SBIR-STTR Award

Detergent-based spermicides are the most popular forms of reversible contraception in the United States the active ingredient in these spermicides is nonoxynol-9 (N-9), a non-ionic surfactant, which has been available in various forms for over 30 years. Surfactant spermicides have high contraceptive failure rate and interfere with natural and protective vaginal mechanisms thereby enhancing the risk of transmission and infection by a sexually transmitted disease. It would be desirable, therefore, to provide improved vaginal spermicides without toxicity. In a systematic search effort to identify non-toxic spermicides potentially capable of performing better and without the drawback of detergent-type spermicides, we have rationally designed and synthesized several disubstituted metallocene derivatives, where bis(cyclopentadienyl) moieties are positioned in a tetrahedral symmetry and in a bent conformation with respect to the central transition metal atoms. We discovered bis (cyclopentadienyl) complexes of vanadium(IV) or vanadocenes to have rapid, potent, and selective spermicidal activity. They work by targeting the motility-apparatus of sperm Vanadocenes lack membrane toxicity and hence have the potential to perform better, than those available today. We have synthesized a series of vanadocenes and studied how chemical modification of simple inorganic vanadium salt alters the properties of vanadium as potent spermicides. Unlike N-9, vanadocenes are spermicidal at nanomolar to micromolar ranges without cytotoxicity to human female genital tract epithelial cells and lack mucosal, systemic, and reproductive toxicity in animal models. Vanadocenes, because of their potent spermicidal activity and lack of inflammatory and toxic effects, may be useful as a new class of vaginal contraceptives for women. Results of our in vitro and in vivo studies indicated that the lead vanadocene complex, vanadocene dithiocatbamate (VDDTC), would be an attractive candidate to further explore as a vaginal spermicide. Therefore, preclinical studies will be performed to test the in vivo contraceptive efficacy in the relevant animal model. The porcine model was found to be a suitable animal model for investigating the in vivo contraceptive efficacy of spermicidal vanadocenes. Using the minipig model, we will test our hypothesis that vaginally delivered gel-microemulsion formulation of VDDTC prior to artificial insemination will prevent the conception without side effects. We will test the dose and duration of vaginally applied gel formulation of VDDTC on fertility rates in artificially inseminated and hormonally primed gilts. The development of a mechanism-based spermicide aimed at mild contraception will be a potentially paradigm shifting area in contraception research. The preclinical data on the in vivo efficacy of gel formulation of VDDTC will be essential to further explore the utility of VDDTC as an intravaginal spermicide in Phase II.

Thesaurus Terms:
cyclopentane, drug design /synthesis /production, female antifertility drug, spermicide, vanadium cytotoxicity, fertility, semen emulsion, miniature swine

There is an urgent need, worldwide, for improved contraceptives, especially prophylactic contraceptives. Barrier methods are the only class of contraceptives that protects users against sexually transmitted diseases. However, currently available spermicidal contraceptives suffer from poor efficacy and/or have undesirable toxicity. In a systematic effort to identify non-toxic spermicides potentially capable of performing better and without the drawbacks of detergent-type spermicides, we have rationally designed and synthesized several disubstituted metallocene derivatives. We discovered bis-cyclopentadienyl complexes of vanadium(IV) or vanadocenes to have rapid, potent, and selective spermicidal activity. Under Phase I funding, we demonstrated: (i) in vivo contraceptive activity of VDDTC via a gel-microemulsion in rabbits and porcine models; (ii) confirmed the lack of mucosal inflammatory potential of VDDTC in mice, rabbits, and pigs; (iii) developed a physiologically relevant and sensitive porcine model for vaginal irritation; and (iv) discovered that VDDTC significantly enhanced the microbicide efficacy of the antiretroviral spermicide WHI- 07 in the feline immunodeficiency virus/cat model of AIDS. Under SBIR Phase II support, we will expand the utility of the porcine and rabbit models to test the in vivo contraceptive efficacy, mucosal safety as well as developmental toxicity studies of VDDTC. We will perform these efficacy and safety studies of VDDTC in combination with WHI-07. We hypothesize that the combination of these two active agents with different mechanisms of action will potentially improve efficacy and duration of dual-protection when compared with VDDTC alone while maintaining an adequate safety profile. The goals of Phase II study are (i) to expand the utility of porcine model for the in vivo contraceptive efficacy of VDDTC versus VDDTC plus WHI-07 gel microemulsion; (ii) to expand the utility of porcine vaginal irritation model for the preclinical evaluation of VDDTC and VDDTC plus WHI-07 by characterizing the extracellular, cellular, molecular and histological endpoints; and (iii) to assess the developmental toxicity potential of VDDTC in rabbits. The proposed Phase II work will complement and enhance the discovery and preclinical development of safe and effective prophylactic contraceptives at Paradigm Pharmaceuticals that may provide the basis for a new strategy to prevent the sexual transmission of HIV while providing fertility control for women.

Thesaurus Terms:
antiAIDS agent, drug design /synthesis /production, metal complex, reproductive system pharmacology, spermicide, thiocarbamate, vanadium antiinfective agent, cytokine, embryo /fetus toxicology, emulsion, gel, inflammation, irritation /irritant, mucosa, sexually transmitted disease, topical drug application, women's health, zidovudine digital imaging, female, flow cytometry, histopathology, immunocytochemistry, laboratory rabbit, swine