Synthesis of a long acting nanoformulated emtricitabine ProTide

While antiretroviral therapy (ART) has revolutionized treatment and prevention of human immunodeficiency virus type one (HIV-1) infection, regimen adherence, viral mutations, drug toxicities and access stigma and fatigue are treatment limitations. These have led to new opportunities for the development of long acting (LA) ART including implantable devices and chemical drug modifications. Herein, medicinal and formulation chemistry were used to develop LA prodrug nanoformulations of emtricitabine (FTC). A potent lipophilic FTC phosphoramidate prodrug (M2FTC) was synthesized then encapsulated into a poloxamer surfactant (NM2FTC). These modifications extended the biology, apparent drug half-life and antiretroviral activities of the formulations. NM2FTC demonstrated a >30-fold increase in macrophage and CD4+ T cell drug uptake with efficient conversion to triphosphates (FTC-TP). Intracellular FTC-TP protected macrophages against an HIV-1 challenge for 30 days. A single intramuscular injection of NM2FTC, at 45 mg/kg native drug equivalents, into Sprague Dawley rats resulted in sustained prodrug levels in blood, liver, spleen and lymph nodes and FTC-TP in lymph node and spleen cells at one month. In contrast, native FTC-TPs was present for one day. These results are an advance in the transformation of FTC into a LA agent. •A lipophilic FTC phosphoramidate prodrug (M2FTC) was synthesized then encapsulated into a poloxamer surfactant (NM2FTC).•NM2FTC demonstrated active macrophage and CD4+ T cells drug uptake of >30- and 8- fold, respectively.•Enhanced potency at half effective concentration (EC50) was observed for NM2FTC compared to native FTC in CD4+ T-cells.•FTC triphosphates (FTC-TP) were retained in macrophages for one month after a single NM2FTC treatment with associated protection against an HIV-1ADA cell challenge of 0.1 infectious viral particles/cell.•A single intramuscular injection of NM2FTC, at 45 mg/kg drug equivalents, into Sprague Dawley rats demonstrated sustained prodrug levels in blood, liver, spleen and lymph nodes for up to a month.