Doctor of Philosophy (PhD)
Pharmacology and Experimental Neuroscience
Antiretroviral therapy (ART) has improved the quality and duration of life for people living with human immunodeficiency virus (HIV) infection. However, opportunities to improve its profile abound. ART is limited by putative viral reservoir penetrance, emergence of viral mutations, inherent toxicities, and regimen non-adherence. These highlight the need improved drug delivery schemes. Previously, our lab has demonstrated that targeting mononuclear phagocytes for antiretroviral drug delivery extends drug half-life and improves penetrance into viral reservoirs, addressing these limitations of ART. Herein, we developed synthetic and biologic antiretroviral (ARV) drug nanocarriers improve the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of ARVs through macrophage-targeted delivery.
We posited that exosomes could be harnessed as biologic nanocarriers of ART, capable of targeting macrophages for drug delivery, building intracellular drug depots, and improving the pharmacokinetic and pharmacodynamic profile of ARVs. In a step towards achieving this goal, we studied the encapsulation of hydrophilic parent ARVs, hydrophobic parent ARVs, and lipophilic prodrug ARVs, using a variety of loading methods. The combination of sonication and lipophilic ARV prodrugs resulted in the highest drug encapsulation into exosomes. The data suggest the method of drug loading and the active pharmaceutical ingredient are important parameters to optimize. Despite these findings, further investigation of optimal cargo and large-scale production of exosome delivery systems are needed.
In tandem, a polymeric nanoparticle delivery system was developed as a means to improve the profile of tenofovir. To this end, we report the synthesis of two lipophilic tenofovir (TFV) ProTides (M1TFV, M2TFV) designed to improve drug stability, half-life, membrane penetrance, and enhance tissue distribution. The lead prodrug candidate M1TFV was nanoformulated to develop a stable LA injectable dosage form (NM1TFV). Specifically, NM1TFV provided PBMC concentrations of the active metabolite, tenofovir diphosphate (TFV-DP) four times above the IC90 for 2 months, while concurrently generating substantial lymphatic and reticuloendothelial drug depots after a single injection in SD rats. Therefore, these results provide proof-of-concept nanoformulated TFV ProTides can effectively extend the apparent half-life and improve tissue distribution, warranting further investigation and optimization.
Cobb, Denise, "Development of Long-Acting Antiviral Drug Nanoformulations" (2021). Theses & Dissertations. 524.
Available for download on Thursday, April 27, 2023