Graduation Date

Summer 8-13-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Howard Gendelman

Second Advisor

Benson Edagwa

Abstract

Long-acting cabotegravir (CAB) extends antiretroviral drug (ARV) dosing to monthly for maintenance of human immunodeficiency virus type one (HIV-1) suppression and to every other month for prevention of viral transmission. However, injection dose volumes, site reactions, and clinical oversights that are required remain obstacles towards broad usage. To meet these needs, surfactant coated hydrophobic and lipophilic CAB prodrugs were created with controlled prodrug dissolution, hydrolysis and drug tissue penetration. To such ends, fatty acid ester CAB nanocrystal prodrugs with 14, 18, and 22 added carbon chains were synthesized then nanoformulated as NMCAB, NM2CAB, and NM3CAB. These nanocrystal formulations were tested for drug release, monocyte-macrophage activation, cytotoxicity and antiretroviral activities in cell systems and for pharmacokinetics (PK), and biodistribution (BD) in mice and rhesus macaques. The lead 18-carbon ester chain NM2CAB, produced plasma CAB levels above the protein-adjusted 90% inhibitory concentration for a year after a single intramuscular injection of 45 mg/kg. When compared against NMCAB and NM3CAB, NM2CAB demonstrated prolonged drug release, plasma circulation time, and tissue drug concentrations. A year-long extended drug release along with superior BD could enable NM2CAB to be used as a chemical vaccine-mimetic for prevention and treatment of HIV-1 infection.

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