合成及长效恩曲他滨前药纳米制剂的表征。
Synthesis and characterization of a long-acting emtricitabine prodrug nanoformulation.
机构信息
Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
Department of Pharmacology, College of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
出版信息
Int J Nanomedicine. 2019 Aug 7;14:6231-6247. doi: 10.2147/IJN.S215447. eCollection 2019.
PURPOSE
A palmitoylated prodrug of emtricitabine (FTC) was synthesized to extend the drug's half-life, antiretroviral activities and biodistribution.
METHODS
A modified FTC prodrug (MFTC) was synthesized by palmitoyl chloride esterification. MFTC's chemical structure was evaluated by nuclear magnetic resonance. The created hydrophobic prodrug nanocrystals were encased into a poloxamer surfactant and the pharmacokinetics (PK), biodistribution and antiretroviral activities of the nanoformulation (NMFTC) were assessed. The conversion of MFTC to FTC triphosphates was evaluated.
RESULTS
MFTC coated with poloxamer formed stable nanocrystals (NMFTC). NMFTC demonstrated an average particle size, polydispersity index and zeta potential of 350 nm, 0.24 and -20 mV, respectively. Drug encapsulation efficiency was 90%. NMFTC was readily taken up by human monocyte-derived macrophages yielding readily detected intracellular FTC triphosphates and an extended PK profile.
CONCLUSION
NMFTC shows improved antiretroviral activities over native FTC. This is coordinate with its extended apparent half-life. The work represents an incremental advance in the development of a long-acting FTC formulation.
目的
合成了恩曲他滨（FTC）的棕榈酰化前药，以延长药物的半衰期、抗逆转录病毒活性和生物分布。
方法
通过棕榈酰氯酯化合成了改良的 FTC 前药（MFTC）。通过核磁共振评估 MFTC 的化学结构。将所创建的疏水前药纳米晶体包封在泊洛沙姆表面活性剂中，并评估纳米制剂（NMFTC）的药代动力学（PK）、生物分布和抗逆转录病毒活性。评估了 MFTC 向 FTC 三磷酸盐的转化。
结果
用泊洛沙姆包被的 MFTC 形成了稳定的纳米晶体（NMFTC）。NMFTC 的平均粒径、多分散指数和 Zeta 电位分别为 350nm、0.24 和-20mV。药物包封效率为 90%。NMFTC 容易被人单核细胞衍生的巨噬细胞摄取，产生可检测到的细胞内 FTC 三磷酸盐和延长的 PK 特征。
结论
NMFTC 显示出比天然 FTC 更高的抗逆转录病毒活性。这与其延长的表观半衰期相一致。这项工作代表了长效 FTC 制剂开发的一个渐进式进展。
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