Macrophage-based nanoformulations of anti-retroviral therapy in NeuroAIDS

基于巨噬细胞的抗逆转录病毒纳米制剂治疗神经艾滋病

基本信息

批准号：
8230866
负责人：
Howard E Gendelman
金额：
$ 21.66万
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：
2003
资助国家：
美国
起止时间：
2003-05-15 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8230866
关键词：
AIDS Dementia Complex AIDS neuropathy Active Sites Address Affect Animal Testing Alternatives Animals Anti-Inflammatory Agents Anti-Retroviral Agents Anti-inflammatory Antibodies Antigen Presentation Area Atazanavir Bile Acids Bilirubin Binding Biochemical Biodistribution Biological Biological Assay Biological Markers Blood Blood - brain barrier anatomy Blood Circulation Bone Marrow Brain Brain region Budgets Bypass C5a anaphylatoxin receptor CD34 gene CD4 Positive T Lymphocytes Cardiac Cell Count Cell Mobility Cells Cellular biology Central Nervous System Infections Cerebrospinal Fluid Chronic Clinical Collaborations Collagen Complex Data Development Disease Disease Outcome Dose Drug Combinations Drug Delivery Systems Drug Formulations Drug Kinetics Drug or chemical Tissue Distribution Drug resistance Drug toxicity Endocytosis Ensure Equus caballus Evaluation Exclusion Family Folate Food Fumarates Gliosis Goals HIV HIV-1 Healthcare Heparin High Pressure Liquid Chromatography Histology Housing Human Image Immune Immunity Immunoglobulins Indinavir Individual Infection Inflammatory Response Injection of therapeutic agent Integrins Intravenous Intravenous Bolus Investigation Laboratories Laboratory Study Laminin Lead Leadership Legal patent Life Ligands Liver Magnetic Resonance Imaging Maintenance Measures Membrane Proteins Modeling Monoclonal Antibodies Morbidity - disease rate Movement Mus Nature Nebraska Neuraxis Neurons Nucleosides Oral Oral Administration Outcome PVRL1 Particle Size Patients Pattern Penetrance Penetration Peptide Hydrolases Phagocytes Phagocytosis Pharmaceutical Preparations Pharmacology Phase Phospholipids Physical Chemistry Physiology Plasma Poloxamer 188 Polyethylene Glycols Proteins Regimen Research Infrastructure Reticuloendothelial System Reverse Transcriptase Inhibitors Ritonavir Rodent Rodent Model SCID Mice Solubility Spleen Stem cells Surface Suspension substance Suspensions System Techniques Tenofovir Testing Therapeutic Tissues Toxic effect Translating Treatment Efficacy United States Universities Vesicular stomatitis Indiana virus Viral Viral Encephalitis Viral Load result Virus Virus Diseases Work antiretroviral therapy base bioimaging brain tissue celecoxib combat comparative cost cytotoxicity design drug distribution drug efficacy emtricitabine experience folate-binding protein gastrointestinal immune activation improved in vitro testing in vivo infancy integrin alpha1beta1 intravenous administration iron oxide killings lymph nodes macromolecule macrophage member microbial migration monoblast monocyte mouse model nanoformulation nanoparticle nanotoxicology nervous system disorder neuroinflammation neuropathology neuroprotection neurotoxicity non-nucleoside reverse transcriptase inhibitors novel optimism particle receptor reconstitution relating to nervous system research study response scavenger receptor single photon emission computed tomography success surfactant trafficking uptake

项目摘要

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, biodistribution, and pharmacokinetic patterns of drug regimens. Despite advances in ART resulting in reductions in cerebrospinal fluid viral loads, neuroAIDS morbidities continue on the rise. One principal issue is achieving robust ART drug levels in affected brain subregions and maintaining the levels. To address this issue, we will develop nanoformulations of commonly used anti-retroviral and adjunctive drugs (for example, Celecoxib) with variable CNS entry profiles and use established or more "novel" means to deliver the drugs directly to diseased brain tissue captured inside blood-borne monocytes or macrophages. To this end, we will determine the means to maximize both the delivery and distribution of ART across the BBB. A three-step approach will be sought. 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 non-nucleoside 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 and will be designed to specifically target macrophages, and as such, improve cell entry. 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. Thus, the abilities of drug to bypass the reticuloendothelial system and cross the BBB will be determined. High performance liquid chromatography analysis of spleen, lymph nodes, liver, and brain will provide confirmation of drug tissue penetrance and 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 NeuroAIDS. 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.

消除其中枢神经系统（CNS）庇护所内的人类免疫缺陷病毒是受到血脑屏障（BBB）的抗逆转录病毒疗法（ART）的影响药物方案的剂量方案，成本，毒性，生物分布和药代动力学模式。尽管艺术的进步导致脑脊液病毒负荷减少，神经辅助病毒继续继续上升。一个主要问题是在受影响的大脑子区域中实现稳健的艺术药物水平和保持水平。为了解决这个问题，我们将开发常用抗逆转录病毒的纳米成型和辅助药物（例如，CNS输入曲线的辅助药物）或更多的“新颖”是指直接将药物直接输送到血液中捕获的患病的脑组织单核细胞或巨噬细胞。为此，我们将确定最大化交付和在整个BBB中分布艺术。将寻求三步的方法。首先，比较度量纳米颗粒（NP）药物制剂将进行测试，以便进入和分泌骨髓衍生巨噬细胞（BMM）和单核细胞衍生的巨噬细胞（MDM）。在这里，病毒蛋白酶和非核苷逆转录酶抑制剂将被包装到磷脂涂层的NP中。细胞毒性，抗逆转录病毒载有药物颗粒的巨噬细胞运输的功效，活动性和功能后果将可以测量。第二，药代动力学（摄取，释放，血浆和组织分布）将使用BMM作为小鼠的药物输送系统研究配方。第三，配体形成的NP 将在体外开发和测试，然后用于测试小鼠直接静脉内给药。或者为了增强NP进入巨噬细胞，将使用叶酸涂料制成配方，将是旨在专门针对巨噬细胞，因此可以改善细胞进入。实验室实验将开发反映人类单核细胞和MDM的免疫激活，以评估最佳方法增强配体涂层的NP配方的摄取。因此，毒品绕过的能力将确定网状内皮系统和穿越BBB。高性能液相色谱分析脾脏，淋巴结，肝脏和大脑将提供药物组织渗透性的确认和BE 与组织学和成像测定法一起使用。最后，开发的NP将进行抗逆转录病毒的测试神经辅助的主要和人源化小鼠模型的受影响大脑的功效。共同的目标是为了增强治疗功效和ART的BBB迁移，以便将其翻译以供人类使用改善神经辅助的疾病结果。