Doctor of Philosophy (PhD)
Pharmacology and Experimental Neuroscience
Howard E. Gendelman
The introduction of highly active antiretroviral therapy led to a paradigm shift in the management of HIV/AIDS changing a disease considered “a death sentence” to “a manageable chronic disease”. Nevertheless, challenges exist for successful treatment of HIV, including patient adherence to the complex daily regimens and the inability of current formulations to target viral sanctuaries. Introduction of nanoformulated antiretroviral therapy (ART) is a promising alternative to tackle these challenges. Our laboratory has been focusing on developing long-acting (LA) nanoformulated antiretrovirals and has succeeded in developing LA integrase inhibitors. However, challenges for this approach extend to a range of short-acting hydrophilic drugs, mainly nucleoside reverse transcriptase inhibitors (NRTIs). To this end, we developed a one-step synthesis scheme to create a hydrophobic ester prodrug of emtricitabine (FTC), an NRTI that is a key component of the initial ART and of a reported pre-exposure prophylaxis measure. The nanoformulation process was optimized to prepare poloxamer 407-encased nanocrystals. To eliminate HIV from the viral sanctuaries, macrophages were harnessed as “Trojan horses” for drug delivery and distribution to these difficult-to-reach sanctuaries. Nanoformulation of the FTC prodrug was facilitated by conjugating it to a long fatty acid chain, palmitoyl chloride. The resultant nanoparticles exhibited long-term stability, higher uptake and longer retention in macrophages, and these properties were translated into extended antiretroviral efficacy for 10 days. Moving this nanoformulation forward into animal studies showed sustained FTC blood concentrations of more than 20-times its EC50 at day 7 after a single intramuscular injection in rats, in contrast to undetectable levels following parent FTC injection. Furthermore, higher concentrations of FTC were observed in liver, spleen lymph nodes, and brain tissues. Interestingly, these results were mirrored by intracellular FTC triphosphate levels that were detectable for up to 10 days in vitro, and for 7 days in peripheral blood mononuclear cells (PBMCs) and in cells isolated from spleen and lymph nodes. We anticipate that this nanoformulation will further extend drug action in humans considering reported species differences in plasma esterase activities. Also, these improvements aided by medicinal chemistry unveils new opportunities for LA FTC formulation and for other NRTIs as well. These simplified manufacturing strategies hold promises for bringing LA ART closer to clinical translation.
Ibrahim, Ibrahim M., "Synthesis and Characterization of a Long-Acting Emtricitabine Prodrug Nanoformulation" (2019). Theses & Dissertations. 360.