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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：
8377756
负责人：
Howard E Gendelman
金额：
$ 21.5万
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 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8377756
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.

在其中枢神经系统(CNS)庇护所内消除人类免疫缺陷病毒受可变抗逆转录病毒疗法(ART)透过血脑屏障(BBB)的影响，复杂给药方案、成本、毒性、生物分布和药物动力学模式。尽管抗逆转录病毒疗法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脑区和维持水平。为了解决这个问题，我们将开发常用抗逆转录病毒的纳米制剂和辅助药物(例如，塞来昔布)，具有可变的CNS条目配置文件和已建立的使用或者更“新颖”的方法是将药物直接输送到通过血液传播的病变脑组织中单核细胞或巨噬细胞。为此，我们将确定最大化交付和交付的方法艺术作品在BBB中的分布。将寻求分三步走的方法。第一，比较措施将对纳米粒(NP)药物配方进行进入和分泌骨髓来源的测试巨噬细胞(BMM)和单核细胞来源的巨噬细胞(MDM)。这里，病毒蛋白水解酶和非核苷将逆转录酶抑制剂(S)包装成磷脂包裹的NP。细胞毒性，抗逆转录病毒携带药物颗粒的巨噬细胞的有效性、流动性和功能后果被测量。第二，药物动力学(摄取、释放、血浆和组织分布) 将使用BMM作为小鼠体内的药物输送系统来研究配方。第三，配基形式的NP 将在体外开发和测试，然后用于在小鼠身上直接静脉给药。另一种选择为了促进NP进入巨噬细胞，将用叶酸涂层制成配方，并将旨在专门针对巨噬细胞，并因此，改善细胞进入。实验室实验将开发反映人单核细胞免疫激活和MDM的最佳方法来评估增强配体包衣NP制剂的吸收。因此，药物绕过网状内皮系统和跨血脑屏障将被测定。高效液相色谱仪对脾、淋巴结、肝脏和脑的分析将提供药物组织渗透性和BE的确认与组织学和成像分析一起使用。最后，开发的NP将进行抗逆转录病毒测试神经艾滋病原始和人源化小鼠模型受累大脑的疗效。总而言之，这些目标是为了提高ART的治疗效果和血脑屏障迁移率，以便将其翻译成人类使用以改善神经艾滋病的疾病结局。