Graduation Date

Spring 5-5-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Dr. Howard E. Gendelman

Abstract

Recent development of long-acting antiretroviral therapeutic regimens has opened a new chapter for HIV/AIDS management. Cabotegravir (CAB), as one of the very first long-acting antiretroviral regimens, has drawn tremendous attention. However, the remaining challenges include suboptimal dosing intervals, large injection volume, injection site reactions, lack of tissue penetration, etc. As one of the pioneers in this field, our lab was successful in harnessing mononuclear phagocytes as “Trojan horses” for antiretroviral drug delivery and transportation to viral reservoirs. We proposed this targeted delivery strategy could address the limitations of current CAB formulation. To this end, we developed folic acid decorated CAB nanoformulation to target macrophages. The manufacturing scheme was optimized for formulation stability and reproducibility. Purification steps, previously considered necessary to remove excess receptor-competing targeted polymer, were eliminated for high drug loading and manufacturing ease. The resultant folic acid targeted CAB formulation exhibited enhanced macrophage uptake and improved pharmacokinetic profiles. To further improve CAB’s cellular retention, myristoylated CAB was synthesized and formulated into poloxamer 407 coated nanocrystal formulation, which exhibited markedly enhanced cellular retention, antiretroviral efficacy, pharmacokinetic and biodistribution profiles. The mechanism for prolonged half-life and enhance tissue penetration lies in the prompt mononuclear phagocytes entry and fast redistribution of the drug into reticuloendothelial system as observed in the injection sites and tissues. We believe these improvements in formulation and medicinal chemistry unveil new opportunities for long-acting CAB formulation by readily addressing current existing limitations. These strategies, with simplified manufacturing schemes, hold translational merit for improved HIV management.

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