pH Responsive anti-HIV Nanoparticles

描述（由申请人提供）：该提案的假设如下：“针对淋巴组织和HIV宿主细胞的pH响应性新型纳米脂质复合物递送系统将大大提高细胞和组织的选择性，从而克服淋巴组织中抗HIV药物的药物不足，从而最大限度地抑制病毒。”我们将用一个完善的感染艾滋病毒的灵长类动物模型来检验这一假设，以确定这种针对淋巴组织和细胞的新型药物输送策略对疾病进展的影响。为此，我们将（在目标 1 中）设计由抗 HIV 药物组合组成的 pH 响应性脂质纳米颗粒，以增强病毒宿主细胞的活性。第二个目的是比较含有 HIV 蛋白酶和逆转录酶抑制剂的最有效的抗 HIV 纳米颗粒的靶组织和细胞选择性以及停留时间。从时程和剂量依赖性药代动力学和组织定位研究中收集的数据将用于为感染艾滋病毒的灵长类动物的原理验证研究确定安全有效的给药方案。最后，我们将评估优化的 pH 响应型抗 HIV 纳米粒子对 HIV 感染和疾病进展的影响。所提出的靶向新型药物递送策略将加速清除淋巴组织和细胞中残留的病毒，这些组织和细胞的口服药物暴露有限。灵长类动物模型用于探索人类无法解决的问题。这些研究获得的结果有望在抗艾滋病毒药物治疗方面取得深刻进展，并为“首次人体”临床测试提供原理验证。这项研究的成功完成将对艾滋病毒感染的治疗模式和结果产生重大影响。有了一个成熟的研究团队，当取得积极结果时，我们可以继续进行首次人体研究。

DESCRIPTION (provided by applicant): The hypothesis for this proposal is as follows: "a pH responsive novel nano-lipid complex delivery system targeted to lymphoid tissues and HIV host cells will greatly improve cell and tissue selectivity, and thus overcome drug insufficiency of anti-HIV drugs in lymphoid tissues, leading to maximum viral suppression." We will test this hypothesis with a well-established HIV-infected primate model to determine the effects of this novel drug delivery strategy targeted to lymphoid tissue and cells on disease progression. To do so, we will (in aim 1) design pH-responsive lipid-nanoparticles composed of anti-HIV drug combination for enhanced activity in virus host cells. The second aim is designed to compare the most potent anti-HIV nanoparticles containing inhibitors of HIV protease and reverse transcriptase with respect to target tissue and cell selectivity and resident time. The data collected from time-course and dose-dependent pharmacokinetic and tissue localization studies will be used to define a safe and effective dosing schedule for the proof-of-principle study in HIV-infected primates. Finally, we will evaluate the impact of the optimized, pH-responsive anti-HIV nanoparticles on HIV infection and disease progression. The proposed targeted novel drug delivery strategy will accelerate clearance of residual virus in lymphoid tissues and cells, which received limited exposure to orally administered drugs. A primate model is used to probe questions that could not be addressed in humans. The results obtained from these studies hold promise for making a profound advance in anti-HIV drug therapy and providing a proof-of-principle for "first-in-human" clinical testing. Successful completion of this study will have significant impact on treatment paradigms and outcome of HIV infections. With an established investigative team, we could proceed with first-in-human studies when a positive outcome is achieved.