Cellulose acetate phthalate (CAP), used in the pharmaceutical industry for enteric film coating of tablets and capsules, is an HIV-1 entry inhibitor blocking the CXCR4/CCR5 coreceptor binding sites on the virus and eliciting """"""""dead-end"""""""" gp41 six-helix bundles on the virus envelope. Micronized CAP is the only candidate topical microbicide with the capacity to adsorb from physiological fluids HIV-1, preventing virus contact with target ceils. The interaction between HIV-1 and micronized CAP leads to virus disintegration and shedding of envelope glycoproteins, resulting in loss of infectivity. CAP also a) inactivates herpesviruses HSV-1, HSV-2, cytomegalovirus, Neisseria gonorrhoeae, Trichomonas vaginalis, Haemophilus ducreyi, Chlamydia trachomatis, Treponema pallidum and bacteria associated with bacterial vaginosis; b) protects mice and rhesus monkeys against vaginal infection by HSV-2 and SIV, respectively. Thus, CAP has the desired properties of combination microbicides. CAP has an established safety record, is widely available in large quantities and is inexpensive. To take further advantages of these properties, it is necessary to develop a commensurate delivery system which is simple, inexpensive, amenable to mass production, with a minimum of disposal problems. These requirements are met by a dispersible CAP film convertible in the presence of water into a gel containing micronized CAP. Further work is needed to optimize the film and bring it into large-scale industrial production. This will be accomplished within the framework of this proposal. CAP films are also suited for delivery of microbicides other than CAP. Hydroxypropyl-beta-cyclodextrin (HP-beta-CD) zinc finger inhibitors (ZnFI) and the reverse transcriptase inhibitor UC781 have been selected for this purpose. They will widen the targets for HIV-1 inhibition.
The aims of this proposal will be accomplished within the framework of all three projects: l) Prevention of infection by primary HIV-1 isolates and distinct clades in vitro and in human cervical tissue models by CAP/HP-beta- CD/ZnFI/UC781 combinations; II) a) Assessing the safety of CAP films and ZnFI and UC781 combination films and --microbicide distribution after vaginal application in monkeys and b) Evaluating the efficacy of the CAP film and combination films against infection with pathogenic X4 and R5 simian/human chimeric HIV-1 viruses (SHIV); III) Pilot Clinical Trials, which by iterative collaboration with the above projects and the Technology & Regulatory Core, will assure the establishment of prerequisites for large-scale commercial production of efficacious CAP-based microbicidal films.
