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: 10448467
• 负责人: Santosh Kumar
• 金额: $ 19.25万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10448467
• 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; 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药理学相关且具有临床意义的药物输送策略 使用针对 CNS HIV 储存库的新型纳米载体和药物疗法。由于无法抗逆转录病毒 药物（ARV）穿越血脑屏障（BBB）和ARV引起的神经毒性，目前的ARV治疗方案 无法治疗 HIV 相关的中枢神经系统功能障碍，包括 HIV 相关的神经认知障碍 （手）。我们的药物输送策略旨在增强 BBB 通透性，促进药物通过 穿过血脑屏障，有效抑制中枢神经系统储存库中的病毒，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型的“生物纳米颗粒”递送方式 使用“细胞外囊泡（EV）”的系统，众所周知，细胞外囊泡可以穿过血脑屏障并大量积聚在 小胶质细胞。对于载药，我们将使用整合酶抑制剂埃维拉韦 (EVG) 及其 药物增强剂考比司他 (COBI)，属于毒性最小的抗逆转录病毒药物类别，并用作首选药物 治疗线。我们将 EVG 与化疗药物结合起来，该药物已被证明在以下方面有效： 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。我们的中心假设是，EVG-COBI 和化学饮食剂在 EV 内的双重负载将 绕过外排转运蛋白，穿过血脑屏障，靶向巨噬细胞和小胶质细胞，并传递 EVG 和 化学饮食剂作用于这些细胞，从而抑制艾滋病毒。我们将通过以下方式检验假设： 目标 1：发展 EV药物配方并使用体外BBB模型确定其在巨噬细胞和小胶质细胞中的功效， 目标 2：确定 EV 药物制剂的药代动力学、组织分布和安全性 动物模型。我们期望在电动汽车中实现 EVG-COBI 和化学饮食剂的新型纳米配方， 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，这些方案最终被 预计将改善中枢神经系统的艾滋病毒治疗结果，并降低手足口病和其他神经系统疾病的患病率 失调。