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Nanomedicine and NeuroAIDS

纳米医学和神经艾滋病

基本信息

批准号：
7492012
负责人：
Howard E Gendelman
金额：
$ 42.45万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-12-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7492012
关键词：
AIDS Dementia Complex AIDS neuropathy Active Sites Address Affect Animals Anti-Retroviral Agents Antibodies Antigen Presentation Area Bile Acids Binding Biochemical Biodistribution Biological Biological Assay Biological Markers Blood Blood - brain barrier anatomy Blood Circulation Bone Marrow Brain Brain region Bypass CD34 gene CD4 Positive T Lymphocytes Cell Count Cell Mobility Cells Cellular biology Central Nervous System Diseases Cerebrospinal Fluid Clinical Collaborations Collagen Complement 5a Complex Corpus striatum structure Data Development Disease Disease Outcome Dose Dose-Limiting Drug Combinations Drug Delivery Systems Drug Formulations Drug Kinetics Drug or chemical Tissue Distribution Drug toxicity Drug usage Endocytosis Endopeptidases Ensure Equus caballus Exclusion Folate Gliosis Goals HIV HIV-1 Healthcare Heparin High Pressure Liquid Chromatography Histology Housing Human Image Immune Immunoglobulins In Vitro Indinavir Infection Injection of therapeutic agent Integrins Intravenous Intravenous Bolus Laboratories Lead Leadership Legal patent Letters Ligands Liver Lopinavir/Ritonavir Lymphocyte Measures Membrane Modeling Molecular Monoclonal Antibodies Morbidity - disease rate Mus Nebraska Neuraxis Neurologic Neurons Oral PVRL1 Patients Pattern Penetrance Peptide Hydrolases Peripheral Phagocytes Phagocytosis Pharmaceutical Preparations Pharmacology Phase Phospholipids Physical Chemistry Physiology Plasma Poloxamer Poloxamers Polyethylene Glycols Progress Reports Proteins Public Health Rate Research Infrastructure Rest Reticuloendothelial System Rodent Rodent Model Site Solubility Spleen Stem cells Surface Suspension substance Suspensions System T-Cell Depletion Techniques Testing Therapeutic Tissues Toxic effect Translating Transplantation Treatment Efficacy Treatment Protocols Universities Vesicular stomatitis Indiana virus Viral Viral Load result Virus Virus Diseases Work antiretroviral therapy base bioimaging brain tissue comparative concept cost cytotoxicity design drug distribution efavirenz experience improved in vivo integrin alpha1beta1 intravenous administration killings lymph nodes macrophage member microbial migration monoblast monocyte mouse model nanoformulation nanomedicine nanoparticle nervous system disorder neuroinflammation neuropathology neuroprotection non-nucleoside reverse transcriptase inhibitors novel optimism particle receptor reconstitution research study response size success surfactant trafficking uptake

项目摘要

DESCRIPTION (provided by applicant): The elimination of the human immunodeficiency virus inside its central nervous system (CNS) sanctuary is affected by variable antiretroviral therapy (ART) penetrance across the blood-brain barrier (BBB), complex dosing regimens, costs, toxicities, and limitations in biodistribution and pharmacokinetic drug patterns. Despite advances in ART and its abilities to cause significant reductions in cerebrospinal fluid viral loads; NeuroAIDS morbidities continue on the rise. A principal issue obstacle in achieving maximal clinical responses is in maintaining high ART drug levels in disease affected brain subregions. To address this issue, we will develop nanformulations of commonly used anti-retroviral drugs (lopinavir, ritonavir, and efavirenz) and deliver the drugs inside circulating blood-borne monocyte-macrophages. The means to improve distribution of ART across the BBB will require a three-step approach. First, comparative measures of nanoparticle (NP) drug formulations will be tested for entry and secretion into and from bone marrow-derived macrophages (BMM) and monocyte-derived macrophages (MDM). Here, viral protease and nonnucleoside reverse transcriptase inhibitor(s) will be packaged into phospholipids coated NP. Cytotoxicity, anti-retroviral efficacy, mobility, and the functional consequences of macrophage carriage of the drug-laden particles will be measured. Second, pharmacokinetics (uptake, release, plasma and tissue distribution) of the formulations will be investigated using BMM as a drug delivery system in mice. Third, ligand-formulated NP will be developed and tested in vitro then used to test direct intravenous administration in mice. Alternatively and to enhance NP entry into macrophages, formulations will be made with folate coatings will be designed to specifically target macrophages. Laboratory experiments reflecting immune activation of human monocytes and MDM will be developed to assess the optimal ways to enhance uptake of ligand-coated NP formulations. In this way, the abilities of drug to bypass the reticuloendothelial system and cross the BBB will be determined. High performance liquid chromatography analyses will be used to measure drug levels in spleen, lymph nodes, liver and brain in NP-treated mice and will provide confirmation of drug tissue penetrance. These tests will be used in tandem with histology and imaging assays. Lastly, the NP developed will be tested for anti-retroviral efficacy in affected brains of a primary and humanized mouse models of human HIV-1 CNS disease. All together, the goals are to enhance therapeutic efficacy and BBB migration of ART so that they can be translated for human use to improve disease outcomes in NeuroAIDS. PUBLIC HEALTH RELEVANCE The elimination of the human immunodeficiency virus inside its central nervous system sanctuary has not been achieved and HIV-1 dementia remains a public health problem. The reasons revolve around variable antiretroviral therapy (ART) penetrance across the blood-brain barrier as well as complex dosing regimens, costs, and drug toxicities. To address this issue, we plan to develop nanoformulations of commonly used ART with variable brain entry profiles and deliver them directly to diseased brain tissue inside blood-borne macrophages.

描述（由申请人提供）：人类免疫缺陷病毒在中枢神经系统（CNS）庇护所内的消除受到跨血脑屏障（BBB）的可变抗逆转录病毒疗法（ART）外显率、复杂的给药方案、成本、毒性以及生物分布和药代动力学药物模式的限制的影响。尽管抗逆转录病毒疗法取得了进步，并且能够显着降低脑脊液病毒载量；神经艾滋病发病率持续上升。实现最大临床反应的主要障碍是在受疾病影响的大脑亚区域中维持高 ART 药物水平。为了解决这个问题，我们将开发常用抗逆转录病毒药物（洛匹那韦、利托那韦和依非韦伦）的纳米制剂，并将药物输送到循环血源性单核巨噬细胞内。改善 ART 在 BBB 中分布的方法需要采取三步法。首先，将测试纳米颗粒（NP）药物制剂进入和分泌骨髓源性巨噬细胞（BMM）和单核细胞源性巨噬细胞（MDM）的比较措施。在此，病毒蛋白酶和非核苷类逆转录酶抑制剂将被包装到磷脂包被的纳米颗粒中。将测量细胞毒性、抗逆转录病毒功效、流动性以及巨噬细胞携带载药颗粒的功能后果。其次，将使用 BMM 作为小鼠药物递送系统来研究制剂的药代动力学（摄取、释放、血浆和组织分布）。第三，将开发配体配制的纳米粒子并进行体外测试，然后用于测试小鼠的直接静脉内给药。或者，为了增强 NP 进入巨噬细胞，将采用叶酸涂层制成制剂，专门针对巨噬细胞。将开发反映人类单核细胞和 MDM 免疫激活的实验室实验，以评估增强配体包被 NP 制剂吸收的最佳方法。这样，就可以确定药物绕过网状内皮系统并穿过血脑屏障的能力。高效液相色谱分析将用于测量 NP 治疗小鼠的脾脏、淋巴结、肝脏和大脑中的药物水平，并提供药物组织外显率的确认。这些测试将与组织学和成像分析同时使用。最后，所开发的 NP 将在人类 HIV-1 CNS 疾病的原代小鼠模型和人源化小鼠模型的受影响大脑中进行抗逆转录病毒功效测试。总而言之，我们的目标是提高 ART 的治疗效果和 BBB 迁移，以便将它们转化为人类使用，以改善 NeuroAIDS 的疾病结果。公共卫生相关性人类免疫缺陷病毒在中枢神经系统庇护所内的消除尚未实现，HIV-1 痴呆症仍然是一个公共卫生问题。原因在于抗逆转录病毒疗法 (ART) 穿过血脑屏障的外显率存在差异，以及复杂的给药方案、成本和药物毒性。为了解决这个问题，我们计划开发具有可变大脑进入特征的常用 ART 纳米制剂，并将其直接输送到血源性巨噬细胞内的患病脑组织。