School of Pharmacy and Health Professions, Creighton University, Omaha, Nebraska, USA
School of Pharmacy and Health Professions, Creighton University, Omaha, Nebraska, USA.
Antimicrob Agents Chemother. 2021 Mar 18;65(4). doi: 10.1128/AAC.02320-20.
The antiretroviral treatment (ART) approach is the best-prescribed approach to date for preexposure prophylaxis (PrEP) for high-risk individuals. However, the daily combination antiretroviral (cARV) regimen has become cumbersome for healthy individuals, leading to nonadherence. Recent surveys showed high acceptance of parenteral sustained-release ART enhancing PrEP adherence. Our approach is to design a parenteral nanoparticle (NP)-based cARV sustained-release (cARV-SR) system as long-acting HIV PrEP. Here, we report a new combination of two potent ARVs (tenofovir alafenamide fumarate [TAF] and bictegravir [BIC]) loaded as a nanoformulation intended as a cARV-SR for PrEP. The BIC+TAF NPs were fabricated by using a standardized in-house methodology. intracellular kinetics, cytotoxicity, and HIV-1 protection studies demonstrated that BIC+TAF encapsulation prolonged drug retention, reduced drug-associated cytotoxicity, and enhanced HIV protection. In human peripheral blood mononuclear cells, nanoformulated BIC+TAF demonstrated significant ( < 0.05) improvement in the drug's selectivity index by 472 times compared to the BIC+TAF in solution. pharmacokinetic study of BIC, TAF, and respective drug metabolites in female BALB/c mice after single subcutaneous doses of BIC+TAF NPs demonstrated plasma drug concentrations of BIC and tenofovir above the intracellular 50% inhibitory concentration during the entire 30-day study period and prolonged persistence of both active drugs in the HIV target organs, including the vagina, colon, spleen, and lymph nodes. This report demonstrates that the encapsulation of BIC+TAF in a nanoformulation improved its therapeutic selectivity and the pharmacokinetics of free drugs. Based on these preliminary studies, we hypothesize that cARV-SR has potential as an innovative once-monthly delivery treatment for PrEP.
抗逆转录病毒治疗 (ART) 方法是迄今为止针对高危个体的暴露前预防 (PrEP) 最推荐的方法。然而，每日联合抗逆转录病毒 (cARV) 方案对健康个体来说变得繁琐，导致不依从。最近的调查显示，人们高度接受注射型长效 ART 增强 PrEP 依从性。我们的方法是设计一种基于纳米颗粒 (NP) 的 cARV 缓释 (cARV-SR) 系统作为长效 HIV PrEP。在这里，我们报告了两种有效的抗逆转录病毒药物 (富马酸替诺福韦艾拉酚胺 [TAF] 和比克替拉韦 [BIC]) 的新组合，作为一种纳米制剂，旨在作为 cARV-SR 用于 PrEP。BIC+TAF NPs 是通过使用标准化的内部方法制备的。细胞内动力学、细胞毒性和 HIV-1 保护研究表明，BIC+TAF 的包封延长了药物保留时间，降低了药物相关的细胞毒性，并增强了 HIV 保护。在人外周血单核细胞中，纳米制剂的 BIC+TAF 与溶液中的 BIC+TAF 相比，药物的选择性指数显著提高（<0.05），提高了 472 倍。BIC+TAF NPs 在雌性 BALB/c 小鼠单次皮下给药后的 BIC、TAF 和各自药物代谢物的药代动力学研究表明，在整个 30 天的研究期间，BIC 和替诺福韦的血浆药物浓度高于细胞内 50%抑制浓度，并且两种活性药物在 HIV 靶器官中的持久性延长，包括阴道、结肠、脾和淋巴结。本报告表明，BIC+TAF 的纳米制剂包封提高了其治疗选择性和游离药物的药代动力学。基于这些初步研究，我们假设 cARV-SR 具有作为 PrEP 创新的每月一次给药治疗的潜力。
