Graduation Date

Spring 5-4-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Interdisciplinary Graduate Program in Biomedical Sciences

First Advisor

Benson J. Edagwa, Ph.D.

Second Advisor

Howard E. Gendelman, M.D.

Abstract

Human immunodeficiency virus (HIV) and opioid use disorder (OUD) are among the top global public health challenges, with a significant overlap in the number of cases and higher mortality risks compared to the general population. Treatment and recreational opioid use lead to addictive disorders. Both conditions require repeated dosing of therapy where adherence to a strict lifelong regimen remains a major challenge. Notably, people living with HIV/AIDS (PLWHA) and struggling with opioid use disorders (OUD) show suboptimal adherence to antiretroviral drugs (ARVs). Also, the risk of transmitting HIV and other blood-borne infections through the sharing of needles and other injection equipment is high in patients with OUD. Recent studies have demonstrated that initiation of long-acting treatments among HIV and OUD patients is not only associated with decreased risk for opioid-related adverse events but also improved viral suppression. We hypothesized that the creation of ultra-long-acting (ULA) prodrug formulations could further improve treatment outcomes. We, therefore, sought to develop ultra-long-acting formulations of a broadly used integrase strand transfer inhibitor called dolutegravir (DTG) and mu-opioid receptor (MOR) partial agonist called buprenorphine (BUP), which has demonstrated a significant advantage in reducing opioid overdose deaths. For DTG, a library of monomeric and dimeric prodrug nanoformulations was synthesized and subjected to in vitro and preclinical pharmacokinetic (PK) screening studies that led to the identification of the lead 18-carbon chain-modified ester prodrug nanocrystal candidate (coined NM2DTG) with the potential to sustain therapeutic drug concentrations for over six months after a single intramuscular (IM) dose. Ideal physiochemical and PK properties facilitated slow DTG release from tissue macrophage depot stores at the muscle injection site and adjacent lymphoid tissues following single parenteral injections. Significant plasma drug levels were recorded for up to a year in rodents following a single injection of NM2DTG. Tissue sites for prodrug hydrolysis were dependent on nanocrystal dissolution and prodrug release, drug-depot volume, perfusion, and cell-tissue pH. Each affected an extended NM2DTG apparent half-life recorded by PK parameters. Similarly, a single IM injection of the lead BUP nanoformulations in Sprague Dawley rats sustains plasma BUP levels at or above the target mu-opioid receptor occupancy concentrations for over three months in ongoing PK studies. We hypothesize that BUP prodrugs will prolong the drug’s apparent half-life and allow for creation of organic solvent free ULA formulations. In summary, the development of ultra-long-acting DTG and BUP injectable formulations can improve treatment of HIV and OUD by enhancing adherence and delivery of the two broadly used drugs into sites of action.

Comments

2023 Copyright, the authors

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