A novel nanochannel system for sustained delivery of Tenofovir Alafenamide Fumarate and Emtricitabine for HIV pre-exposure prophylaxis

摘要 需要一种能够长期持续释放抗逆转录病毒药物的植入性系统来克服 HIV暴露前预防(PrEP)中患者的依从性问题和预期的临床结果 感染。这项建议的目标是利用一个已完成的团队的丰富经验 具有多学科背景并基于令人鼓舞的初步发现的调查人员将制定一项 基于纳米技术的新型可植入药物输送装置，纳米通道药物输送系统(NDS)， 用于持续和持续释放抗逆转录病毒药物。这种植入物的安全性和有效性，用于 替诺福韦、富马酸阿拉芬胺和恩曲他滨(TAF/FTC)的释放将在体外和在 已建立的动物模型。这一广泛目标将通过以下具体目标实现：目标1) 开发能够在大鼠和NHP体内持续和持续释放TAF/FTC 60天的NDS植入物。 两个NDS植入物，专为小动物和大动物模型设计，并结合远程控制的 失活机制，将开发和测试与TAF/FTC，以建立体外释放速率。活体内 分析评价植入物的安全性，测试失活机制，并测定其药代动力学 NDS传递的TAF/FTC将在健康大鼠模型上进行。目的2)评价阿司匹林的药代动力学 非人灵长类动物体内靶向释放速率持续60d的TAF/FTC缓释剂 (NHP)。目的3)评价缓释片对猴-人免疫缺陷病毒(SHIV)感染的预防作用。 NHP中NDS植入物经直肠激发的TAF/FTC。在此之后将进行药物计量 为未来的人类临床评估建立模型。拟议的工作重点是开发一部小说 用于抗逆转录病毒药物持续给药的植入式给药装置及其临床前验证 用于暴露前预防艾滋病毒感染的药物-设备组合。NDS-TAF/FTC组合 预计将通过消除问题提供关于抗逆转录病毒药物在PrEP中的疗效的独特信息 与患者的依从性、肠道吸收和口服给药的生物利用度有关。成功者 该项目的完成将标志着NDS的临床翻译向前迈出了重要的一步 植入HIV PrEP，并为有很大感染风险的个人制定有效的预防策略 艾滋病毒感染。

Abstract An implantable system capable of long-term sustained release of antiretroviral drugs is needed to overcome patient adherence issues and achieve desired clinical outcomes in pre-exposure prophylaxis (PrEP) of HIV infection. The goal of this proposal, leveraging the extensive experience from a team of accomplished investigators with multidisciplinary backgrounds and based on encouraging preliminary findings, is to develop a novel, nanotechnology-based, implantable drug delivery device, the nanochannel drug delivery system (nDS), for sustained and constant release of antiretroviral drugs. The safety and efficacy of this implant, used for the delivery of tenofovir alafenamide fumarate and emtricitabine (TAF/FTC), will be validated in vitro and in established animal models. This broad objective will be achieved through the following specific aims: Aim 1) to develop nDS implants capable of sustained and constant release of TAF/FTC in rats and NHP for 60 days. Two nDS implants designed for small and large animal models, and incorporating a remotely controlled deactivation mechanism, will be developed and tested with TAF/FTC to establish release rates in vitro. In vivo analysis to evaluate safety of implant, test the deactivation mechanism, and determine the pharmacokinetics of nDS-delivered TAF/FTC will be conducted in healthy rat models. Aim 2) to assess the pharmacokinetics of constant delivery of TAF/FTC from nDS implants at target release rates for 60 days in non-human primates (NHP). Aim 3) to evaluate prevention of simian-human immunodeficiency virus (SHIV) infection by release of TAF/FTC from nDS implants through rectal challenge in NHP. This will be followed by pharmacometric modeling for future clinical evaluation in humans. The proposed work focuses at developing a novel implantable drug delivery device for the sustained delivery of antiretroviral drugs and the preclinical validation of the drug-device combination for pre-exposure prophylaxis of HIV infection. The nDS-TAF/FTC combination is expected to provide unique information about antiretroviral drugs’ efficacy in PrEP by eliminating issues related to patient compliance, gut absorption, and bioavailability from oral administration. The successful completion of this project will represent a significant step forward toward the clinical translation of the nDS implant for HIV PrEP and an effective preventive strategy for individuals who are at substantial risk of acquiring HIV infection.