Doctor of Philosophy (PhD)
Howard E Gendelman
Over the past decade, work from our laboratory has demonstrated the potential of targeted nanoformulated antiretroviral therapy (nanoART) to produce sustained high plasma and tissue drug concentrations for weeks following a single intramuscular (IM) administration that can suppress ongoing viral replication and mitigate dose associated viral resistance. While progress has occurred towards developing long-acting nanoformulations for protease and nonnucleoside reverse transcriptase (RT) inhibitors, development of nanoformulations of hydrophilic nucleoside RT inhibitor drugs have remained elusive. Abacavir (ABC); a hydrophilic molecule exhibited limited utilities to develop into long-acting nanoformulation platform. Furthermore, inefficient conversion of ABC to its biological active metabolites; carbovir triphosphate jeopardizes its therapeutic index. Thus, improving bioavailability and the therapeutic index of the ABC is urgently needed. To this end, a phosphoramidate prodrug of ABC (PABC), and a myristoylated prdrug of ABC (MABC) was synthesized to improve the therapeutic index of its native hydrophilic counterpart.
The notion of PABC synthesis was to increase intracellular nucleoside 5’-O- triphosphate levels by bypassing rate-limiting monophosphorylation of the parent drug. We reasoned that long-acting PABC nanoformulations could improve ABC’s Pharmacokinetic (PK) and pharmacodynamics (PD). Herein, PABC was successfully synthesized and characterized by 1H-NMR and FTIR spectroscopy. PABC was incorporated into a PLGA-lipid nanoformulation. In vitro and in vivo viral efficacy of PABC and PABC encased nanoformulation were evaluated in human monocytes derived macrophages (MDM) and Hu-PBL reconstituted NSG mice respectively. Concomitantly, a platform was constructed to convert the hydrophilic ABC into a hydrophobic derivative through esterification at 5’-OH position of ABC (MABC). MABC was loaded with high concentration into a polymer and decorated with appropriate targeting ligands for improvement in biodistribution, half-life and antiretroviral efficacy. Antiretroviral activity, uptake, retention and cellular trafficking of both the pro-drug and MABC encased in poloxamer nanoformulations were assessed in MDM. Drug PK was evaluated over 14 days for ABC and nanoformulated MABC after intramuscular injection in Balb/c mice.
Singh, Dhirender, "Synthesis and Development of Long-Acting Abacavir Prodrug Nanoformulations" (2016). Theses & Dissertations. 140.