pH Responsive anti-HIV Nanoparticles

pH 响应抗 HIV 纳米颗粒

基本信息

批准号：
8077736
负责人：
RODNEY J.Y. HO
金额：
$ 10万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-07 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8077736
关键词：
Abbreviations Acetic Acids Address Adverse effects Antiviral Agents Artificial nanoparticles Binding Blood Circulation CD4 Positive T Lymphocytes Cells Clinical Combination Drug Therapy Complex Data Disease Progression Dose Drug Carriers Drug Combinations Drug Delivery Systems Drug Formulations Drug Kinetics Drug or chemical Tissue Distribution Drug-sensitive Encapsulated Exhibits Exposure to Gadolinium HIV Highly Active Antiretroviral Therapy Human Human Virus Indinavir Individual Infection Investigation Kinetics Lead Life Lipids Literature Lymphatic System Lymphoid Tissue Macaca Magnetic Resonance Magnetic Resonance Imaging Medical Membrane Modeling Nucleosides Omniscan Oral Organ Outcome Pentas Peptide Hydrolases Peptide Signal Sequences Pharmaceutical Preparations Pharmacotherapy Primates Protease Inhibitor Public Health RNA-Directed DNA Polymerase Residual state Reverse Transcriptase Inhibitors Schedule Surface System Technology Testing Time Tissues Viral Viral load measurement Viremia Virus Virus Activation Virus Diseases aqueous design diethylenetriamine improved inhibitor/antagonist lymph nodes nano nanoparticle novel novel strategies particle phosphonylmethoxypropyl adenine pinacolyl methylphosphonic acid public health relevance research clinical testing research study response

项目摘要

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.

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反应型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，从而最大程度地抑制病毒。”我们将使用良好的HIV感染的灵长类动物模型检验这一假设，以确定针对淋巴组织和细胞对疾病进展的新型药物输送策略的影响。为此，我们将（在AIM 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。第二个目的旨在比较含有HIV蛋白酶抑制剂和逆转录酶相对于靶组织和细胞选择性和居民时间的最有效的抗HIV纳米颗粒。从时间课和剂量依赖性的药代动力学和组织定位研究收集的数据将用于定义HIV感染的灵长类动物的原理学证明研究的安全有效剂量时间表。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。拟议的有针对性的新型药物输送策略将加速淋巴组织和细胞中残留病毒的清除，这些病毒受到口服药物的暴露有限。灵长类动物模型用于探究人类无法解决的问题。从这些研究中获得的结果有望在抗HIV药物疗法方面取得深远的进步，并为“人类第一”临床测试提供原则证明。这项研究的成功完成将对治疗范例和艾滋病毒感染的结果产生重大影响。有了一个既定的调查团队，我们可以在实现积极的结果时进行第一研究。公共卫生相关性：虽然抗病毒药物疗法的组合延长了感染HIV的个体的寿命，但组织中的残留病毒和病毒重新激活导致疾病进展。拟议的新型策略旨在满足这种未满足的医疗需求，并最终可能导致治疗艾滋病毒/艾滋病。