? DESCRIPTION (provided by applicant): Approximately 34 million people are infected with human immunodeficiency type-1 (HIV-1) world-wide. More than two million new infections occur annually (1,2). These statistics could be reduced if at-risk individuals were provided antiretrovirl drugs for HIV pre-exposure prophylaxis (PrEP). We propose to develop a combination nano-microbicide containing cellulose acetate phthalate (CAP) as a HIV-1 entry inhibitor with dolutegravir (DTG), a HIV-1 integrase strand transfer inhibitor, for highly effective PrEP. Our preliminary data show that novel CAP-DTG combination nano-microbicide reduce cytotoxicity of DTG to cells. In vitro HIV prophylaxis using HIV indicator TZM-bl cells show that CAP-DTG combination nano-microbicide offers significantly higher protection from HIV-1 infection as compared to DTG solution and CAP nanoparticles indicating the importance of combination nano-microbicide. This proposal will extend our preliminary experiments and evaluate CAP-DTG nano-microbicide in thermosentive gel and DTG solution based conventional gel for cytotoxicity, intra-cellular delivery of DTG, in vitro HIV PrEP, and vaginal pharmacokinetics. In order to reach this goal, Specific Aim 1 focuses on development of DTG solution based conventional gel (DTG-gel), optimization and characterization of CAP-DTG combination nanomicrobicide for DTG loading, and incorporation of CAP-DTG combination nanomicrobicide into a thermosensitive gel (CAP-DTG-NPs-Gel) for vaginal delivery. Chemical stability of DTG in conventional gel and CAP-DTG-NPs-Gel will also be assessed. Specific Aim 2 employs various cell lines and primary human cells to evaluate DTG-gel and CAP- NPs-DTG-Gel for cytotoxicity and intra-cellular delivery of DTG. The ability of DTG-gel and CAP-NPs-DTG-Gel to offer protection from HIV-1 infection will be tested in TZM-bl cells, PBMCs, and MDMs. We will evaluate vaginal pharmacokinetics of DTG-gel and CAP-DTG-NPs-Gel using female NOD SCID gamma (NSG) mice for up to 7 days. Drug dissemination will be determined using HPLC analysis to measure DTG levels in dissected tissue. We will evaluate tolerability of DTG-gel and CAP-DTG-NPs-Gel after repeated administration for 7 days by analyzing inflammatory cytokines in cervicovaginal fluid and immunohistochemical analysis of NSG tissue. As a laboratory within an undergraduate biology department with collaborators in attached professional schools, we are uniquely situated to expose undergraduates to state-of-the-art nanoparticle research. This project will incorporate education of undergraduate students in our investigation of the utility of combination CAP and DTG nano-microbicide in a thermosensitive gel delivery system as cost-effect, highly efficacious modality for HIV pre-exposure prophylaxis.
|Effective start/end date||2/4/15 → 1/31/18|
- National Institute of Allergy and Infectious Diseases: $436,500.00
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