pH Responsive anti-HIV Nanoparticles

描述（由申请人提供）：该提案的假设如下：“靶向淋巴组织和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选择性，从而克服抗HIV药物在淋巴组织中的药物不足，导致最大程度的病毒抑制。“我们将用一个成熟的HIV感染灵长类动物模型来测试这一假设，以确定这种靶向淋巴组织和细胞的新型药物递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，以增强在病毒宿主细胞中的活性。第二个目的是比较最有效的抗艾滋病毒纳米粒子含有HIV蛋白酶和逆转录酶的抑制剂，相对于靶组织和细胞的选择性和驻留时间。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定义HIV感染灵长类动物中原理验证研究的安全有效给药方案。最后，我们将评估优化的pH响应性抗HIV纳米颗粒对HIV感染和疾病进展的影响。提出的靶向新型药物递送策略将加速淋巴组织和细胞中残留病毒的清除，这些组织和细胞接受有限的口服给药药物暴露。灵长类动物模型被用来探索人类无法解决的问题。从这些研究中获得的结果有望在抗艾滋病毒药物治疗方面取得重大进展，并为“首次人体”临床试验提供原理证明。本研究的成功完成将对HIV感染的治疗模式和结局产生重大影响。有了一个成熟的调查团队，我们可以在取得积极成果时进行首次人体研究。公共卫生相关性：虽然联合抗病毒药物治疗延长了艾滋病毒感染者的生命，但组织中残留的病毒和病毒再活化导致疾病进展。拟议的新战略旨在解决这一未得到满足的医疗需求，并可能最终导致治愈艾滋病毒/艾滋病。

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. PUBLIC HEALTH RELEVANCE: While combination antiviral drug therapies have extended the life of individuals infected with HIV, the residual virus in tissues and virus reactivation leads to disease progression. The proposed novel strategies are designed to address this unmet medical need and may eventually lead to a cure for HIV/AIDS.