Graduation Date

Spring 5-4-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Immunology, Pathology & Infectious Disease

First Advisor

Benson J. Edagwa, Ph.D.

Second Advisor

Howard E. Gendelman, M.D.

Abstract

Over the past decade, the global burden of infectious diseases has increased substantively, underscoring the need for more effective treatment strategies. However, the discovery and development of new drugs with desirable safety, pharmacokinetics, and efficacy is a time consuming and costly process with great uncertainty around success rate. As an alternative to new drug development, prodrugs and novel drug delivery systems have increasingly been explored. Both serve to overcome the drug development challenges. Such drug formulations that permit extended dosing intervals of potent native drugs serve multiple purposes by promoting patient adherence to in improving treatment outcomes. This is especially noteworthy in treating chronic infectious diseases that include, but are not limited to, the human immunodeficiency virus (HIV), hepatitis B virus (HBV), and tuberculosis (TB). Each demonstrates immediate needs and strong preferences for long acting (LA) treatments. At the time of writing this dissertation, no US Food and Drug Administration (FDA) approved LA injectable regimen for HBV and TB infections were available. Therefore, this work describes our efforts towards development of LA prodrug formulations for treatment and prevention of HIV, HBV, and TB infections. To this end, a library of tenofovir (TFV) ProTides and diester (phosphonate) prodrugs were synthesized and shown to exhibit efficacy against both HIV and HBV infections. Notably, using two mouse models of HBV infection, we demonstrate that transformation of daily TFV into LA ProTide and phosphonate prodrug formulations could potentially overcome the limitations of existing regimens to significantly improve treatment of chronic HBV infection. Specifically, a single intramuscular injection of the LA TFV ProTide and phosphonate prodrug formulations into infected mice achieved sustained suppression of HBV replication with no notable adverse events. By contrast, a parenterally administered tenofovir alafenamide (TAF) control exhibited minimal effects. The viral load remained unchanged from baseline or increased in non-treated control animals. We also describe transformation of lamivudine (3TC), a highly water-soluble nucleoside reverse transcriptase inhibitor used in combination with other drugs to treat HIV and HBV infections, into a hydrophobic lipidated phenylalanine carboxylate ester prodrug named 3TC-F-C18. The new formulation demonstrated improved intracellular drug delivery in vitro and pharmacokinetics (PK) profiles in BALB/cJ mice. We also demonstrate how the LA prodrug approach could potentially be applied to TB therapies. Specifically, isoniazid (INH), a highly water-soluble anti-TB drug used for treatment and prevention of TB infection was chemically modified into two hydrophobic and lipophilic prodrugs named INHP and INHP1. Both INH prodrugs were then nanoformulated into aqueous surfactant stabilized nanosuspensions that improved drug uptake and retention by human monocyte derived macrophages with no observed cytotoxic effects. Collectively, this dissertation demonstrates how compound specific prodrug strategies could potentially be used to transform frequently administered HIV, HBV, and TB therapies into LA formulations with improved PK and efficacy profiles.

Comments

2024 Copyright, the authors

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