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

• 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
• 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' 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

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具有临床意义的药物输送策略 使用新的纳米载体和药物方案，靶向中枢神经系统艾滋病毒水库。由于抗逆转录病毒药物 抗逆转录病毒药物（ARV）通过血脑屏障（BBB）和ARV诱导的神经毒性，目前的ARV方案 不能治疗HIV相关的CNS功能障碍，包括HIV相关的神经认知障碍 （手）。我们的药物递送策略旨在增强BBB渗透性，促进药物通过 通过BBB并有效抑制CNS储库中的病毒，特别是巨噬细胞和 小胶质细胞，具有最小/可耐受的神经毒性。我们寻求开发一种新的“生物纳米颗粒”输送 使用“细胞外囊泡（EV）"的系统，已知其穿过BBB并在BBB中大量积累。 小胶质细胞对于药物负载，我们将使用埃替格韦（EVG），一种整合酶抑制剂，沿着其 药物增强剂，cobicistat（COBI），其是毒性最小的ARV类别的成员，并用作第一个 治疗线。我们将联合收割机EVG与一种已被证明有效的化学饮食剂联合使用， 治疗许多中枢神经系统疾病，并减少炎症和氧化应激，艾滋病毒的标志 发病机制我们的中心假设是，EVG-COBI和化学膳食剂在EV内的双重负载， 旁路外排转运蛋白，穿过BBB，靶向巨噬细胞和小胶质细胞，并递送EVG和 化学饮食剂对这些细胞，导致艾滋病毒抑制。我们将通过以下方式检验假设：目标1：发展 EV-药物制剂并使用体外BBB模型确定它们在巨噬细胞和小胶质细胞中的功效， 和目的2：确定EV-药物制剂的药代动力学、组织分布和安全性特征， 动物模型我们期望在EV中实现EVG-COBI和化学膳食剂的新型纳米制剂， 穿过血脑屏障并靶向巨噬细胞和小胶质细胞。通过我们未来的研究，这些方案最终 预计将改善CNS中的HIV治疗结果，并降低HAND和其他神经系统疾病的患病率。 紊乱