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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.

在中枢神经系统（CNS）保护区内消除人类免疫缺陷病毒，受可变抗逆转录病毒治疗（ART）影响，血脑屏障（BBB），复杂给药方案、成本、毒性、生物分布和药物方案的药代动力学模式。尽管 ART的进展导致脑脊液病毒载量的减少，神经艾滋病的发病率继续上升，崛起。一个主要问题是在受影响的大脑亚区域中实现稳健的ART药物水平，保持水平。为了解决这个问题，我们将开发常用的抗逆转录病毒药物的纳米制剂，和具有不同CNS进入特征和已确定用途的抗肿瘤药物（例如塞来昔布）或更"新颖"的方法，将药物直接递送到血液传播的脑组织中捕获的患病脑组织。单核细胞或巨噬细胞。为此，我们将确定最大限度地提高交付和 ART在BBB中的分布。将寻求一种分三步走的办法。第一，比较措施将测试纳米颗粒（NP）药物制剂进入和分泌入骨髓来源的细胞和从骨髓来源的细胞分泌。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将逆转录酶抑制剂包装到磷脂包被的NP中。细胞毒性，抗逆转录病毒载药颗粒的巨噬细胞运载的功效、移动性和功能性结果将被衡量。第二，药物的药代动力学（摄取、释放、血浆和组织分布）。将使用BMM作为小鼠中的药物递送系统来研究制剂。第三，配体配制的NP 将在体外开发和测试，然后用于测试小鼠中的直接静脉内给药。替代地为了增强NP进入巨噬细胞，制剂将用叶酸涂层制备，专门针对巨噬细胞设计，因此，可以改善细胞进入。实验室实验将开发反映人单核细胞和MDM的免疫活化的方法，以评估增强配体包被的NP制剂的摄取。因此，药物绕过将确定网状内皮系统和穿过BBB。高效液相色谱脾、淋巴结、肝和脑的分析将提供药物组织转移的确认，与组织学和成像分析一起使用。最后，将对开发的NP进行抗逆转录病毒测试在NeuroAIDS的原代和人源化小鼠模型的受影响脑中的功效。所有这些目标是为了增强ART的治疗功效和BBB迁移，使得它们可以被转化为人类使用来改善神经艾滋病的治疗效果。