Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
Nat Commun. 2021 Sep 16;12(1):5458. doi: 10.1038/s41467-021-25690-5.
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.
通过广泛使用抗逆转录病毒疗法（ART），人类免疫缺陷病毒 1 型（HIV-1）的治疗和预防发生了转变。然而，ART 在需要终身每日服用方面存在局限性。这些局限性导致了长效（LA）ART 的产生。虽然核苷逆转录酶抑制剂（NRTI）仍然是 ART 的基础，但据我们所知，没有一种药物已转化为 LA 制剂。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（分别称为 NM1TFV 和 NM2TFV），从而增强了细胞内药物摄取和保留。单次肌肉注射 NM1TFV、NM2TFV 或纳米制剂替诺福韦艾拉酚胺（NTAF），以 75mg/kg TFV 当量（相当于 75mg/kg TFV 当量）给 Sprague Dawley 大鼠，可维持活性 TFV-二磷酸（TFV-DP）水平≥四个月 90%有效剂量。NM1TFV、NM2TFV 和 NTAF 分别在直肠组织中引发 11、276、1651 和 397 fmol/g 的 TFV-DP 水平。这些结果是朝着 LA TFV ProTide 迈出的重要一步。
