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Gaurav T. Tolia*, MS, PMP, is a senior scientist and group leader of formulations with Altea Therapeutics, 387 Technology Circle NW, Suite 100, Atlanta, GA 30093, tel. 404.835.6340, fax 404.835.6450, email@example.com
Hannah H. Choi, PhD, is a principal scientist with GlaxoSmithKline.
This review provides an update of how dendrimer technology is being applied to the development of novel systems for various topical delivery applications.
Nanotechnology has been of great interest in academic and industrial research for the past several decades. After many years of intense research efforts, nanoscaled technology is beginning to yield commercial applications in the automotive, electronics, consumer, and healthcare industries (1–8). The pharmaceutical and cosmetics industries have used the unique properties of nanosized molecules for diagnosing and monitoring diseases, delivering drugs, repairing damaged tissues, and mitigating disease states (9–18). Classes of nanosized systems used in the pharmaceutical industry are liposomes, nanocrystals, micelles, colloidal particles, quantum dots, and dendrimers (19–24), to name a few. Dendrimers, in particular, have attracted attention for their drug-delivery applications because of the ease of their synthesis, the ability to achieve well-defined shapes and sizes (monodispersity), and their chemical diversity compared with synthetic polymers (25). Because of dendrimers' interior void space and surface functional groups, they are well-suited for use as carrier molecules in drug delivery (26).
Technical evolution of dendrimers
Dendrimers are a unique class of synthetic macromolecules that can be distinguished from classical linear polymers by their highly branched, monodispersed, circular, and symmetrical architecture (see Figure 1). The term dendrimer was derived from its 'tree-like' structural architecture. A typical dendrimer structure consists of a core molecule (C), multiple layers or generations of branched molecules (G), and surface molecules (S). The first synthetic procedure for producing these structures was published in 1978 by Vögtle, who used a procedure described as a "cascade" synthesis (27). It was Tomalia's group, working at Dow Chemical (Midland, MI), which extensively studied the first dendritic structures of polyamidoamine (PAMAM) (28). It was discovered that these polymeric macromolecules synthesized by the "divergent" synthesis technique provided rich functionality on the outer surface (see Figure 1).
Figure 1: Schematic illustration of a G3 dendrimer. (FIGURE 1 IS COURTESY OF DENDRITIC NANOTECHNOLOGIES.)
In 1989, Fréchet introduced a more convenient and superior synthetic procedure for producing greater purity dendrimers described as the "convergent" technique (29). This revolutionized the field of dendrimer science. Irrespective of the synthetic routes, each route has its own advantages and disadvantages.
A dendrimer: a polymeric macromolecule
Dendrimers are synthesized by a repetitive step-growth polymerization process. For example, Starburst (Starpharma, Melbourne, Australia) (PAMAM) dendrimers with a diaminobutane core are synthesized with alternating reaction with acrylic acid methyl ester and ethylenediamine (28). This repetitive sequence of reaction steps theoretically allows the macromolecular dimensions of dendrimers to be controlled precisely. This resulting impressive structure has much more monodisperse molecules than is possible for classical linear polymers, which tend to be polydispersed.
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 assumes a densely packed globular shape (30). This change in dendrimer conformation imparts solution and bulk properties that differ from regular linear or branched polymers. Another important characteristic that distinguishes dendrimers from more conventional polymers is their intrinsic viscosity (31). It is well known that the intrinsic viscosity of linear polymers is proportional to its molecular weight and concentration. 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 a higher molecular weight. This feature is very useful in formulation science, as these high-molecular-weight, higher-generation dendrimers do not tend to be highly viscous and are therefore easy to handle and formulate. Another important attraction of using dendrimers for delivery systems comes from their property of being highly soluble in a large number of organic solvents (32).
The surface functional groups impart significant physical properties to the dendrimer in the solid and solution states. By proper choice of surface functional group chemistry and building units, unique physical and chemical properties can be created (29, 32). This approach has been exploited by pharmaceutical scientists in designing carrier systems of molecules, for linking to individual molecules (dendrimer-molecule conjugates) and for engineering specific interactions with biological systems such as receptors (33–34).
Several excellent review articles describing applications of dendrimers in nanomedicines have been published (35–39). Dendrimers such as PAMAM have been widely studied, and researchers have found diverse applications for them in biomedical and biological sciences (40–44). In particular, dendrimers have been used as carriers for drug delivery by various routes of administration, including parenteral, oral, topical, transdermal, and ocular. Although widely researched for more than two decades, only one clinical study is underway using dendrimers as microbicides (43). Studies performed for ocular or topical application have not shown dendrimers to be irritating or toxic to the biological tissue. This review will focus on the use of dendrimers for topical routes of administration, including applications in cosmetics or personal care products, as well as for drug delivery to or through skin or to the eye.
Cosmetics and personal care applications
Because of their excellent carrier properties, dendrimers have utility in cosmetics and personal care products such as hair-styling gels, shampoos, sunscreens, and anti-acne products. Cosmetic compositions comprising hydroxyl-functionalized dendritic macromolecules are described in a patent filed by Unilever's Home & Personal Care division for application in a hair-styling spray, gel, or mousse formulation (45). The dendritic macromolecules indicated for the hairstyling application in this patent use the polyhydric polyester alcohol or hyperbranched polyol functionalized groups. Another patent filed by L'Oreal described terminal hydroxyl functional group polyester dendritic macromolecules in combination with film-forming polymers for use in cosmetic and dermatological products intended for application to the skin, keratinous fibers, nails, or mucous membranes (46). Such a combination of a film-forming polymer with a dendritic polymer allowed the inventors to develop a low-viscosity product that was easily applied to the intended topical skin site and that formed a dry film capable of being peeled-off after the application period. This property allowed for superior cosmetic product performance and ease of use. Here, the unique ability of dendrimers to form lower viscosity solutions was used to the advantage of the formulation chemist.
Surface modifications of dendrimers have been used as molecular-carrying systems. For example, dendrimers containing at least one free amino group have been used to carry anti-acne agents in a patent filed by Revlon consumer products (47). A keratolytic or anti-acne agent was complexed with a carrying molecule such as a dendrimer containing free amino groups to obtain cosmetically acceptable formulations for treatment of acne vulgaris. In another example of a dendrimer-molecule conjugate system, coupling of aminobutadiene with an amine-rich dendritic molecule provided advantageous UV-absorbing capabilities to the final product (48). This high-molecular-weight dendrimer-aminobutadiene-complexed molecule allowed ease in formulating a clear sunscreen composition without developing high-viscosity gels, which in turn provided ease of application to the skin. Because of the high molecular weight of the resulting molecule, it was nonpenetrating into the skin, which would minimize risk of irritation or sensitization reactions while acting as a UV-light absorber when applied on the skin's surface. In another application, amine-terminated cationic dendrimers have been used in personal-care cleansing compositions as mildness agents (49). Linear cationic polymers used as mildness agents usually precipitate in the presence of anionic surfactants, which reduces their lathering, skin conditioning, or cleansing effects. Dendrimers, on the other hand, are capable of interacting favorably and can bind with anionic surfactants in the composition to remain dispersed in salt solutions. This interaction of cationic dendrimers with skin-irritating anionic surfactants could potentially be used by the personal care chemist for reducing the skin irritation potential of cosmetic formulations containing harsh anionic surfactants.
US patent 6,001,342 described the use of dendrimers containing terminal amine groups such as polyamidoamines (Starburst, Starpharma) in antiperspirant deodorant compositions to reduce underarm odors (50). Some of the selected dendrimers were found to have odor-absorbing properties and were claimed as deodorant active agents. These dendrimers could be formulated in water-based compositions in appreciable amounts and were found to be nontoxic or nonirritating. Novel self-tanning cosmetic compositions described in US Patent 6,399,048 contain amine-terminal group dendrimers in addition to a tanning agent (51). The dendrimer-containing composition was shown to have improved efficacy and self-tanning activity on application to skin. Dendrimer-containing compositions in this case were shown to increase the intensity and quality of skin coloration produced, as well as providing a shade that was closer to a natural tan. As shown in various examples of dendrimer application, the rich functional surface groups and the viscosity characteristics of dendrimers have been used to add unique claims and product differentiation to personal-care products.
Dendrimers as ophthalmic vehicles
The majority of topically applied ocular drug-delivery systems are formulated either as solutions, ointments, or suspensions and suffer from various disadvantages such as quick elimination from the precorneal region, poor bioavailability, or failure to deliver the drug in a sustained fashion. Several research advances have been made in ocular drug delivery systems by using specialized delivery systems such as polymers, liposomes, or dendrimers to overcome some of these disadvantages. Ideal ocular drug-delivery systems should be nonirritating, sterile, isotonic, biocompatible, and biodegradable. The viscosity of the final product should be optimized so that the dosage form does not run out of the eye. Dendrimers provide solutions to some complex delivery problems for ocular drug delivery.
Some recent research efforts in dendrimers for ocular drug delivery include PAMAM dendrimers that were studied by Vandamme and Brobeck as ophthalmic vehicles for controlled delivery of pilocarpine and tropicamide to the eye (52). In the New Zealand albino rabbit model, the residence time of pilocarpine in the eye was increased by using dendrimers with carboxylic or hydroxyl surface groups. These surface-modified dendrimers were predicted to enhance pilocarpine bioavailability.
In another study, dendrimer end groups were conjugated with aminosaccharides and sulfated aminosaccharides to obtain anionic dendrimers with unique biological properties (53). These glucosamine and glucosamine 6-sulfate dendrimers were studied in a rabbit model of scar tissue formation after glaucoma filtration surgery. These unique polymeric macromolecules increased the long-term success of the surgery from 30% to 80% when used together.
In another study, lipophilic amino-acid dendrimers were used to study the long-term effect of use of dendrimer for delivery of an antivascular endothelial growth factor (VEGF) oligonucleotide (ODN-1) to the eye of rats with the aim of inhibiting laser-induced choroidal neovascularization (CNV). It was shown that dendrimer containing ODN-1 showed significantly greater inhibition of CNV over a 4–6 month period compared with ODN-1 alone (54). Immunohistochemistry of the eye tissue after long-term treatment with dendrimers was conducted to determine if an immune response was generated after use of the dendrimer as a drug conjugate for treating eye diseases. It was determined that there was no significant increase in inflammatory response, proving that dendrimers could be used as a viable option for delivery of oligonucleotide to the eye for treating angiogenic eye diseases without concern of generating unwanted biological response.
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 drugs. PAMAM dendrimers have been studied as carrier transdermal systems for the model NSAIDs: ketoprofen and diflunisal (55). 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 (56). The bioavailability of indomethacin was increased by usingG4-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. The study was carried out in an in vitro assay to determine dendrimer activity against herpes simplex virus (HSV) types 1 and 2 (43). 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: 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 (57). 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 (see Figure 2). 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.
Figure 2: Schematic mechanism of a dendrimer as a topical vaginal microbicide. HIV viral particles (black) attach to T-cell receptors on the surface of the T-cells (blue) as an initial step in infection (left, without dendrimer gel application). Dendrimers bind to the surface of the HIV particles and block attachment, reducing or preventing infection (right, with dendrimer gel application). (FIGURE 2 IS COURTESY OF THE AUTHORS.)
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 (58-59). 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 NanoJuice Transfection Kit in addition to the Starburst- and Priostar-based dendrimer family (60). 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 (61). 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.
Scientists have explored the use of dendrimers for various applications in topical and cosmetic product development. Use of dendrimers in commercial pharmaceutical and cosmetic products will largely be driven by mitigating risk factors such as cost, large-scale availability, safety concerns, and regulatory issues. Although no pharmaceutical or cosmetic products containing dendrimers are currently on the market, dendrimer technology holds great potential to add value to pharmaceutical or cosmetic products. Use of dendrimers as topical microbicide products is marching ahead with positive results and, in the process, leading the field for HIV prevention. The authors expect that dendrimer technology will find increasing applications in commercial products of all types in coming years.
The authors would like to thank Ross Durland, PhD, director of product development at AM Biotechnologies LLC (Galveston, TX) for providing valuable input for this article.
Gaurav T. Tolia*, MS, PMP, is a senior scientist and group leader of formulations with Altea Therapeutics, 387 Technology Circle NW, Suite 100, Atlanta, GA 30093, tel. 404.835.6340, fax 404.835.6450, firstname.lastname@example.org. Hannah H. Choi, PhD, is a principal scientist with GlaxoSmithKline.
*To whom all correspondence should be addressed.
Submitted: June 23, 2008; Accepted: Aug. 3, 2008.
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