To adequately reduce new HIV infections, development of highly effective pre-exposure prophylaxis (PrEP) against HIV infection in women is necessary. Cellulose acetate phthalate (CAP) is a pH sensitive polymer with HIV-1 entry inhibitory properties. Dolutegravir (DTG) is an integrase strand transfer inhibitor with potent antiretroviral activity. DTG delivered in combination with CAP may significantly improve current PrEP against HIV. In the present study the development of DTG-loaded CAP nanoparticles incorporated in thermosensitive (TMS) gel at vaginal pH 4.2 and seminal fluid pH 7.4 is presented as proof-of-concept for improved PrEP. Water–oil–in–water homogenization was used to fabricate DTG-loaded CAP nanoparticles (DTG–CAP–NPs). Size, polydispersity, and morphological analyses illustrate that DTG–CAP–NPs were smooth and spherical, ≤200 nm in size, and monodispersed with a polydispersity index PDI ≤ 0.2. The drug encapsulation (EE%) and release profile of DTG–CAP–NPs was determined by HPLC analysis. The EE% of DTG in DTG–CAP–NPs was evaluated to be ∼70%. The thermal sensitivity of the TMS gel was optimized and the pH dependency was evaluated by rheological analysis. DTG release studies in TMS gel revealed that DTG–CAP–NPs were stable in TMS gel at pH 4.2 while DTG–CAP–NPs in TMS gel at pH 7.4 rapidly release DTG (≥80% release within 1 h). Cytotoxicity studies using vaginal cell lines revealed that DTG–CAP–NPs were relatively non-cytotoxic at concentration <1 μg/mL. Confocal microscopic studies illustrate that ≥98% cells retained DTG–CAP–NPs intracellularly over seven days. Antiretroviral drug loaded nanocellulose fabrications in TMS gel delivered intravaginally may enhance both microbicidal and antiretroviral drug efficacy and may present a novel option for female PrEP against HIV.

HIV continues to be one of the greatest challenges facing the global health community. More than 36 million people currently live with HIV and, in 2015 2.1 million new infections were reported globally. Pre-Exposure Prophylaxis (PrEP) prevents HIV infection by inhibiting viral entry, replication, or integration at the primary site of pathogenic contraction. Failures of large antiretroviral drug (ARV) PrEP clinical trials indicate the current insufficiencies of PrEP for women in high-risk areas, such as sub-Saharan Africa. A combination of social, adherence, and drug barriers create these insufficiencies and limit the efficacy of ARV. Nanotechnology offers the promise of extended drug release and enhances bioavailability of ARVs when encapsulated in polymeric nano-particles. Nanoparticle encapsulation has been evaluated in vitro in comparative studies to drug solutions and exhibit higher efficacy and lower cytotoxicity profiles. Delivery systems for nanoparticle PrEP facilitate administration of nano-encapsulated ARVs to high-risk tissues. In this mini-review, we summarize the comparative nanoparticle and drug solution studies and the potential of two delivery methods: thermosensitive gels and polymeric nanoparticle films for direct prophylactic applications.