Transformation of tenofovir into stable ProTide nanocrystals with long-acting pharmacokinetic profiles.

Treatment and prevention of human immunodeficiency virus type one (HIV-1) infection was transformed through widespread use of antiretroviral therapy (ART). However, ART has limitations in requiring life-long daily adherence. Such limitations have led to the creation of long-acting (LA) ART. While nucleoside reverse transcriptase inhibitors (NRTI) remain the ART backbone, to the best of our knowledge, none have been converted into LA agents. To these ends, we transformed tenofovir (TFV) into LA surfactant stabilized aqueous prodrug nanocrystals (referred to as NM1TFV and NM2TFV), enhancing intracellular drug uptake and retention. A single intramuscular injection of NM1TFV, NM2TFV, or a nanoformulated tenofovir alafenamide (NTAF) at 75 mg/kg TFV equivalents to Sprague Dawley rats sustains active TFV-diphosphate (TFV-DP) levels ≥ four times the 90% effective dose for two months. NM1TFV, NM2TFV and NTAF elicit TFV-DP levels of 11,276, 1,651, and 397 fmol/g in rectal tissue, respectively. These results are a significant step towards a LA TFV ProTide. Antiretroviral therapy (ART) for the treatment of HIV-1 requires life-long daily adherence to supress viral replication, and nucleoside reverse transcriptase inhibitors that are commonly used in ART have not been converted into long-acting agents. Here, the authors report two lipophilic tenofovir (TVF) ProTide nanoformulations, NM1TFV and NM2TFV, which sustain drug levels above therapeutic concentrations for two months after a single intramuscular dose in rats.