Doctor of Philosophy (PhD)
Howard E. Gendelman
The introduction of nanoformulated antiretroviral therapeutic regimens is a promising alternative to standard once a day oral treatment of HIV infection. Our lab has pioneered this effort and was successful in harnessing mononuclear phagocytes (monocytes, dendritic cells and macrophages) as nanoformulated drug carriers. The approach was developed as Trojan horses for drug transport, delivery and distribution to sites of viral replication in order to facilitate microbial elimination in HIV sanctuaries. However, the remaining challenges for current antiretroviral nanoformulations include to formulate a broad range of hydrophilic short-acting drugs, and to elucidate the mechanism of sequestered nanoparticles in macrophages at the subcellular level. To this end, we developed a two-step synthesis to create a long-acting lamivudine (2’,3’-dideoxy-3’-thiacytidine, 3TC). A stable hydrophobic pro-drug crystal formulation was produced by poloxamer drug encasement. Conversion of the hydrophilic 3TC significantly extended its bioavailability facilitated by chemical drug conjugation to a fatty acid and creating a myristoylated drug. A folate targeted poloxamer 407 coated a newly formed nanocrystalline pro-drug markedly improving cell uptake, bioavailability and pharmacokinetic profiles. Reduced cytotoxicity and robust antiretroviral activities were also achieved. The nanoparticle interactions at the subcellular level were investigated vial nanoformulated protease inhibitor. Quantitative SWATH-MS proteomics for complete recording of fragment ion peptide precursors in biological sample. and cell profiling were applied for endolysosomal trafficking for HIV-1 assembly and nanoformulation depot formation. We believe these findings unveil new opportunities for nanoformulated antiretroviral therapy and have brought the idea of long-acting antiretroviral therapy closer to the clinical translation.
Guo, Dongwei, "Long-Acting Antiretroviral Nanoformulation Development and Subcellular Trafficking" (2016). Theses & Dissertations. 117.