Development of sustained and tunable release of antiretrovirals with polymeric prodrugs synthesized via RAFT polymerization

Abstract

Antiretroviral therapy (ART) is highly effective in treating and preventing human immunodeficiency virus (HIV), but its success relies on strict adherence to dosing regimens to suppress viral replication. Long-acting formulations (LAFs) address this challenge by reducing dosing frequency. However, the diverse physicochemical properties of antiretrovirals make some drugs incompatible with traditional diffusion- and dissolution-based delivery systems. To overcome the limitations associated with the physical properties of individual antiretrovirals that prevent sustained delivery, we propose the chemical modification of drugs to obtain prodrug monomers, and the subsequent reversible addition-fragmentation chain-transfer (RAFT) polymerization of said prodrug monomers to obtain "drugamers". Drugamers have been demonstrated to have an extended duration of action when subcutaneously injected to obtain an in situ forming depot. Despite their promise, the broader applicability of this approach to other antiretrovirals with varying properties has not been fully investigated. Here, we synthesized raltegravir (RAL) and atazanavir (ATV) polymeric prodrugs, or drugamers, to evaluate their potential for sustained release. Drugamers were dissolved in dimethylsulfoxide (DMSO) and subcutaneously injected as in-situ forming implants in murine models. The release profile was tunable by adjusting the hydrophilicity by modification of the polymer composition with distinct comonomers. Furthermore, co-injections of different copolymers of RAL drugamers could achieve summations of release profiles of individual RAL drugamers to sustain the release of RAL for 42 days, which is the longest duration that has been reported. RAL drugamers were well-tolerated and are excreted renally after drug release without the need for surgical removal. This study demonstrates the versatility of RAFT polymeric prodrugs for the sustained delivery of hydrophilic drugs, highlighting the tunability and broad applicability of the drugamer platform to improve adherence to antiretroviral regimen.