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

• 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
• 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

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）： 自由基诱导的损伤在脑卒中继发性神经元损伤中起重要作用。目前没有治疗方法可以预防或减轻这些影响。利用自由基的催化降解是一种很有前途的治疗方法，以解决中枢神经系统的继发性损害。抗氧化酶及其低分子量模拟物最近被提出作为潜在的强大的治疗剂，用于减少中风中自由基诱导的损伤，并已被证明是有效的，在许多动物模型。然而，由于这些药剂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脂质体构建体穿透血脑屏障的能力。在这里，我们建议实现靶向交付的SOD模拟AEOL 10150的中枢神经系统损伤的网站使用抗体包被的纳米粒子（NP）和脂质体。靶向将通过抗NR1受体抗体的偶联来实现，在我们的初步研究中发现该抗体特异性靶向损伤的脑实质。我们的工作假设是，增强靶向抗氧化剂NPs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。本研究的战略目标是开发一种静脉给药的药物，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。然后将使用大鼠皮质神经元培养物进行实验，以评价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价所提出的治疗方法的疗效。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新的治疗中风继发性神经元损伤的疗法。更广泛地说，这项研究的结果将对开发治疗各种CNS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。