(569e) Self-Assembling Prodrugs As Effective Antiretroviral Therapeutics

Long-acting antiretroviral (ARV) therapy, which can ease the burden of daily adherence and reduce development of drug resistance, is particularly important for HIV prevention and treatment. However, most ARV combinations rely on water-soluble drugs that are unsuitable for nanoformulation, thereby creating an obstacle in the development of long-acting regimens. Here we report on a supramolecular hydrogel that enables the linear, sustained release of ARVs over weeks. Covalent linkage of a hydrophilic nucleoside reverse transcriptase inhibitor (NRTI), Lamivudine(3TC), to the side chains of short amphiphilic peptide segments produces self-assembling prodrug hydrogelators. The prodrug associates into one-dimensional nanostructure in aqueous conditions, which were characterized by their size, shape, and stability. Under physiological conditions, the self-assembling prodrug forms a supramolecular hydrogel depot that enhances retention and prolongs drug release. The hydrogels exhibit linear and sustained drug release profiles with tunable release rates that are controlled by engineering the stability of the supramolecular network. Pharmacokinetic studies in Balb/cJ mice demonstrated that the hydrogels maintain plasma 3TC levels at or above their inhibitory concentration for more than 4 weeks, with no recorded adverse events in the animals. We believe these results demonstrate that this system offers an exciting platform for injectable long-acting regimens consisting of NRTIs and other hydrophilic therapeutic agents to improve current antiretroviral therapy.