Leveraging Chylomicron-Mediated Transport to Advance Long-Acting Oral HIV Therapeutics Restricted; Files & ToC
Gold, Hannah (Spring 2025)
Abstract
Lipid-derived prodrugs offer a strategy to improve the oral bioavailability of nucleos(t)ide antiretrovirals by enabling their absorption into the lymphatic system, providing access to HIV reservoirs such as lymph nodes, lung, and gut-associated lymphoid tissue. We hypothesized that chylomicrons (CMs), lipoproteins responsible for the transport of dietary lipids into the lymphatics, may facilitate the distribution of these lipidic drugs through this pathway.
To test this hypothesis, this dissertation presents the development of a novel in vitro assay that models CM-mediated drug transport, enabling direct measurement of prodrug incorporation into Caco-2 cell-derived CMs. Using this platform, a series of lipid prodrugs of tenofovir (TFV)—a widely used antiretroviral agent—was evaluated. These prodrugs featured a benzyloxyglycerol (BOG) linker in the lipid chain and/or an ω-trifluoromethyl (CF₃) motif to enhance lipophilicity, thereby promoting incorporation into CMs, and metabolic stability, ensuring maximal systemic delivery of these agents. In vitro, these modifications improved antiviral potency and resistance to metabolism compared to tenofovir exalidex (TXL), an exploratory unfunctionalized lipid prodrug of TFV. Moreover, we observed that prodrug incorporation into CMs in vitro correlated strongly with lipophilicity, with BOG and ω-CF₃ derivatives exhibiting the highest levels of CM-association relative to TXL.
To assess the translatability of this assay in vivo, we carried out a pharmacokinetic (PK) study in mice. This experiment revealed that the more lipophilic prodrugs achieved significantly higher systemic exposure levels and enhanced lung delivery when compared with TXL. Given that lymph drains into the venous system upstream of pulmonary circulation, lung concentrations were used as a surrogate marker for lymphatic transport. These data offer the first direct evidence of drug packaging into cell-derived CMs and demonstrate that CM uptake in vitro correlates with lymphatic distribution in vivo.
Together, this work establishes a new framework to study lymphatic drug delivery. Moreover, it supports the development of our lipid prodrugs of TFV as potentially affordable, orally available therapies that target HIV-enriched tissues and improve adherence, particularly in resource-limited settings.
Table of Contents
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File download under embargo until 22 May 2026 | 2025-04-07 16:04:29 -0400 | File download under embargo until 22 May 2026 |
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