Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Biomaterials. 2019 Nov;222:119441. doi: 10.1016/j.biomaterials.2019.119441. Epub 2019 Aug 20.
While antiretroviral therapy (ART) has revolutionized treatment and prevention of human immunodeficiency virus type one (HIV-1) infection, regimen adherence, viral mutations, drug toxicities and access stigma and fatigue are treatment limitations. These have led to new opportunities for the development of long acting (LA) ART including implantable devices and chemical drug modifications. Herein, medicinal and formulation chemistry were used to develop LA prodrug nanoformulations of emtricitabine (FTC). A potent lipophilic FTC phosphoramidate prodrug (M2FTC) was synthesized then encapsulated into a poloxamer surfactant (NM2FTC). These modifications extended the biology, apparent drug half-life and antiretroviral activities of the formulations. NM2FTC demonstrated a >30-fold increase in macrophage and CD4+ T cell drug uptake with efficient conversion to triphosphates (FTC-TP). Intracellular FTC-TP protected macrophages against an HIV-1 challenge for 30 days. A single intramuscular injection of NM2FTC, at 45 mg/kg native drug equivalents, into Sprague Dawley rats resulted in sustained prodrug levels in blood, liver, spleen and lymph nodes and FTC-TP in lymph node and spleen cells at one month. In contrast, native FTC-TPs was present for one day. These results are an advance in the transformation of FTC into a LA agent.
虽然抗逆转录病毒疗法 (ART) 已经彻底改变了人类免疫缺陷病毒 1 型 (HIV-1) 感染的治疗和预防，但方案依从性、病毒突变、药物毒性以及获得性耻辱感和疲劳感是治疗的限制因素。这些为长效 (LA) ART 的发展提供了新的机会，包括可植入装置和化学药物修饰。在此，我们运用药物和制剂化学方法，开发了恩曲他滨 (FTC) 的长效前药纳米制剂。合成了一种有效的亲脂性 FTC 磷酰胺前药 (M2FTC)，然后将其包裹在泊洛沙姆表面活性剂 (NM2FTC) 中。这些修饰延长了制剂的生物学、表观药物半衰期和抗逆转录病毒活性。NM2FTC 使巨噬细胞和 CD4+T 细胞对药物的摄取增加了 30 多倍，并有效地转化为三磷酸酯 (FTC-TP)。细胞内 FTC-TP 使巨噬细胞在 30 天内免受 HIV-1 攻击。单次肌肉注射 45mg/kg 相当于 NM2FTC 的 NM2FTC 可使药物原型在血液、肝脏、脾脏和淋巴结中持续存在，并使 FTC-TP 在淋巴结和脾脏细胞中持续存在一个月。相比之下，天然 FTC-TP 仅存在一天。这些结果是将 FTC 转化为长效药物的一项进展。
