Transformation of tenofovir into stable ProTide nanocrystals with long-acting pharmacokinetic profiles.
Transformation of tenofovir into stable ProTide nanocrystals with long-acting pharmacokinetic profiles.
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DOI：
10.1038/s41467-021-25690-5
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发表时间：
2021-09-16
影响因子：
16.6
通讯作者：
Edagwa B
中科院分区：
文献类型：
--
作者：
Cobb DA;Smith N;Deodhar S;Bade AN;Gautam N;Shetty BLD;McMillan J;Alnouti Y;Cohen SM;Gendelman HE;Edagwa B
通过广泛使用抗逆转录病毒疗法，人类免疫缺陷病毒1型（HIV-1）感染的治疗和预防发生了变化。然而，ART在需要终身每日坚持方面具有局限性。这些限制导致了长效（LA）ART的产生。虽然核苷逆转录酶抑制剂（NRTI）仍然是ART的支柱，但据我们所知，没有一种药物被转化为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NM 1 TFV和NM 2 TFV），增强细胞内药物摄取和保留。以75 mg/kg TFV当量向Sprague道利大鼠单次肌内注射NM 1 TFV、NM 2 TFV或纳米制剂替诺福韦艾拉酚胺（NTAF），可维持活性TFV-二磷酸（TFV-DP）水平≥ 90%有效剂量的4倍，持续2个月。NM 1 TFV、NM 2 TFV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。这些结果是朝着LA TFV磷酰胺酯前药迈出的重要一步。用于治疗HIV-1的抗逆转录病毒疗法（ART）需要终生每日坚持以抑制病毒复制，并且常用于ART的核苷逆转录酶抑制剂尚未转化为长效剂。在这里，作者报告了两种亲脂性替诺福韦（TVF）ProTide纳米制剂，NM 1 TFV和NM 2 TFV，它们在大鼠单次肌内注射后两个月内维持药物水平高于治疗浓度。
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.
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影响因子：
5
作者：
Bressani RF;Nowacek AS;Singh S;Balkundi S;Rabinow B;McMillan J;Gendelman HE;Kanmogne GD
通讯作者：
Kanmogne GD
影响因子：
4.9
作者：
Gunawardana, Manjula;Remedios-Chan, Mariana;Bauma, Marc M.
通讯作者：
Bauma, Marc M.
HIV-1 的细胞储存库及其在病毒持久性中的作用。
影响因子：
1
作者：
Alexaki A;Liu Y;Wigdahl B
通讯作者：
Wigdahl B
影响因子：
6.6
作者：
Edagwa B;McMillan J;Sillman B;Gendelman HE
通讯作者：
Gendelman HE
DOI：
10.1016/j.jpba.2016.08.022
发表时间：
2016-11-30
影响因子：
3.4
作者：
Golla, Vijaya Madhyanapu;Kurmi, Moolchand;Singh, Saranjit
通讯作者：
Singh, Saranjit