DENDRIMER: A NOVEL SYSTEM IN PHARMACEUTICALS

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ABOUT AUTHORS:
Abhishek Shah*, Gautam Singhvi
Department of Pharmacy, Industrial Research Lab,
Birla Institute of Technology and Science,
Pilani, Rajasthan, India., Pin: 333 031
abhishah200291@gmail.com

ABSTRACT
Dendrimers are a new class of synthetic polymers which have a tree or star shape like structure, with a central core, interior branches and terminal groups which embellish the surface. It can be synthesized by a repetitive step-growth polymerization process. They are highly branched and monodisperse macromolecules. The structure of dendrimers mainly affected to its physical and chemical properties; so, it is widely used in biomedical, pharmaceuticals and industrial applications. In Drug delivery system, dendrimer plays major roles in ophthalmic, topical, transdermal, targeted drug delivery since last decade. Recent progress has been made in the application of biocompatible dendrimers to cancer and AIDS treatment, including their use as delivery systems for potent anticancer drugs such as cisplatin and doxorubicin, as well as agents for both boron neutrons capture therapy and photodynamic therapy. It is alsoinhibiting the entry of HIV and herpes simplex virus (HSV). This review articles giveswhole idea about various dendrimers, its type and its properties. Also it considers brief idea about various dendrimers used in various areas of research, treatment and diagnosis.

REFERENCE ID: PHARMATUTOR-ART-1922

PharmaTutor (ISSN: 2347 - 7881)

Volume 2, Issue 1

Received On: 22/012/2014; Accepted On: 07/01/2014; Published On: 15/01/2014

How to cite this article: A Shah, G Singhvi, Dendrimer: A Novel System in Pharmaceuticals, PharmaTutor, 2014, 2(1), 83-97

INTRODUCTION:
Dendrimers are synthetic macromolecules which can be differentiated from linear polymers by its unique characteristics. It has ‘tree-like’ structure which makes dendrimers distinctive from other polymers. Typical structure of dendrimer consist of a core molecule C, surface molecules S, interior branching, and multiple layers in which first generation G1, second generation G2 as shown in Fig. 1. In 1978, Vogtle produced first dendrimer by synthesis procedure known as a “cascade” synthesis. Interior void space and surface functional groups in dendrimers are well-suited for use as carrier molecules in drug delivery.[1,2] The results of Tomalia’s group efforts on the first dendritic structures of polyamidoamine (PAMAM)[3] notified that the "divergent" synthesis technique provided rich functionality area on the outer surface. In July 2003 the FDA allowed the First clinical trials of a dendrimer based pharmaceutical VivagelTM which is used as Vaginal Gel for preventing HIV. Nowadays so many products like Stratus®CS (Cardiac Marker)[4], Alert TicketTM (Anthrax Detection)[4] and SuperFectTM (Gene Transfection)[5] easily accessible in marketin dendrimer form.

Dendrimer: A Polymeric Macromolecule
The word “dendrimer” originated from two words, the Greek word dendron, meaning tree, and meros, meaning part.[4]Dendrimers are synthesized by a repetitive step-growth polymerization process. For example, diaminobutane core containing Starburst®(Starpharma, Melbourne, Australia) (PAMAM) dendrimers are synthesized with alternating reaction with acrylic acid methyl ester and ethylenediamine.[3] When a dendrimer reaches generation greater than about four during the step-wise synthetic process (depending on its chemistry), it undergoes a significant conformational change and predicts a densely packed globular shape.[6]

Intrinsic viscosity is another important characteristic that distinguishes dendrimers from more conventional polymers.[7] In contrast, dendrimers exhibit a bell-shaped viscosity curve, where viscosity increases at lower generation numbers, reaching a maximum, which corresponds to a change in the conformation and beyond which the intrinsic viscosity decreases at its higher molecular weight (Fig. 2).[8] This feature is very useful in formulation science, as this high molecular weight, higher-generation dendrimers do not tend to be highly viscous therefore handling and formulation is easy compare to other linear polymers. Another one of the important desirability of using dendrimers for delivery systems comes from their property of being highly soluble in a large number of organic solventsso, they are highly suitable in drug delivery vehicle. Also dendrimers are being developed as in vitro as well as in vivo diagnostics, as gene transfection agents.[9]

A single dendrimer is capable of making many binding contacts with multiple copies of a cellular target.This multiplicity of binding is known as multivalency or polyvalency.[10] It is increasingly being recognised to overcome intrinsically weak monovalent interactions, and of generating drugs with totally new activities, modes of action and pharmacokinetic profile. Also a half-life of various drugs which are used for the drug delivery system can be enhanced with the use of different types of dendrimers. Unmodified drug doxorubicin & methotrexate both have 0.5 hr. Half-life while in dendrimer form their half-life is extended up to 34 hr. and >50 hr. respectively.[11]Furthermore insulin-dendrimer shows prolonged suppression of blood glucose in vivo.[11]Although widely researched for more than two decades, only one clinical study is underway using dendrimers as microbicides.[12]

Advantages of Dendrimers
Dendrimers offers various advantages over linear polymers:
i. Dendrimers have nanoscopic particle size range from 1 to 100 nm, which makes dendrimers less susceptible for reticuloendothelial system (RES) uptake.

ii. Dendrimers might show an enhanced permeability and retention effect (depending on their M.W) that allows them to target tumor cells more effectively than any other small molecules.

iii. Multiple functional groups which are present at outer surface of the dendrimers, which can be used to attach vector devices for targeting to particular site in the body.

iv. Dendrimers can be modified as stimuli responsive to release drug.

v. They have lower polydispersity index. As the density of branches increases the outer most branches arrange themselves in the form of spheres, surrounding a lower density core and outer surface density is more; so, most of the space remains hollow towards core. This region can be utilized for drug entrapment.

vi. They are ideal drug delivery systems due to their feasible topology, functionality and dimensions; and also, their size is very close to various important biological polymers and assemblies such as DNA and proteins which are physiologically ideal. [13-15]

Mechanisms of Drug Loading onto Dendrimer Carriers
The internal cavity of an appropriately designed dendritic structure could be used for the entrapment of drugs with the possibility of successive controlled release. Studies by several research groups[16]have shown that the interior of a dendrimer is capable of encapsulating guest molecules. The first strategy for the entrapment of guest molecules in dendrimers is physical encapsulation. It was reported that guest molecules such as Rose Bengal can be physically entrapped in the internal cavity of high generation poly (propylene imine) dendrimers when an amino acid derivative is used to lid each end group of the dendrimer (the ‘dendritic box’).[16]

The second strategy for the encapsulation of guest molecules in dendrimers is based on multiple noncovalent chemical interactions, such as hydrogen bonding, between guest molecules and the dendritic arrangement. Newkomeet al. reported a dendritic host containing multiple hydrogen bonding sites at its core; it was evaluated by 1H NMR titration.[17]

The third, and easily implemented, strategy for the encapsulation of guest molecules in dendrimers makes use of hydrophobic interactions. Newkomeet al prepared dendritic macromolecules with a hydrophobic interior and hydrophilic chain ends (Fig. 3) [17]

PROPERTIES OF DENDRIMER
Various significant properties for dendrimers are there which makes dendrimers more effective and useful in drug encapsulation.

Monodispersity:
Dendrimers are the class of dendritic polymers that can be assemble with a well-defined molecular structure, i.e. being mono-disperse, unlike to linear polymers. Monodispersity offers researchers the opportunity to work with a tool for well-defined scalable size for different types of research work.

Nanoscale size and shape:
These fundamental properties have in actual fact lead to their commercial use for gene therapy, immunodiagnostics and variety of other biological applications like drug delivery, therapeutics and diagnostics.

Polyvalency:
Polyvalency shows the outward arrangement 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. VivagelTMa topical vaginal microbicideprevents infection by HIV and other sexually transmitted diseases during intercourse takes benefit of dendrimers polyvalent properties.[4]

Physicochemical properties of dendrimers
Dendrimers have some unique properties because of their spherical shape and the presence of internal cavities. The most significant one is the possibility to encapsulate guest molecules in the macromolecule interior. Also the use of dendrimers as protein mimics has been optimistic scientists to investigate the physicochemical properties of dendrimers in comparison to proteins shows that dendrimers, similar to protein.[18]

Biocompatibility of dendrimers
In order to using of dendrimers as biological agents, they should be nontoxic, non-immunogenic, able to cross bio-barriers (bio-permeable), able to stay in circulation for the time needed to have a clinical effect and also able to target to specific structures. The cytotoxicity of dendrimers has been chiefly evaluated in vitro; however, a few in vivo studies have been published.[19] Dendrimers with positively charged surface groups is prone to subvert cell membranes and cause cell lysis. Comparative toxicity studies on anionic (carboxylate-terminated) and cationic (amino-terminated) PAMAM dendrimers using Caco-2 cells have shown significantly lesser cytotoxicity of the anionic compounds.[20] Furthermore, the cytotoxicity was found to be generation reliant with higher generation dendrimers are being most toxic.[21] The degree of substitution as well as the type of amine functionality is also very important. Dendrimer with primary amines is being more toxic than secondary or tertiary amines. [22]

Immunogenicity
Immunogenicity is one of the essential biological properties of the dendrimers. As per research of unmodified amino terminated PAMAM dendrimers are showing no or only weak immunogenicity of the G3–G7. PAMAM dendrimers with polyethylene glycol (PEG) chains decrease immunogenicity and gives longer lifetime in the blood stream in comparison to unmodified dendrimers. [23]

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