Abstract
A long acting (LA) hydrophobic and lipophilic lamivudine (3TC) was created as a phosphoramidate pronucleotide (designated M23TC). M23TC improved intracellular delivery of active triphosphate metabolites and enhanced antiretroviral and pharmacokinetic (PK) profiles over the native drug. A single treatment of human monocyte derived macrophages (MDM) with nanoformulated M23TC (NM23TC) improved drug uptake, retention, intracellular 3TC triphosphates and antiretroviral activities in MDM and CD4+ T cells. PK tests of NM23TC administered to Sprague Dawley rats demonstrated sustained prodrug and drug triphosphate levels in blood and tissues for 30 days. The development of NM23TC remains a substantive step forward in producing LA slow effective release antiretrovirals for future clinical translation.
•Synthesis of a hydrophobic 3 TC ProTide (M23TC) and subsequent formulation (NM23TC).•NM23TC enhanced drug uptake in multiple HIV-1 relevant cell lines, rapidly converting to 3 TC-TP.•M23TC was released from monocyte-derived macrophages (MDM) over 30 days after single administration.•NM23TC exerted substantial antiretroviral activity in MDM over 30 day HIV-1ADA challenge.•A single IM injection of 75 mg/kg (3TC eq.) in rats produced detectable 3TC-TP in spleen and lymph nodes for 28 days.