INTRODUCTION:

Dendrimers

Since the commencement in the late 1970s and early 1980s the unique properties of dendrimers have spawned a whole range of new research areas ranging from drug and gene delivery applications to processing, diagnostics, and nanoengineering¹ .In comparison to the long-established polymers that initiated a materials revolution in the second half of the last century, dendrimers are relative newcomers. Nevertheless, their special properties have made these highly branched three dimensional macromolecules the focus of much research over the last one to two decades. Dendrimers (from the Greek dendron: tree, and meros: part) consist of a central core molecule which acts as the root from which a number of highly branched, tree-like arms originate in an ordered and symmetric fashion Fig. 1.Dendritic structures emerged from a new class of polymers named cascade molecules, initially reported by Vogtle and his group at the end of the 1970’s ² and developed further by Tomalia, Newkome, and others to give rise to the larger dendritic structures ^3–6These hyper-branched molecules were called “dendrimers” or “arborols” (from the Latin arbor also meaning tree⁷.

Their unique molecular architecture means that dendrimers have a number of distinctive properties which differentiate them from other polymers; specifically the gradual stepwise method of combination means that they have in general a well defined size and structure with a comparatively low polydispersity index. Furthermore, dendrimer chemistry is quite adaptable thus facilitating synthesis of a broad range of molecules with different functionality⁸. Key properties in terms of the potential use of these materials in drug and gene delivery are defined by the high density of terminal

groups. These contribute to the molecules surface characteristics, offer multiple attachment sites e.g. for conjugation of drugs or targeting moieties, and determine the molecular volume which is important for the ability to confiscate other molecules within the core of the dendrimer⁹.

Dendrimers lend themselves to nanoengineering of these key properties in order to fashion materials for applications in drug and gene delivery, imaging, boron neutron capture therapy, but also various biotechnological diagnostics and sensing functions^10-14

Dendritic architecture is undoubtedly one of the most pervasive topologies observed across the world throughout biological systems¹⁵. These patterns are found at virtually all dimensional length scales (a term that refers to the best use of space). They appear in many diverse prototypes including those that can be measured in m (e.g. tree branching and roots), in circulatory topologies in the human anatomy (e.g. lungs, kidney, liver, spleen) that are found in mm and cm, or in cerebral neurons in μm. The reasons for such extensive mimicry at all dimensional length scales is not entirely clear. However, it could be speculated that these architectures have evolved to provide maximum interfaces for optimum energy extraction and distribution, nutrient extraction and distribution or information storage and retrieval¹⁷. There are only two examples of molecular level (nm) Dendritic structures in biological systems; in each case, they are derived from polysaccharides. These include glycogen, amylopectin and proteoglycans. The former is involved in energy storage in plants and animals, and the latter are important constituents that determine the viscoelastic properties of connective tissue^16,18.

Dendrimers are macromolecules with defined mass, size, shape, topology and surface chemistry. Starburst dendrimers are characterized by a unique tree-like branching architecture that starts from an initiator core around which branches of the dendrimers originates. These are hyper –branched structure with precisely placed functional group that bear important role in controlling the properties of therapeutics moieties that are encapsulated or complexed with it. Most eminent properties of dendrimers are its mono dispersive nature, globular shape, highly controlled architecture, which also makes them efficient carrier system for drugs. In contrast, various polymers and other hyper branched structures have randomly distributed functional.¹⁹

The object of this review will focus on the synthesis, properties and applications of dendrimer’s in drug delivery systems. Particular emphasis will be placed on the first and most extensively studied family of dendrimers; namely, the poly (amidoamine) (PAMAM) dendrimers.

SYNTHESIS OF DENDRITIC ARCHITECTURE

Staudinger initiated a synthetic macromolecular revolution 65 years ago, with the introduction of his ‘macromolecular hypothesis’²⁰ This seminal event has led to the evolution of three major macromolecular architectures, namely: linear (class I), cross-linked (bridged; class II) and branched types (class III). These three architectural classes are recognized as traditional synthetic polymers. In all these classes, structures or architectures are produced by largely statistical polymerization processes, rather than exact distribution processes (Fig. 2). These processes produce polydispersed (i.e. Mw/Mn >2-10) products of many different molecular weights. In general, these are not structure-controlled macromolecular architectures such as those observed in biological systems. However, considerable progress has occurred recently in the areas of living anionic²¹ cationic ²² and radical polymerizations²³. As early as 1979 the first synthetic strategies to produce monodispersed, structure-controlled, dendritic macromolecules in regular laboratory glassware were started ²⁴.even though dendrimer structures display structural control suggestive of biological systems, the synthetic approaches did not require biological components. They did, however, involve significant innovation and digression from classical organic synthesis methods. Now Commercial quantities (kg) of controlled macromolecular structures with polydispersities of 1.0005-1.10 are routinely synthesized using traditional organic reagents and monomers such as ethylenediamine and alkyl acrylates. These new structures are referred to as dendrons or dendrimers. Since 1979 two major strategies have evolved for dendrimer synthesis²⁵. The first was the divergent method in which growth of a dendron (molecular tree) originates from a core site (root) (Fig. 3). During the 1980s, virtually all dendritic polymers were produced by construction from the root of the molecular tree. This approach involved assembling monomeric modules in a radial, branch-upon-branch motif according to certain dendritic rules and principles ²⁶. This divergent approach is currently the preferred commercial route used by worldwide producers including Dendrimax (Ann Arbor, MI, USA), DSM Fine Chemicals (Geleen, The Netherlands) and the Perstorp Group (Perstorp, Sweden). A second method that was pioneered by Frechet and colleagues²⁷ is the convergent growth process. It proceeds from what will become the dendron molecular surface (i.e. from the leaves of the molecular tree) inward to a reactive focal point at the root (Fig. 3). This leads to the formation of a single reactive dendron. To obtain a dendrimer structure, several dendrons are reacted with a multi-functional core to yield such a product. Using these two synthetic strategies, >100 compositionally different dendrimer families have been synthesized ^28-32.

Dendrimer Synthesis: Divergent and Convergent Methods

In contrast to traditional polymers, dendrimers are unique core–shell structures possessing three basic architectural components (Fig. 4): a core (I), an interior of shells (generations) consisting of repeating branch-cell units (II), and terminal functional groups (the outer shell or periphery) (III). In general, dendrimer synthesis involves divergent or convergent hierarchical assembly strategies that require the construction components shown in Scheme 1. Within each of these major approaches there may be variations in methodology for branch-cell structure or dendron creation ^33–35.

PAMAM Dendrimers

PAMAM Poly (amidoamine) dendrimers were the first complete dendrimer family to be synthesized, characterized and commercialized ^27,36. They are synthesized by the ‘divergent’ approach. This methodology involves in situ branch-cell construction in stepwise, iterative stages around a desired core to produce mathematically defined core–shell structures. Typically, ethylenediamine [core multiplicity (N_c= 4), ammonia (N_c=3), or cystamine (N_c=4) may be used as cores and allowed to undergo reiterative, two-step reaction sequences. These sequences consist of: (a) an exhaustive alkylation of primary amines. (Michael addition) with methyl acrylate, and (b) amidation of amplified ester groups with a large excess of ethylenediamine to produce primary amine terminal groups (Scheme 2). This first reaction sequence on the exposed core creates G =0 (i.e. the core branch cell), wherein the number of artillery (i.e. dendrons) anchored to the core is determined by N_c. Iteration of the alkylation–amidation sequence produces an amplification of terminal groups from 1 to 2 with the in situ creation of a branch cell at the anchoring site of the dendron that constitutes G=1. Repeating these iterative sequences (see scheme 2) produces additional shells (generations) of branch cells that amplify mass and terminal groups according to the mathematical expressions described in the box (see Fig. 4). It is apparent that both the core multiplicity (N_c) and branch cell multiplicity (N_b) determine the precise number of terminal groups (Z) and mass amplification as a function of generation (G).

PPI and DAB Dendrimers

Commercially available dendrimer are based on polypropylenimine (PPI) units with butylenediamine (DAB) used as the core molecule. The repetitive reaction sequence involves Michael addition of acrylonitrile to a primary amino group followed by hydrogenation of nitrile groups to primary amino groups ³⁷ .These dendrimers are frequently referred to as DAB-x, or DAB-Am-x, with x giving the number of surface amines depending on the source DAB-Am4 is sometimes referred to as G0 or G1(Fig. 5).

PROPERTIES OF DENDRIMERS

Dendrimers are mono disperse macromolecules, unlike linear polymers. The classical polymerization process which results in linear polymers is usually random in nature and produces molecules of different sizes, whereas size and molecular mass of dendrimers can be specifically controlled during synthesis. Because of their molecular architecture, dendrimers show some significantly improved physical and chemical properties when compared to traditional linear polymers. In solution, linear chains exist as flexible coils; in contrast, dendrimers form a tightly packed ball. This has a great impact on their rheological properties. Dendrimer solutions have significantly lower viscosity than linear polymers³⁸. When the molecular mass of dendrimers increases, their intrinsic viscosity goes through a maximum at the fourth generation and then begins to decline ³⁹ .Such behaviour is unlike that of linear polymers. For classical polymers the intrinsic viscosity increases continuously with molecular mass. The presence of many chain-ends is responsible for high solubility and miscibility and for high reactivity ³⁸. Dendrimers’ solubility is strongly influenced by the nature of surface groups.

Dendrimers terminated in hydrophilic groups are soluble in polar solvents, while dendrimers having hydrophobic end groups are soluble in non polar solvents. In a solubility test with tetrahydrofuran (THF) as the solvent, the solubility of dendritic polyester was found remarkably higher than that of analogous linear polyester. A marked difference was also observed in chemical reactivity. Dendritic polyester was debenzylated by catalytic hydrogenolysis whereas linear polyester was unreactive. Lower generation dendrimers which are large enough to be spherical but do not form a tightly packed surface, have enormous surface areas in relation to volume (up to 1000 m²/g) ⁴⁰. Dendrimers have some unique properties because of their globular shape and the presence of internal cavities. The most important one is

the possibility to encapsulate guest molecules in the macromolecule interior. Meijer and co-workers⁴¹trapped small molecules like rose bengal or p-nitrobenzoic acid inside the ‘dendritic box’ of poly(propylene imine) dendrimer with 64 branches on the periphery. Then a shell was formed on the surface of the dendrimer by reacting the terminal amines with an amino acid (L-phenylalanine) and guest molecules were stably encapsulated inside the box. Hydrolysing the outer shell could liberate the guest molecules. The shape of the guest and the architecture of the box and its cavities determine the number of guest molecules that can be entrapped. Meijer’s group described experiments in which they had trapped four molecules of rosebengal or eight to ten molecules of p-nitrobenzoic acid in one dendrimer⁴².

Fig 1. Dendrimer structure (The generation count is not always consistent: normal generation 0 refers to the core while sometimes it is used to describe the dendrimer after the first reaction cycle.) The number of branching poinangles, and the length of the branching units determine to what extent each generation increases molecular volume vs. surface area. For the higher generations the density of the terminal groups reaches a point where for steric reasons no groups can be added (starburst effect).

In nature tree-like structures have evolved to maximize the exposed surface area, e.g. to maximize the light exposure/number of leaves of a tree. In a similar fashion dendritic architecture creates molecules where a large proportion of the groups are exposed at the surface and which can have very high molecular surface to volume ratios (up to 1000 m²/g) ⁴³. The presence of numerous terminal groups in dendrimers facilitates multiple simultaneous interactions of surface groups with the solvent, surfaces or other molecules and as a consequence, dendrimers tend to show high solubility, reactivity, and binding ⁴⁴.

Applications of Dendrimers

Dendrimers Glycodendrimers and Peptide dendrimers.

In the past year, significant advances have been made in the synthesis and study of glycoldendrimers and peptide dendrimers. Application of these dendrimers to the study of carbohydrate–protein and protein–protein interactions has facilitated the understanding of these processes. In addition, dendrimers show great promise as DNA- and drug-delivery systems.⁴⁵. The vast majority of glycodendrimers have saccharide residues on their outer surface, but glycodendrimers containing a sugar unit as the central core from which all branch points emanate as well as glycodendrimers with carbohydrates as the main dendrimer building blocks have also been described (Figure 7a). Glycodendrimers have been used for a variety of biologically relevant applications. Most notably, glycodendrimers with surface carbohydrate units have been used to study the protein carbohydrate interactions that are implicated in many intercellular recognition events. Physiologically significant affinities of lectins for carbohydrates generally occur only when multivalent interactions are achieved⁴⁶. Thus, dendrimers, in which a large number of carbohydrate units can be placed onto a relatively well-characterized framework, are very attractive for the study of protein–carbohydrate interactions. Compared with other frameworks that have been used to study such interactions, dendrimers are appealing because of their size (between those typical of small glycoclusters and large glycopolymers) and their low polydispersity (compared with that of most large glycopolymers). Also, the sizes of glycodendrimers can be varied depending on the generation of dendrimer used. Carbohydrate binding properties of many of the glycodendrimers that incorporate surface sugar residues ⁴⁷.

Several additional studies of protein–carbohydrate interactions with surface saccharide functionalized dendrimers have been reported. For a series of mannose-functionalized dendrimers, the sixth-generation PAMAM dendrimers (170 mannose units) were approximately twice as active as fourth-generation glycodendrimers (55 sugars) on a per-sugar basis toward con-conavalin A (Con A) in hem-agglutination assays. In addition, fourth through sixth-generation mannose-functionalized dendrimers were two orders of magnitude more active than monomeric mannose (on a per-sugar basis) ^{48, 49} Comparison of fourth- through sixth-generation PAMAM dendrimers with varying concentrations of surface mannose residues suggests that activity is highest for all generations at 30% to 50%. In another example, up to 32 T-antigen units (βGal-(1-3)-α GalNAc, a cancer-related epitope) were added to PAMAM dendrimers. Turbid metric assays, enzyme-linked lectin assay (ELLA), and enzyme-linked immunosorbent assay (ELISA) all indicated that the dendrimers are about 20 times more efficient than T-antigen monomer when interacting with peanut lectin and mouse monoclonal IgG antibody ⁵⁰.

Peptide dendrimers

Dendrimers having surface peptides grafted onto a customary (organic) dendrimer framework and dendrimers incorporating amino acids into the framework as branching or core units are both defined as ‘peptide dendrimers.’

Peptide dendrimers have potential applications as protein mimics, antiviral and anticancer agents, vaccines and drug and gene delivery systems. Synthetically, amino acids are appealing dendrimer building blocks because peptide-coupling techniques including solid-phase synthesis can be used. Both the synthesis and applications of peptide dendrimers have been reviewed ⁵¹. Lysine is the most common amino acid branching unit from which peptide dendrimers are assembled lysine core dendrimers with tetrapeptide and octapeptide surface units have been used as antimicrobial agents. The peptide dendrimers were more soluble in water, more stable to proteolysis, and less toxic to human cells than their linear polymeric analogs; comparable antimicrobial potency was demonstrated ⁵². Lysine core dendrimers with arginine surface residues were designed to be antiangiogenesis agents ⁵³, and surface azobenzene residues were added to a lysine core with the ultimate goal of designing photoresponsive drug-delivery systems⁵⁴. Also, lysine core dendrimers with an 11-mer peptide surface residue that is a ligand of neural cell adhesion molecule (NCAM) were synthesized and shown to induce an increase in intracellular calcium, which appears to be necessary for NCAM-dependent neurite outgrowth⁵⁵. Tetramers of immunogenic peptides displayed on a lysine dendrimer recognized Plasmodium falciparum, indicating possible applications of lysine dendrimers to vaccine development ⁵⁶. Lysine branch units linked to a DNA hexamer core and bearing quinolones on their surface degraded more slowly when exposed to nuclease S1 than unfunctionalized DNA⁵⁷.

Attachment of surface peptide groups to a customary dendrimer core was performed by Higashi et al⁵⁸. Who functionalized a G (3)-PAMAM dendrimer with poly (benzyl-L-glutamate) peptides. Dynamic light scattering and other studies suggested that the peptides form -helices on the dendrimer surface. Similar dendrimers with poly (glutamic acid) segments also showed helicity and could bind tryptophan, phenylalanine and tyrosine in aqueous solution ⁵⁹. Multivalent protein–protein interactions were studied using a dendrimer with the peptide EILDVPST on the surface. Slightly higher integrin-binding was shown for dendrimers (relative to monomeric peptide) in an ELISA assay⁶⁰. Although not actually peptide dendrimers, it seems appropriate to mention that other dendrimers have also been shown to bind peptides ⁶¹ and proteins ⁶². Dendrimers have also been used to increase resin loading for more efficient solid-phase peptide synthesis⁶³.

Much less research on peptide dendrimers has been reported than on glycodendrimers. However, preliminary studies with peptide dendrimers (and other peptide-binding dendrimers) to evaluate peptide–protein and protein–protein interactions indicate that dendrimer research will ultimately make significant contributions to understanding these processes.

Dendrimers in gene therapy

Because of their improved immunogenicity, effective non-viral vectors for gene delivery are actively sought. Non-viral vectors are thought to protect DNA from enzymatic degradation and to help deliver it into the cell⁶⁴. Because they form compact polycations under physiological conditions, PAMAM dendrimers, poly (propylene imine) dendrimers and partially hydrolyzed⁶⁵. PAMAM dendrimers have been used as DNA delivery systems^66,67. Scanning force microscopy data indicates that DNA wraps around the dendronized polymers⁶⁸. In recent reports, electroporation⁶⁹ and addition of β-cyclodextrin⁷⁰ were combined with DNA dendrimer systems. Electroporation caused significant increases in gene expression (relative to DNA/dendrimer systems) ⁷¹ and addition of β-cyclodextrin caused formation of smaller and more monodisperse particles⁷². PAMAM dendrimers functionalized with α-cyclodextrin showed luciferase gene expression about 100 times higher than for unfunctionalized PAMAM or for non-covalent mixtures of PAMAM and α-cyclodextrin⁷³. Poly (ethylene glycol) functionalization of G (5)-PAMAM dendrimers produced a 20-fold increase in transfection efficiency using plasmid. DNA coding for a reporter protein β-galactosidase relative to partially degraded PAMAM Dendrimers.

Dendrimers in drug delivery

Nanoparticle drug-delivery systems are of interest because they might be able to increase the selectivity and stability of therapeutic agents^74.Dendrimer drug-delivery systems of several different types have been proposed; encapsulation of guest molecules in the void spaces in the dendrimer interior is a common design (Figure 1). One could also envision dendrimer–drug networks. Prodrugs, where a therapeutic agent is linked to a dendrimer surface (covalently or via non-covalent interactions) are also a target of active research^75,76.

Host–guest interactions with dendrimers are well established ⁷⁷. In recent work, a hydrophilic–hydrophobic core-shell dendrimer with PAMAM interior and long alkane chain exterior was shown to bind 5-flurouracil, a water-soluble anti-tumor drug. After phospholipids’ coating of the dendrimer–fatty- acid macromolecule, oral bioavailability in rats of 5-flurouracil was nearly twice the level of free 5-flurouracil ⁷⁸ Liposomal formulations including dendrimers entrapped and then slowly released methotrexate⁷⁹. Dendrimer-formulated gels that could have applications in drug delivery have been described ^77,80. Pro-drugs with 5-aminolevulinic acid residues (for photodynamic therapy) on the surface of second and third-generation dendrimers⁸¹, and with insecticide (fipronil) residues on the surface of phosphorus containing dendrimers have been reported ⁷⁶.

Topical and transdermal delivery:

Dendrimers have found recent applications in novel topical and transdermal delivery systems, providing benefits such as improved drug solubilization, controlled release, and drug-polymer conjugates (pro-drugs). The viscosity-generation-number property of a dendrimer solution allows for ease of handling of highly concentrated dendrimer formulations for these applications. Dendrimers have been shown to be useful as transdermal and topical drug delivery systems for nonsteroidal anti-inflammatory drugs (NSAIDs), antiviral, antimicrobial, anticancer, or antihypertensive drugs⁸². PAMAM dendrimers have been studied as carrier transdermal systems for the model NSAIDs: ketoprofen and diflunisal⁸³. It was found that the PAMAM dendrimer-drug formulations showed increased transdermal drug delivery compared with formulations lacking dendrimers. In vivo studies in mice showed prolonged pharmacodynamic responses and 2.73-fold higher bioavailability over 24 h for certain dendrimer-containing drug solutions.

In another study, transport of indomethacin through intact skin was enhanced in vitro and in vivo ⁸⁴. The bioavailability of indomethacin was increased by using G4-PAMAM dendrimers with terminal amino groups. There have also been studies where dendrimers failed to show enhancement in drug transport through intact skin. It is well known that the molecular diffusion through intact skin is related to the molecular weight of the permeant molecule. Because of their high molecular weights, dendrimers generally have low diffusion coefficients. Diffusion through skin is more favorable for molecules that have solubility in lipids as well as in water. It could be possible to synthesize dendrimers with appropriate physical-chemical properties to facilitate drug transport through intact skin. Dendrimers with such favorable physicochemical properties could enhance transdermal transport of drugs by this mechanism. More research is warranted in this area to understand the structural-activity relationship of dendrimers in relation to skin transport.

In contrast to transdermal delivery, the use of dendrimers for topical delivery to the skin has shown to be more promising. Two different kinds of dendrimers were shown to have antiviral activity in vitro when the dendrimers were added to the cells before being challenged with the viruses. The dendrimers studied were either PAMAM or polylysine dendrimers. In contrast, dendrimers added to the cells after they were challenged with the virus showed no antiviral activity ⁸⁵. The study was carried out in an in vitro assay to determine dendrimer activity against herpes simplex virus (HSV) types 1 and 2. When tested in human foreskin fibroblast cells, both PAMAM and polylysine dendrimers showed activity against the virus. This study suggested that dendrimers could potentially be used as topical microbicides to be applied to the vaginal or rectal mucosa to protect against sexually transmitted diseases such as HIV or genital herpes. When tested against genital HSV infection in mice, two of the compounds showed significant reduction in infection rates when applied prior to intravaginal challenge.

Dendrimers to Boron Neutron capture therapy:

Boron neutron capture therapy is a cancer treatment based on a nuclear capture reaction^86,87. When ¹⁰B is irradiated with low energy or thermal neutrons, highly energetic α-particles and ⁷Li ions are produced that are toxic to tumor cells. To achieve the desired effects, it is essential to deliver ¹⁰B to tumor cells at a concentration of at least 109 atoms per cell. High levels of boron in tumor tissue can be achieved by using boronated antibodies that are targeted towards tumor antigens.⁸⁸however; the direct attachment of large numbers of boron-containing molecules to antibodies can impair the solubilities and targeting efficiencies of the antibodies⁸⁹.

The use of dendrimers as boron carriers for antibody conjugation was stimulated by their well-defined structure and multivalency. In early studies⁹⁰ conjugated isocyanato polyhedral borane [Na (CH₃)₃NB₁₀H₈NCO] to the periphery of second and fourth generation PAMAM dendrimers. The boronated dendrimers were then conjugated to the monoclonal antibody IB16-6, which is directed at the murine B16 melanoma. However, in biodistribution studies, the conjugates accumulated in the liver and the spleen. In subsequent studies, boronated PAMAM dendrimers were designed to target the epidermal growth factor (EGF) receptor, a cell surface receptor that is frequently over expressed in brain tumors⁹¹. The dendrimers were covalently linked to EGF and the resulting conjugates were found to be effectively endocytosed in vitro, resulting in an accumulation of boron in cell lysosomes.⁹² However, on intravenous injection into rats bearing intracerebral implants of a C6 glioma transfected with the gene encoding the EGF receptor, these boron carriers were taken up by the liver and showed low levels of accumulation in the tumor.⁹³Coupling to targeting molecules such as antibodies. A fluorescent dansyl group and PEO chain can be also conjugated to the linker for spectroscopic monitoring and water solubility, respectively. A single carborane cluster has been coupled to a dendritic polyalcohol for solubility in water by contrast, covalently incorporated carboranyl groups near the core of dendritic unimolecular forms micelles. However, to the best of our knowledge, a full biological evaluation of these systems has not been reported.

Dendrimers: research fascination or commercial reality:

Confidence in the use of dendrimers for drug delivery was boosted in May 2008, with the announcement of positive clinical trial results by Starpharma Holdings Limited, demonstrating that its topical vaginal microbicide gel product (3% SPL7013 Gel) was found to be safe and well tolerated in sexually abstinent women, when administered twice daily for a 14-day treatment period. In this case, dendrimers act by binding to the gp120 glycoprotein binding sites on the HIV virus, which prevents the virus from attaching to the T-cells, thereby blocking infection. This topical vaginal microbicide is designed to prevent transmission of sexually transmitted infections, including HIV and genital herpes, and uses dendrimers as an active agent. This was the first dendrimer-based product to be approved by regulatory authorities for human clinical testing under an investigational new drug application for prevention of genital herpes. It was reported that no participants showed untoward effect from using the fourth-generation polylysine dendrimer-based gel. In addition, no absorption of the active agent used in the gel was found in the systemic blood circulation after vaginal topical application. Also, vaginal microflora was found to be unaffected after VivaGel (Starpharma) treatment. Currently, the topical vaginal gel is in Phase II human clinical trials.

Other dendrimer-based products that are in process of reaching commercial reality include Avidimers (Avidimer Therapeutics, Ann Arbor, MI) for cancer prevention and treatment and gadolinium-based MRI contrast agent. Starpharma, in collaboration with its US-based wholly owned company. Dendritic Nanotechnologies (Mount Pleasant, MI), recently announced the commercial launch of its Priostar dendrimer-based technology research product called the Nano Juice Transfection Kit in addition to the Starburst- and Priostar-based dendrimer family. Because of the presence of large numbers of functional groups, these highly branched dendrimers are capable of binding to DNA. They will be useful for transfection of DNA into the variety of difficult-to-transfect cells. As the number of commercial applications of dendrimer technology increases, acceptance and confidence in this novel technology will gain strength for use in future products.

CONCLUSION:

Scientist has explored the synthesis, properties and their uses for various applications in drug delivery systems. Use of dendrimer’s in commercial pharmaceuticals will largely be driven by mitigating risk factors such as cost, large scale availability, safety concerns and regulatory issues the technology of dendrimer’s hold great potential to add value to pharmaceutical products. The authors anticipate that dendrimer’s technology will find increasing applications in commercial products of pharmaceuticals in coming years.

ACKNOWLEDGEMENT:

The Principal and Management of SR College of Pharmacy, Warangal for his constant encouragement.

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Received on 07.02.2012 Modified on 13.02.2012

Research J. Pharm. and Tech. 5(3): Mar.2012; Page 307-316