Antiretroviral drug discovery and formulation design will facilitate viral clearance in infectious reservoirs. While progress has been realized for select hydrophobic integrase and nonnucleoside reverse transcriptase inhibitors, limited success was seen to date with hydrophilic nucleosides. To overcome these limitations hydrophobic long-acting drug nanoparticles were created for the commonly used nucleoside reverse transcriptase inhibitor, lamivudine (2′,3′-dideoxy-3′-thiacytidine, 3TC).
A two-step synthesis created a slow release long-acting hydrophobic 3TC. Conjugation of 3TC to a fatty acid created a myristoylated prodrug was encased into a folate-decorated poloxamer 407. Both in vitro antiretroviral efficacy in human monocyte-derived macrophages (MDM) and pharmacokinetic (PK) profiles in mice were evaluated for the decorated nanoformulated drug.
A stable drug formulation was produced by poloxamer encasement that improved monocyte-macrophage uptake, antiretroviral activities and drug PK profiles over native drug formulations.
Sustained release of long-acting antiretroviral therapy is a new therapeutic frontier for HIV/AIDS. 3TC depot formation in MDM can be facilitated through stable subcellular internalization and slow drug release.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.