Starpharma focuses on the use of dendrimers as drugs in their own right, in contrast to dendrimers as drug delivery vehicles or diagnostics. This contextual review describes how dendrimers offer a unique platform for exploring chemical diversity on the nanoscale and how the production of dendrimer libraries covering a diverse array of macromolecular structures can be used in drug discovery and development. Using Starpharma's work on the prevention of HIV and sexually transmitted infections (STIs) through the development of microbicide candidates as an example, the process from which SPL7013 emerged as a development candidate is described. Following a range of preclinical studies, Starpharma submitted an investigational new drug application (IND) for SPL7013 gel (VivaGel) to the United States Food and Drug Administration (FDA) in June 2003, the first such submission for a dendrimer-based drug. The first clinical trial under this IND was completed in 2004.

BackgroundTopical microbicides, used by women to prevent the transmission of HIV and other sexually transmitted infections are urgently required. Dendrimers are highly branched nanoparticles being developed as microbicides. However, the anti-HIV and HSV structure-activity relationship of dendrimers comprising benzyhydryl amide cores and lysine branches, and a comprehensive analysis of their broad-spectrum anti-HIV activity and mechanism of action have not been published.Methods and FindingsDendrimers with optimized activity against HIV-1 and HSV-2 were identified with respect to the number of lysine branches (generations) and surface groups. Antiviral activity was determined in cell culture assays. Time-of-addition assays were performed to determine dendrimer mechanism of action. In vivo toxicity and HSV-2 inhibitory activity were evaluated in the mouse HSV-2 susceptibility model. Surface groups imparting the most potent inhibitory activity against HIV-1 and HSV-2 were naphthalene disulfonic acid (DNAA) and 3,5-disulfobenzoic acid exhibiting the greatest anionic charge and hydrophobicity of the seven surface groups tested. Their anti-HIV-1 activity did not appreciably increase beyond a second-generation dendrimer while dendrimers larger than two generations were required for potent anti-HSV-2 activity. Second (SPL7115) and fourth generation (SPL7013) DNAA dendrimers demonstrated broad-spectrum anti-HIV activity. However, SPL7013 was more active against HSV and blocking HIV-1 envelope mediated cell-to-cell fusion. SPL7013 and SPL7115 inhibited viral entry with similar potency against CXCR4-(X4) and CCR5-using (R5) HIV-1 strains. SPL7013 was not toxic and provided at least 12 h protection against HSV-2 in the mouse vagina.ConclusionsDendrimers can be engineered with optimized potency against HIV and HSV representing a unique platform for the controlled synthesis of chemically defined multivalent agents as viral entry inhibitors. SPL7013 is formulated as VivaGel® and is currently in clinical development to provide protection against HIV and HSV. SPL7013 could also be combined with other microbicides.

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BackgroundThe angiotensin II (AngII) receptor subtype 2 (AT2R) is expressed in sensory neurons and may play a role in nociception and neuronal regeneration.MethodsWe used immunostaining with characterized antibodies to study the localization of AT2R in cultured human and rat dorsal root ganglion (DRG) neurons and a range of human tissues. The effects of AngII and AT2R antagonist EMA401 on capsaicin responses in cultured human and rat (DRG) neurons were measured with calcium imaging, on neurite length and density with Gap43 immunostaining, and on cyclic adenosine monophosphate (cAMP) expression using immunofluorescence.ResultsAT2R expression was localized in small-/medium-sized cultured neurons of human and rat DRG. Treatment with the AT2R antagonist EMA401 resulted in dose-related functional inhibition of capsaicin responses (IC50 = 10 nmol/L), which was reversed by 8-bromo-cAMP, and reduced neurite length and density; AngII treatment significantly enhanced capsaicin responses, cAMP levels and neurite outgrowth. The AT1R antagonist losartan had no effect on capsaicin responses. AT2R was localized in sensory neurons of human DRG, and nerve fibres in peripheral nerves, skin, urinary bladder and bowel. A majority sub-population (60%) of small-/medium-diameter neuronal cells were immunopositive in both control post-mortem and avulsion-injured human DRG; some very small neurons appeared to be intensely immunoreactive, with TRPV1 co-localization. While AT2R levels were reduced in human limb peripheral nerve segments proximal to injury, they were preserved in painful neuromas.ConclusionsAT2R antagonists could be particularly useful in the treatment of chronic pain and hypersensitivity associated with abnormal nerve sprouting.

SPL7013 is a dendrimer with a polyanionic outer surface that allows multiple interactions with target sites. It potently binds and blocks HIV-1 and chimeric simian/HIV-1 viruses (SHIVs) replication in vitro. Gels containing different concentrations of SPL7013 were used as topical microbicides in female pigtailed macaques (Macaca nemestrina) to study their ability to prevent vaginal transmission of SHIV(89,6P). On virus challenge, all untreated macaques (8/8) and seven of eight macaques treated with placebo gel were infected within 2 weeks postinfection (PI) and showed high plasma viremia and dramatic CD4(+) cell decline within 4 weeks PI. In contrast, 6/6 macaques, 5/6 macaques, and 2/6 macaques treated with 5% w/w (50 mg/ml), 3% w/w (30 mg/ml), and 1% w/w (10 mg/ml) SPL7013 gels, respectively, resisted viral challenge. The results showed that animals treated with SPL7013 showed a dose-dependent resistance to virus challenge. Neither SPL7013 nor placebo gels produced any adverse effects following the single application in the study. These results showed that 3-5% w/w SPL7013 gels were effective in blocking vaginal transmission of SHIV in macaques after single gel application followed by single virus challenge. These results suggest that SPL7013 gel may be a promising anti-HIV microbicide formulation for further evaluation.