Strategies towards improved development of semisolid vaginal microbicide gels for the prevention of heterosexual transmission of HIV-1

The work described in this dissertation attempts to advance the science of developing semisolid microbicide products through (a) application-oriented design of drug delivery vehicles and (b) selection of HIV-specific active ingredients that yield advantage over the current antiretroviral strategies, particularly in regards to the mechanism of action through inhibition of HIV entry. Two approaches that exploit the underlying composition-structureproperty- performance relationship in polymeric systems to improve semisolid gels for the prevention of sexual transmission of HIV were explored. Firstly, an algorithm that allows de novo engineering of a delivery vehicle was developed, optimizing the composition and consequently the properties of the material to meet a predefined set of performance criteria for vaginal drug delivery. Secondly, a pH-responsive mucus-like material with the ability to attenuate the transport of virus and immune cells was engineered. Inhibition of viral transport was observed at pH above 4.8, with minimal signs of toxicity to vaginal tissue. Second part of this dissertation describes the assessment of two potent antiretroviral agents that inhibit HIV entry. The ingenuity of these agents lies in (a) the dual mechanism of HIV inhibition associated with the small molecule pyrimidinedione analogs, and (b) the design of a gp120 targeted macromolecular therapeutic that is synthetic in nature and shows activity comparable to that of iv the protein-based lectins. Hydroxyethyl cellulose gels formulated with 0.25 w% pyrimidinedione analog showed activity at ~ 14 ug/mL in an in vitro antiviral assay. In the design of gp120 targeted synthetic lectins, benzoboroxole showed weak affinity for nonreducing sugars; however, it demonstrated antiviral activity at nanomolar concentrations when incorporated into high molecular weight polymers. Activity increased with increasing degree of functionalization and molecular weight of the polymer. Supplementing the polymer backbone with sulfonic acid increased its aqueous solubility in addition to a synergistic increase in antiviral activity. These strategies support the paradigm shift from use of generic semisolid drug delivery systems to a performance-based design of polymeric materials for vaginal drug delivery. Furthermore, formulating semisolid systems to deliver antiretroviral agents, such as the pyrimidinediones or the synthetic lectins, may provide a versatile microbicide candidate that is potent, affordable and nontoxic.