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.

抗逆转录病毒疗法（ART）的广泛使用改变了人类免疫缺陷病毒一型（HIV-1）感染的治疗和预防。然而，ART 在需要终生每日坚持方面存在局限性。这些限制导致了长效 (LA) ART 的诞生。虽然核苷逆转录酶抑制剂 (NRTI) 仍然是 ART 的支柱，但据我们所知，尚未将其转化为 LA 药物。为此，我们将替诺福韦 (TFV) 转化为 LA 表面活性剂稳定的水性前药纳米晶体（称为 NM1TFV 和 NM2TFV），从而增强细胞内药物的摄取和保留。单次肌肉注射 NM1TFV、NM2TFV 或纳米制剂替诺福韦艾拉酚胺 (NTAF)，剂量为 75 mg/kg TFV，相当于斯普拉格道利大鼠，可维持活性 TFV-二磷酸 (TFV-DP) 水平≥ 90% 有效剂量的四倍，持续两个月。 NM1TFV、NM2TFV 和 NTAF 在直肠组织中分别引起 11,276、1,651 和 397 fmol/g 的 TFV-DP 水平。这些结果是迈向 LA TFV ProTide 的重要一步。