The development of a nano-based colorectal pre-exposure prophylaxis for HIV

Antoinette Gail Nelson
2018
The colorectal mucosa is a highly vulnerable site for Human Immunodeficiency Virus (HIV) transmission. The epithelium of this region is comprised of a thin single-cell layer that serves as a protective barrier, to prevent foreign pathogens from entering the body. Beneath the epithelial layer, the lamina propria provides direct access to an extensive population of immune cells that are highly susceptible to HIV infection. There is also access to the lymphatic system, which serves as an outlet
more » ... HIV to enter the systemic circulation, initiating permanent infection. To prevent HIV infection, it is important to achieve, and maintain, therapeutically effective concentrations of anti-HIV drugs within mucosal tissues. The objective of the current thesis is to fabricate and assess a nanoparticle (NP) platform, for use in a colorectal PrEP, with the goal to (1) deliver antiretroviral agents directly to the colorectal mucosa to minimize dosage requirements; (2) achieve high drug loading and sustained drug release; and (3) establish prolonged, therapeutically effective, drug concentrations within mucosal tissue to minimize dosing frequency to once-a-week. Based on average epithelial cell turnover rates in the colon of rodents and humans, 2-3 days in a murine model is considered equivalent to 5-8 days in humans. The overall objective of this thesis is to design, fabricate, and evaluate a nanoparticle (NP) drug delivery system (DDS), for colorectal mucosal pre-exposure prophylaxis (mPrEP) of HIV. Within the first part of this thesis, the feasibility of a modified cell penetrating peptide (CPP) bactenicin 7 (Bac7), to transport poly(ε-caprolactone)-poly(ethylene glycol) (PCL-PEG) NPs into, and across, a colorectal epithelial barrier, was evaluated. The hypothesis is that by functionalizing NPs with Bac7, NP transport across Caco-2 colonic cells will increase in vitro. Additionally, NPs of optimal architecture (dense PEG corona and effective Bac7 ligand density) will successfully traverse the colorectal mucus mesh lining in [...]
doi:10.7282/t3st7t8p fatcat:ziuxdgkhyreu3kqy4j7sw5se5i