ORCID ID

0000-0002-3819-9372

Graduation Date

Fall 12-20-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmacology and Experimental Neuroscience

First Advisor

Dr. Howard E. Gendelman

Abstract

Patient adherence is critical for ART success to ensure adequate viral suppression, therefore, long-acting antiretrovirals are soon replacing current daily regimens. In recent years, two drugs were successfully transformed into long-acting injectables; CAB LA and RPV LA. These long-acting nanoformulations made it possible to abandon the daily pill burden, instead approximately a bimonthly injection of both drugs is enough to suppress and maintain viral load suppression. Our laboratory has been instrumental in transforming FDA-approved and experimental-HIV medications into long-acting slow effective release drugs, also known as LASER ART. LASER ART consists of slow drug metabolism and high permeability and retention inside cellular reservoirs eventually increasing the apparent life of the drugs. In this work, we apply LASER strategies to darunavir, a protease inhibitor (PI). DRV is a preferred PI due to its potency against wild type HIV as well as many mutant resistant viral strains. Among other drugs from its class, DRV is considered to have the highest genetic barrier to HIV mutations. To transform DRV into a LASER DRV, we chemically modified DRV to a prodrug, an inactive form of the drug, by conjugation of different lengths of fatty acids/lipids; M1DRV and M2DRV. These prodrugs were encased in amphiphilic polymer, NM1DRV and NM2DRV, to increase nanoparticles stability and permeability across cell membranes. The prodrug nanoformulations improved uptake, retention, release and antiretroviral activities in macrophages and T cells. Pharmacokinetics studies in mice affirmed the advantage of the modifications in extending the apparent half-life of DRV in animal models. Long-acting DRV offers the option of a long-acting PI that does not require a booster to maintain high concentrations in plasma, blood, and tissues. Therefore, DRV prodrugs nanoformulations can eliminate heavy pill burden and reduce drug-drug interactions that are prominent with PI boosters such as ritonavir and cobicistat.

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