is done after each step whereas in divergent method since the reactant and product remains same it is difficult to purify by chromatographic technique. several advantages like relatively easy to purify the desired product, occurrence of defects in the final structure is minimized, does not allow the formation of high generation dendrimer because stearic problems occur in the reactions of the dendrons and the core molecule.

Linkage of the oligomeric species in a radial, branch-upon-branch. Core is reacted with two or more moles of reagent containing at least two protecting branching sites, followed by removal of the protecting groups. The subsequent liberated reactive sites lead to the first generation Dendrimers.

Fig 4: ‘Hypercores’ & ‘Branched’ monomer growth

(d) Double Exponential’ or mixed growth

In this approach two products (monomers for both convergent and divergent growth) are reacted together to give an orthogonally protected trimer, which may be used to repeat the growth process again. Strength of double exponential growth is more subtle than the ability to build large dendrimers in relatively few steps.

Fig 5:Double exponential growth

APPLICATION OF DENDRIMERS:^[25-32]

Therapeutic Application:

Dendrimer in photodynamic therapy

Dendrimers for Boron Neutron capture therapy

Diagnostic Application:

Dendrimers as MRI contrast agent

Dendrimers as X-Ray contrast

Dendrimer as molecular probe agent

Pharmaceutical Application:

Dendrimers in pulmonary drug delivery

Dendrimers in Transdermal drug delivery

Dendrimers in ocular drug delivery

Dendrimers in oral drug delivery

Dendrimers for controlled release drug delivery

Dendrimers in targeted drug delivery

Dendrimers in gene delivery

Dendrimers as solubility enhancer

Cellular delivery using dendrimers carrier

Dendrimers based product in cosmetics

Dendrimers based commercial products

Dendrimers in Gene Delivery:

Dendrimers can be use as a carrier in gene therapy. Example- PAMAM dendrimers have terminal amino groups which interact with phosphate group of nucleic acid. So PAMAM have been tested as a genetic material vector [15 Super Fect TM is a transfection reagent, it consist of activated dendrimers. Activated dendrimers carry a large amount of genetic material than viruses.

Dendrimers as solubility enhancer:

Dendrimers are unimolecularmicellar in nature because these have both hydrophobic and hydrophilic layer. Hydrophylic layer forms the outer surface. Dendrimers do not have a critical micelle concentration. Due to these properties dendrimers enhance the solubility of poorly soluble drug by forming covalent. Non-covalent complexes with drug molecules and hydrophobes.

Dendrimers as cellular drug delivery carrier:

Pure drug entered into the cell in 3 hours but the dendrimers ibuprofen complexes entered into the cell in 1 hour. So these results show that dendrimers can carry the complex drug efficiently inside the cell.

Dendrimers in targeted and controlled release drug delivery:

The dendrimers facilitate the passive targeting of drug to solid tumours. This is due to their enhanced solubility and plasma circulation time. EPR (Enhanced Permiation and Retention) in tumour tissues leads to reduce cytotoxicity of anticancer drug and increased uptake by cancer cell lines.

Dendrimers in cosmetics:

Dendrimers have a great contribution on cosmetics. Various cosmetic industry used dendrimers in the formulation. L’Oreal has a patent for using dendrimers in the production of cosmetics like mascara or nail polish.

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Received on 24.04.2016 Accepted on 17.05.2016

Asian J. Pharm. Res. 2016; 6(3): 188-192.

DOI: 10.5958/2231-5691.2016.00027.7