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Targeted Delivery of Antioxidant Drugs Following Cerebral Ischemic Injury

脑缺血性损伤后抗氧化药物的靶向递送

基本信息

批准号：
9812773
负责人：
MARK S. KINDY
金额：
--
依托单位：
JAMES A. HALEY VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-10-01 至 2019-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9812773
关键词：
Achievement Address Adverse effects Animal Experiments Animal Model Animals Antibodies Antioxidants Attention Behavior assessment Binding Biodistribution Blood Blood - brain barrier anatomy Brain Brain Injuries CASP3 gene Carotid Arteries Cause of Death Cell Culture Techniques Cerebral Ischemia Clinical Continuous Infusion Data Development Disease Dose Doxorubicin Hydrochloride Liposome Drug Carriers Drug Delivery Systems Drug Evaluation Drug Modelings Electrophysiology (science)Ensure Enzymes FDA approved Fc Receptor Free Radical Scavengers Free Radicals Generations Glycolic-Lactic Acid Polyester Goals Human In Vitro Infarction Injury Ischemia Ischemic Stroke Lead Ligands Lipids Liposomes Measures Mediating Microspheres Middle Cerebral Artery Occlusion Modeling Molecular Weight Mus N-Methyl-D-Aspartate Receptors NR1 gene Neuraxis Neurologic Neurologic Deficit Neuronal Injury Neurons Outcome Outcome Measure Oxygen Peroxides Pharmaceutical Preparations Pharmacologic Substance Phase I Clinical Trials Price Process Production Prophylactic treatment Quality of life Rattus Reactive Oxygen Species Reducing Agents Reperfusion Therapy Reporting Research Rodent Model Safety Secondary to Series Serious Adverse Event Site Spinal cord injury Stream Stroke Superoxide Dismutase Superoxides System Testing Therapeutic Therapeutic Agents Therapeutic Effect Therapeutic Uses Time Toxic effect Translations Traumatic Brain Injury United States Vitamin E Water antioxidant enzyme base brain parenchyma brain tissue catalase central nervous system injury cerebral ischemic injury cytotoxicity disability dosage drug candidate drug distribution drug efficacy drug release profile efficacy evaluation experimental study immunogenicity improved improved outcome in vitro testing in vivo in vivo evaluation intravenous administration mimetics nanoparticle nanoparticulate nanoscale neuron loss novel therapeutics oxidation preclinical study prevent public health relevance receptor safety study side effect stroke model stroke outcome stroke patient stroke survivor stroke therapy targeted delivery vector

项目摘要

DESCRIPTION (provided by applicant): Free radical-induced damage makes an important contribution to secondary neuronal injury in stroke. No therapy exists at present to prevent or alleviate these effects. The use of catalytic degradation of free radicals is a promising therapeutic approach to address the secondary damage in CNS. Antioxidant enzymes and their low molecular weight mimetics have recently been proposed as potentially powerful therapeutic agents for reducing free radical-induced injury in stroke, and have been shown to be efficient in a number of animal models. However, therapeutic use of these agents for treatment of stroke is limited due to their inability to efficiently penetrate blood-brain barrier. Recently, ability of several targeted nanoparticulate an liposomal constructs to penetrate the blood-brain barrier has been demonstrated. Here, we propose to achieve targeted delivery of a SOD mimetic AEOL 10150 to the site of CNS injury using antibody-coated nanoparticles (NPs) and liposomes. Targeting will be achieved through conjugation of anti-NR1 receptor antibody, which was found to specifically target injured brain parenchyma in our preliminary studies. Our working hypothesis is that enhanced delivery of targeted antioxidant NPs to the site of injury can reduce free radical damage and reduce the degree of secondary neuronal damage in stroke. The strategic goal of this study is to develop a medication for intravenous administration, which could be used as neuroprotective treatment to reduce free radical mediated secondary neuronal damage in stroke. To accomplish this goal, we will first prepare optimized targeted conjugates with maximized binding ability. Experiments with rat cortical neuronal cultures will then be used to evaluate safety and efficacy in vitro, and estimate dosage ranges for animal experiments. Finally, a mouse stroke model will be used for the in vivo evaluation of the efficacy of the proposed therapeutic approach. The short-term goal of this project is to collect in vivo data necessary for translation to a large animal model. In th long term, this research will lead to the development of a novel therapy for treatment/prophylactics of secondary neuronal injury in stroke. More broadly, results of this research will have implications in development new targeting approaches for treatment of various CNS conditions including traumatic brain injury and spinal cord injury.

描述（由申请人提供）：