Dendrimers: A Novel Approach for Drug Delivery to Cancer
New drug delivery technology that could improve the treatment of cancer, avoid side effects and even report back on the success of treatment. Dendrimers belong to a novel and exciting class of highly branched three-dimensional polymers.
Dendrimers: A Novel Approach For Drug Delivery
Sourabh K Jain, Rajendra Jangde, Dr. S. Saraf, Dr. Swarnlata Saraf* * Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur (C.G)Email- This email address is being protected from spambots. You need JavaScript enabled to view it.
Abstract-
Dendrimers belong to a novel and exciting class of highly branched three-dimensional polymer in which growth emanates from a central core molecule such as ammonia, ethylenediamine, and polydiamine or benzene tricarboxylic acid chloride. Compared with traditional linear polymers, dendrimers have much more accurately controlled structures with a globular shape, a single molecular weight rather than a distribution o molecular weight and a large number of ‘controllable’ peripheral functionalities.
In recent years, there has been an increasing interest in the field of dendrimers. In particular, the intrinsic connectivity of the dendrimer such as the multivalency of the focal core and the multiplicity of the branches, both controlling the geometrical rate of growth, or the dendritic generation, plays a crucial role and influences at various stages the subtle relationships between the supermolecular structure and the mesophase structure. Stability Dendrimers belong to a novel and exciting class of highly branched three-dimensional polymer in which growth emanates from a central core molecule such as ammonia, ethylenediamine, and polydiamine or benzene tricarboxylic acid chloride. Compared with traditional linear polymers, dendrimers have much more accurately controlled structures with a globular shape, a single molecular weight rather than a distribution of molecular weight and a large number of ‘controllable’ peripheral functionalities. They are truly nanoscale molecules with sizes ranging from 10–30 Å. and the excitement associated with this class of polymers is mainly because of their applications as synthetic vector systems for gene delivery. Polyaminodiamine (PMAM) is a promising polycationic polymer from this class that can form complexes with the negatively charged nucleic acids; additionally, the surface positive charge can interact and fuse with phospholipids of the cell membrane, thereby facilitating the translocation of DNA into cells.
Introduction
The term dendrimer is derived from the word dendron a Greek word for tree/branches, due to its resemblance with a tree and meros means part. Dendrimers posses three distinguishing architectural component: an interior core, interior layers [generations] and exterior [terminal] functionality. Dendrimer, from the Greek word “dendron” for tree, refers to a synthetic, three-dimensional molecule with branching parts. Dendrimers are formed using a nano-scale, multistep fabrication process. Each step results in a new “generation” that has twice the complexity of the previous generation - a first generation dendrimer is the simplest; a tenth generation dendrimer is the most complex and can take months to prepare. Donald Tomalia, a researcher working for chemical giant Dow, first synthesized and named dendrimers in 1979. Dendrimer are also known by various names such as -Cascade molecules, Arborols, Dendritic molecule, Starburst polymers [1].
Biomedical benefits
Commercial development of dendrimers has been slow because of the difficulty of scaling-up production and because their cost is prohibitively high. Diagnostic-grade, tenth generation dendrimers go for US$1,650/100mg. A new, copper-catalyzed process for dendrimer synthesis announced in 2004 has reportedly increased yields. Dendritic Nanotechnologies has reportedly filed for patents on a new, one-step process to synthesize dendrimers, which could potentially drive down the cost of production. Dendrimers are “stealth molecules” that have many potential applications, including diagnostic and therapeutic applications. By customizing and controlling dendrimer “architecture,” nanotechnologists are developing dendrimers for drug delivery, diagnostic imaging and as carriers of genetic material. Dendrimers can easily move across biological membranes and they can store a wide range of metals, organic or inorganic molecules among their branches. Companies developing these synthetic molecules claim that most dendrimers don’t trigger the immune system when injected or used topically, and have low cytotoxicity that is, toxicity to cells [3]. However, some forms of dendrimers can induce clotting in the bloodstream - a potential concern for in vivoapplications. Structural uniformity and monodispersity. Better/greater targeting efficiency. The surface modification may allow to design dendrimers mimicking biological exo recepter, substrates, inhibitors or cofactors. Similarity structures with IgM antibodiesDeliver the drug inside the cell or they may improve intracellular trafficking. Capability to variety of drugs shaving different types of functional group. Dendrimers can be made stimuli responsive.dendrimers have limited toxicity and immunogenicity but good biodegradability. They have better colloidal, biological and self-stability. They may be intrinsically anticancer agent [4]. Dendrimers could also be used in coatings and materials, electronics and photonics. A look at the patent assignees for dendrimer technology reveals the wide range of potential applications - patents are assigned to chemical, petroleum, tire, cosmetics and pharmaceutical companies, among others [5] . [2]
Dendrimer-based products:
A dendrimer-based tool for detecting cardiac damage is being developed by Dade Behring, one of the world’s largest medical diagnostic firms [6]. The world’s first drug based on dendrimers, developed by Australian-based Starpharma, is a topical gel for use as a “liquid condom” to reduce the risk of HIV infection in women. StarPharma’s “VivaGel” microbicide has gone through initial animal testing and phase-one safety trials in humans. The US Army Research Laboratory is developing a dendrimer-based anthrax detection agent, dubbed “Alert Ticket”; ExxonMobil owns patent 5,906,970 on a “flow improver” based on dendrimer technology - an additive that will increase the flow of oil in cold temperatures [7].
Preparation of dendrimers
1) Divergent growth method- dendrimer synthesis based on Divergent growth method exhibit the unique feature of transferring molecular level information from the initiator core generation to generation for that reson these constructions are referred to as genealogically directed synthesis. In these methods the core is reacted with two or more moles of reagent containing atleast two protecting branching sites, followed by removal of the protecting groups.the subsequent liberated reactive sites lead to the first generation dendrimer. This process is repeated until the dendrimer of the desired size obtained. For eaxmle poly (amidoamine) starburst dendrimer prepared by divergent method [8].
2) Convergent growth method – This is an alternative approach to dendrimer synthesis. The difficulty of many reactions that have to be performed on an one molecules overcome by starting the synthesis at the periphery and ending at the core.convergent method involve two stages: a reiterative coupling of coupling of protected/deprotected branched to produce a focal point functionalized dendron,followed by a divergent core anchoring step to produce various multidendron dendrimers[8].Structure validation of dendrimers -it is done by Thin layer chromatography, Infra red spectroscopy End group determination [Aqueous titration /Non Aqueous titration] HPLC, Encapsulation of drug in dendrimer C, H, N analysis Mass spectroscopy Low angle laser light scattering Vapour phase osmometry Size exclusion chromatography Electron microscopy IR 15N, 13C and 1H NMR spectroscopy Titrimetry Electrospry ionization (ESI) Matrix assisted laser desorption ionization (MALDI) [9]ApplicationsCapping dendrimer surface with amino acid could irreversibly solublize up to 4 molecules of Bengal rose and 8-10 molecules of 4 nitro benzoic acid per molecules of dendrimer .the solubility of myoglobin in dimethyl formamide was dramatically increased with first generation dendrimer probably because of binding of lipophilic dendrimer at protein surface gene have been complexed with different generation of dendrimer thorough electrostatic interaction of their terminal amines with the the phosphate group of DNA molecules it is also important for non viral gene delivery.High charge density on dendrimers used for making methotrexate –dendrimer was found to be pH dependent and remain stable at physiological pH complex/conjugates for improve cancer therapy. Dendrimers based metal chelate as magnetic resonance imaging contrast agents. Dendrimers also used as vaccine, artificial protein and enzymes. Starburst dendrimers for enhanced performance and flexibility for immunoassays Dendrimers are isotropically soluble functional polymer can be used steric isolation of metalloporphyrin, which is important to achieve certain biological function [10].
Conclusion
The future of dendrimer drug delivery lies is fine tuning the carrier to incorporate variety of drugs and complex protein to ensure the vectorization of dendrimer-complex\conjugates to desired cells\tissues. The major focus will be on development of dendrimer based on new concept of biommetism\biomorphism with plasma stability and capability to target cell in various body compartments. Novel supramolecular structures based on polyethylene oxide copolymers and dendrimers are being intensively researched for delivery of genes and macromolecules. Hydrogels that can respond to a variety of physical, chemical and biological stimuli hold enormous potential for design of closed-loop drug-delivery systems. Design and synthesis of novel combinations of polymers will expand the scope of new drug-delivery systems in the future.
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