Extracellular vesicles-based drug delivery of antiretroviral regimen to target CNS HIV reservoirs

基于细胞外囊泡的抗逆转录病毒治疗方案的药物递送以靶向 CNS HIV 储存库

基本信息

批准号：
10252514
负责人：
Santosh Kumar
金额：
$ 23.1万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10252514
关键词：
Adult Alzheimer&apos s Disease Animal Model Anti-HIV Agents Anti-Retroviral Agents Antineoplastic Agents BALB/cJ Mouse Biological Biological Markers Blood - brain barrier anatomy Brain Brain-Derived Neurotrophic Factor Bypass Calcium Binding Calcium ion Cardiovascular system Cells Central Nervous System Diseases Clinical Clinical Trials Cognitive Curcumin Diffusion Doxorubicin Drug Delivery Systems Drug Formulations Drug Kinetics Drug or chemical Tissue Distribution Drug usage Enrollment FDA approved Follow-Up Studies Formulation Functional disorder Future Glial Fibrillary Acidic Protein Goals Grant HIV HIV-associated neurocognitive disorder Impaired cognition In Vitro Inflammation Integrase Inhibitors Investigation Ischemic Stroke Laboratories Lead Malignant neoplasm of brain Measures Mediating MicroRNAs Microglia Microtubule-Associated Proteins Modeling Multiple Sclerosis Neuraxis Neurons Oxidative Stress Paclitaxel Parkinson Disease Pathogenesis Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology Phase Plasma Preparation Prevalence Regimen Rodent Model Safety Site Sterility Stimulus Synaptophysin System Testing Therapeutic Intervention Therapeutic Studies Tissues Toxic effect Transgenic Organisms Treatment outcome Virus base blood-brain barrier permeabilization brain cell chemo-dietary clinically relevant clinically significant combat design drug repurposing extracellular vesicles improved improved outcome inhibitor/antagonist macrophage member mouse model nanocarrier nanoformulation nanoparticle nanoparticle delivery nervous system disorder neurotoxicity novel peripheral pain personalized medicine preclinical study respiratory response small molecule targeted delivery translational impact treatment strategy triple-negative invasive breast carcinoma

项目摘要

We propose to design and develop pharmacologically relevant and clinically significant drug delivery strategies using novel nanocarrier and drug regimens that target CNS HIV reservoirs. Due to the inability of antiretroviral drugs (ARVs) to cross the blood-brain-barrier (BBB) and ARV-induced neurotoxicity, the current ARV regimens are incapable of treating HIV-associated CNS dysfunction, including HIV-associated neurocognitive disorders (HAND). Our drug delivery strategies are designed for enhanced BBB permeability, facilitating drug passage across the BBB and effectively suppressing the virus in CNS reservoirs, especially in macrophages and microglia, with minimal/tolerable neurotoxicity. We seek to develop a novel “biological nanoparticle” delivery system using “extracellular vesicles (EVs)”, which are known to cross the BBB and largely accumulate in microglia. For drug loading, we will use elvitegravir (EVG), an integrase inhibitor, along with its pharmacoenhancer, cobicistat (COBI), which are a member of the least toxic class of ARVs and used as first line of therapy. We will combine EVG with a chemodietary agent, which has been proven to be effective in treating many CNS diseases and in reducing inflammation and oxidative stress, the hallmark of HIV pathogenesis. Our central hypothesis is that dual loading of EVG-COBI and chemodietary agent within EVs, will bypass efflux transporters, cross the BBB, target macrophages and microglia, and deliver EVG and chemodietary agent to these cells, leading to HIV suppression. We will test the hypothesis by: Aim 1: Developing EV-drug formulations and determining their efficacy in macrophages and microglia using an in vitro BBB model, and Aim 2: Determining pharmacokinetic, tissue distribution, and safety profile of EV-drug formulations in an animal model. We expect to achieve novel nano-formulations of EVG-COBI and chemodietary agent in EVs that cross the BBB and target macrophages and microglia. Through our future studies, these regimens are eventually expected to improve HIV treatment outcomes in the CNS and reduce prevalence of HAND and other neurological disorders.

我们建议设计和开发与药物相关和临床上重要的药物输送策略使用针对CNS HIV储层的新型纳米载体和药物方案。由于无法进行抗逆转录病毒药物（ARV）越过血脑屏障（BBB）和ARV诱导的神经毒性（当前的ARV方案）无法治疗与HIV相关的中枢神经系统功能障碍，包括与HIV相关的神经认知疾病（手）。我们的药物输送策略旨在增强BBB渗透性，支持药物密码跨BBB，有效地抑制了中枢神经系统储层中的病毒，尤其是在巨噬细胞中小胶质细胞，具有最小/可耐受的神经毒性。我们试图开发一种新颖的“生物纳米颗粒”输送使用“细胞外蔬菜（EV）”的系统，已知可以越过BBB并在很大程度上丙烯酸小胶质细胞。对于药物加载，我们将使用整合酶抑制剂ElviteGravir（EVG）及其 Pharmacoenhancer，Cobicistat（Cobi），它是毒性最小的ARV类的成员，用作第一个治疗线。我们将将EVG与化学剂相结合，该化学剂已被证明有效治疗许多CNS疾病并减少感染和氧化应激，这是HIV的标志发病。我们的核心假设是，EVS内EVG-COBI和化学剂的双重负载将绕过外排转运蛋白，越过BBB，靶巨噬细胞和小胶质细胞，并提供EVG和这些细胞的化学剂，导致HIV抑制。我们将通过以下方式检验假设：目标1：开发 EV-Prug公式并使用体外BBB模型确定其在巨噬细胞和小胶质细胞中的效率，和目标2：确定药代动力学，组织分布和ev-drug公式的安全性动物模型。我们希望在电动汽车中实现EVG-COBI和化学剂的新型纳米形成。越过BBB，靶巨噬细胞和小胶质细胞。通过我们未来的研究，这些方案有时是预计将改善中枢神经系统中的HIV治疗结果，并降低手的患病率和其他神经系统疾病。