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：
9398913
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/9398913
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 Patients 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 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 efficacy evaluation experimental study immunogenicity improved improved outcome in vitro testing in vivo intravenous administration mimetics nanoparticle nanoparticulate nanoscale neuron loss novel therapeutics oxidation preclinical study prevent public health relevance receptor safety study spinal cord and brain injury stroke survivor stroke treatment 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）：自由基引起的损伤对中风继发性神经元损伤起着重要作用。目前尚无治疗方法可以预防或减轻这些影响。使用自由基的催化降解是解决中枢神经系统继发性损伤的一种有前景的治疗方法。抗氧化酶及其低分子量模拟物最近被提议作为潜在的强大治疗剂，用于减少自由基引起的中风损伤，并且已被证明在许多动物模型中有效。然而，由于这些药物不能有效地穿透血脑屏障，因此它们用于治疗中风的治疗用途受到限制。最近，已经证明了几种靶向纳米颗粒和脂质体结构穿透血脑屏障的能力。在这里，我们建议使用抗体包被的纳米颗粒 (NP) 和脂质体实现将 SOD 模拟物 AEOL 10150 靶向递送至中枢神经系统损伤部位。靶向将通过抗 NR1 受体抗体的缀合来实现，在我们的初步研究中发现该抗体专门针对受损的脑实质。我们的工作假设是，增强靶向抗氧化纳米粒子向损伤部位的递送可以减少自由基损伤并降低中风中继发性神经元损伤的程度。这项研究的战略目标是开发一种静脉给药药物，可用作神经保护治疗，以减少中风中自由基介导的继发性神经元损伤。为了实现这一目标，我们将首先制备具有最大结合能力的优化靶向缀合物。然后，用大鼠皮质神经元培养物进行的实验将用于评估体外安全性和有效性，并估计动物实验的剂量范围。最后，小鼠中风模型将用于体内评估所提出的治疗方法的功效。该项目的短期目标是收集转化为大型动物模型所需的体内数据。从长远来看，这项研究将导致开发一种治疗/预防中风继发性神经元损伤的新疗法。更广泛地说，这项研究的结果将对开发治疗各种中枢神经系统疾病（包括创伤性脑损伤和脊髓损伤）的新靶向方法产生影响。