(379d) Antiretroviral Supramolecular Prodrug Hydrogelators for Long-Acting Injectable HIV Treatment

According to the Joint United Nations Program on HIV/AIDS, an estimated 38.0 million people are currently living with human immunodeficiency virus (HIV) world-wide, with approximately 1.7 million new infections annually. Additional therapeutic formulations, including long-acting injectable (LAI) versions of existing antiretrovirals, are necessary to meet the diverse needs of the patient population and to address the ongoing prevention crisis. Through the conjugation of tenofovir (TFV), an FDA approved nucleoside reverse transcriptase inhibitor (NRTI), to peptide amphiphiles, we created prodrug hydrogelators (TFV-DAs) that self-assemble into one-dimensional nanostructures in aqueous environments and that undergo a rapid solution to gel transformation upon injection to create a hydrogel drug depot in situ. Transmission electron microscopy, circular dichroism, Nile Red encapsulation assays, gel inversion tests, and dynamic oscillatory rheometry revealed that simple modifications to the molecular design significantly impacted self-assembly and gelation behavior of the TFV-DAs. In turn, these variations in supramolecular packing and stability influenced in vitro gel release and pharmacokinetic distribution of TFV following subcutaneous injection in a mouse model, as assessed by RP-HPLC and UPLC-MS-MS, respectively. The changes that can be induced in the morphology, stability, gelation, and degradation of the TFV-DAs through simple adjustments to the design indicate that the prodrug hydrogelator system is an easily modifiable platform that allows for the precise control of therapeutic release rate, thereby enabling us to optimize TFV delivery for the intended clinical application. This work represents an important step in the development of a LAI TFV formulation that displays facile and repeatable synthesis and that can attain 100% fixed prodrug loading without the need for excipient materials. The reported findings demonstrate the feasibility of this novel delivery platform for the sustained, linear release of an NRTI at rates that can be precisely tuned to attain therapeutically relevant TFV plasma concentrations.