Novel carbon nanoparticle superoxide dismutation pathways

新型碳纳米颗粒超氧化物歧化途径

• 批准号: 9134869
• 负责人: Thomas Kent
• 金额: $ 42.43万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9134869
• 关键词: Acute; Adamantane; Address; Antihypertensive Agents; Antioxidants; Biochemistry; Brain; Brain Injuries; Carbon; Carbon nanoparticle; Characteristics; Chemicals; Clinic; Clinical Trials; Coal; Data; Defense Mechanisms; Dose; Drug Metabolic Detoxication; Effectiveness; Electron Spin Resonance Spectroscopy; Environment; Enzymes; Equilibrium; Failure; Freezing; Functional disorder; Glutathione; Health; Hydrogen Peroxide; Hydroxyl Radical; In Vitro; Injury; Iron; Ischemia; Kinetics; Laboratories; Lead; Lesion; Life; Mitochondria; Modeling; Modification; Monitor; Nanostructures; Nanotubes; Natural regeneration; Nervous System Trauma; Nitric Oxide; One-Step dentin bonding system; Organism; Oxidative Stress; Oxygen; Pathologic Processes; Pathway interactions; Patients; Polyethylene Glycols; Process; Proteins; Quantum Dots; Rattus; Reaction; Reactive Oxygen Species; Reperfusion Injury; Reperfusion Therapy; Role; Sampling; Scanning; Scheme; Series; Shock; Site; Spin Trapping; Stroke; Structure; Superoxide Dismutase; Superoxides; Testing; Time; Toxic effect; Toxin; Transgenic Organisms; Translating; Traumatic Brain Injury; Ursidae Family; Vitamin E; Work; acute toxicity; analog; antioxidant therapy; base; brain tissue; catalyst; cerebrovascular; complex biological systems; coping; functional group; improved; improved outcome; in vivo; injured; mimetics; nanomaterials; nanoparticle; neurovascular unit; novel; overexpression; particle; prevent; prototype; small molecule; tissue culture; tool

 DESCRIPTION (provided by applicant): Oxidative stress accompanies both normal and pathological processes. Organisms have developed protective mechanisms to deal with release of reactive oxygen species resulting from oxidative stress. However, the initial injury can unleash a cascade of radicals and the products of these detoxification steps can yield other radicals or unstable molecules that require additional detoxification. Normally, sufficient levels f protective enzymes cope with these products. Under pathological circumstances these intermediate steps are overwhelmed; radicals and their deleterious products accumulate. Antioxidants with limited capacity that modify only one radical in this cascade may, in the face of inadequate downstream protective mechanisms, lead to injury propagation. Most antioxidants with broader activity have limited capacity to deal with this cascade while others require regeneration, often by the same molecules consumed in the injured environment. Because most antioxidants share one or more limitations, it is not surprising that clinical trials of conventionl antioxidant therapies administered after injury have generally failed. We developed a new class of antioxidant based on highly modified carbon nanoparticles we term PEGylated hydrophilic carbon clusters (PEG-HCCs). We show that these particles have high radical quenching capacity, are active against two major oxy-radicals without effect on nitric oxide and are consistent with high capacity superoxide (SO) dismutase mimetics. Unlike 2 prototype antioxidants, PEG-SOD and PBN, PEG-HCCs were effective after administration of a mitochondrial toxin in culture and rapidly restored neurovascular unit function in vivo ischemia/reperfusion model. Our overall hypothesis is that these features of PEG-HCCs can be optimized in structures more readily translatable to the clinic through an integrated project in which the biochemistry of radical quenching drives chemical modifications that are confirmed in-vivo ischemic/reperfusion. We will address this hypothesis via the following specific aims to determine whether: Aim 1. Highly conjugated planar graphene domain(s) with (or without) polarized spin distribution of the intrinsic radical of carbon nanostructures is responsible for th rapid dismutation of SO. Aim 2. Carbon nanoparticles and polyaromatics developed in Aim 1 efficiently turn over ROS by direct neutralization (e.g., OH•) or catalytic turnover (e.g., SO). Aim3. Materials developed in Aim 1 and tested in Aim 2 will improve oxidative balance, reverse cerebrovascular dysfunction and reduce brain lesion size when tested in a rat model of traumatic brain injury. Completion of these aims will lead to better antioxidants with the potentia to treat oxidative stress in patients.

 描述（由申请人提供）：氧化应激伴随着正常和病理过程。生物体已经发展出保护机制来应对氧化应激导致的活性氧的释放。然而，最初的损伤可能会释放出一系列自由基，而这些解毒步骤的产物可能会产生其他自由基或不稳定的分子，需要额外的解毒。通常，足够水平的保护酶可以应对这些产品。在病理情况下，这些中间步骤不堪重负；自由基及其有害产物不断积累。能力有限的抗氧化剂只能修饰这一级联中的一个自由基，面对 下游保护机制不完善，导致损伤传播。大多数具有更广泛活性的抗氧化剂处理这种级联反应的能力有限，而其他抗氧化剂则需要再生，通常是通过在受损环境中消耗的相同分子进行再生。由于大多数抗氧化剂都有一个或多个局限性，因此损伤后施用的常规抗氧化剂疗法的临床试验普遍失败也就不足为奇了。我们开发了一种基于高度改性的碳纳米颗粒的新型抗氧化剂，我们称之为聚乙二醇化亲水碳簇（PEG-HCC）。我们证明这些颗粒具有高自由基猝灭能力，对两种主要氧自由基具有活性，而不影响一氧化氮，并且与高容量超氧化物（SO）歧化酶模拟物一致。与两种原型抗氧化剂 PEG-SOD 和 PBN 不同，PEG-HCC 在培养物中施用线粒体毒素后有效，并在体内缺血/再灌注模型中快速恢复神经血管单元功能。我们的总体假设是，通过一个综合项目，PEG-HCC 的这些特征可以在结构上进行优化，更容易转化为临床，其中自由基猝灭的生物化学驱动化学修饰，这些修饰已在体内缺血/再灌注中得到证实。我们将通过以下具体目标来解决这一假设，以确定是否： 目标 1. 具有（或不具有）碳纳米结构固有自由基的极化自旋分布的高度共轭平面石墨烯域是否负责 SO 的快速歧化。目标 2。目标 1 中开发的碳纳米粒子和聚芳烃通过直接中和（例如 OH•）或催化转化（例如 SO）有效地转化 ROS。目标3。在大鼠脑外伤模型中进行测试时，目标 1 中开发并在目标 2 中测试的材料将改善氧化平衡、逆转脑血管功能障碍并减少脑损伤大小。这些目标的完成将带来更好的抗氧化剂，具有治疗患者氧化应激的潜力。