Augmenting carbon nanoparticles as novel antioxidants for ischemic stroke

增强碳纳米颗粒作为治疗缺血性中风的新型抗氧化剂

• 批准号: 8701712
• 负责人: Thomas Kent
• 金额: $ 24.33万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8701712
• 关键词: Acute; Adamantane; Address; Aftercare; Albumins; Antibodies; Antioxidants; Ascorbic Acid; Blood - brain barrier anatomy; Brain; Carbon; Carbon nanoparticle; Cell Culture Techniques; Cerebral Ischemia; Cerebrovascular Circulation; Chemicals; Clinical; Clinical Trials; Clinical assessments; Coagulation Process; Comorbidity; Defense Mechanisms; Dependence; Dose; Drug Formulations; Drug Metabolic Detoxication; Effectiveness; Environment; Enzymes; Equilibrium; Event; Excision; Failure; Free Radicals; Glutathione; Human; Hydrogen Peroxide; Hydroxyl Radical; Hyperglycemia; In Vitro; Infarction; Injury; Ischemia; Ischemic Stroke; Laboratories; Lead; Life; Medical; Middle Cerebral Artery Occlusion; Modeling; Modification; Natural regeneration; Nervous System Physiology; Nervous System Trauma; Nitric Oxide; Outcome; Oxidative Stress; Oxygen; Pathologic Processes; Patients; Peptide antibodies; Permeability; Physiological; Proteins; Rattus; Reactive Oxygen Species; Relative (related person); Reperfusion Therapy; Research; Selectins; Series; Stroke; Superoxide Dismutase; Superoxides; Temperature; Testing; Therapeutic; Time; Toxic effect; Traumatic Brain Injury; Variant; antioxidant therapy; base; clinically relevant; coping; design; diabetic rat; effective therapy; free radical oxygen; functional outcomes; improved; in vivo; innovation; lipophilicity; mortality; nanomaterials; nanoparticle; novel; novel strategies; novel therapeutics; particle; pre-clinical; preclinical study; public health relevance; small molecule; stoichiometry

DESCRIPTION (provided by applicant): Oxidative stress accompanies both normal and pathological processes. Because we live in an oxygen rich environment, we need protective mechanisms to deal with inevitable release of highly reactive oxygen free radicals resulting from both normal and pathological events such as stroke. Our primary defense against oxidative radicals consists of a series of enzymes and proteins. However, the products of these detoxification steps can yield another radical, e.g. hydroxyl, or an unstable molecule, hydrogen peroxide requiring another step of detoxification. Normally, there are sufficient levels of protective enzymes to cope with these products. However, under pathological circumstances, these intermediate steps are overwhelmed; radicals and their deleterious products accumulate. Antioxidant therapies that modify only one radical in this cascade may generate unstable intermediates that, in the face of inadequate downstream protective mechanisms, can lead to the accumulation of more radicals. It is not therefore surprising that clinical trials of conventinal antioxidant therapies have generally failed. Our laboratories have developed a new, innovative class of antioxidant using highly modified carbon nanoparticles termed PEGylated hydrophilic carbon clusters (PEG-HCCs). These particles have a high radical quenching capacity and generate oxygen during superoxide quenching, potentially ideal to treat ischemia/reperfusion. Furthermore, PEG-HCCs can be targeted using antibodies, peptides and small molecules. Importantly, they were effective after oxidative stress in cell culture while conventional antioxidants required pre-treatment. Based on our finding that PEG-HCCs rapidly restored cerebral blood flow in a model of traumatic brain injury, we hypothesize that we can develop an effective formulation in stroke. Preliminary results in a severe test in hyperglycemic transient middle cerebral artery occlusion (tMCAO) in the rat suggested improved survival. In Aim 1, we will test the ability to extend the therapeutic window using PEG-HCCs in a model of normo- and hyper-glycemic tMCAO. In Aim 2, we will test modifications intended to augment their targeting and distribution to the brain. We selected hyperglycemic stroke since it is a common co-morbidity in stroke causing increased mortality and poorer outcomes, particularly afer recanalization therapies such as clot removal. While oxidative stress is important in normoglycemic stroke, the mechanisms are quantitatively much greater in extended periods of ischemia and in hyperglycemia. Should these be successful, we will pursue the additional pre-clinical studies necessary for an IND application for human testing in stroke as a potential treatment for those who otherwise would have the worst outcomes.

描述（由申请人提供）：氧化应激伴随正常和病理过程。 因为我们生活在富氧环境中，所以我们需要保护机制来处理由正常和病理事件（如中风）引起的高活性氧自由基的不可避免的释放。 我们对氧化自由基的主要防御由一系列酶和蛋白质组成。 然而，这些解毒步骤的产物可以产生另一种自由基，例如羟基，或不稳定的分子，过氧化氢，需要另一个解毒步骤。 通常情况下，有足够的保护酶来科普这些产品。 然而，在病理情况下，这些中间步骤被淹没;自由基及其有害产物积累。 抗氧化剂治疗，修改只有一个自由基在这个级联可能会产生不稳定的中间体，在面对不足的下游保护机制，可能会导致更多的自由基的积累。 因此，常规抗氧化剂治疗的临床试验普遍失败也就不足为奇了。 我们的实验室已经开发出一种新型的创新抗氧化剂，使用高度改性的碳纳米颗粒，称为聚乙二醇化亲水碳簇（PEG-HCCs）。 这些颗粒具有高的自由基猝灭能力，并在超氧化物猝灭过程中产生氧气，可能是治疗缺血/再灌注的理想选择。 此外，可以使用抗体、肽和小分子靶向PEG-HCC。 重要的是，它们在细胞培养中的氧化应激后有效，而传统的抗氧化剂需要预处理。 基于我们发现PEG-HCC在创伤性脑损伤模型中快速恢复脑血流，我们假设我们可以开发一种有效的中风制剂。 在高血糖短暂性大脑中动脉闭塞（tMCAO）大鼠中进行的严格试验的初步结果表明，存活率有所改善。 在目标1中，我们将测试在正常和高血糖tMCAO模型中使用PEG-HCC延长治疗窗的能力。 在目标2中，我们将测试旨在增强其对大脑的靶向和分布的修改。 我们选择高血糖卒中，因为它是卒中中常见的合并症，导致死亡率增加和结局较差，特别是在再通治疗（如凝块清除）后。 虽然氧化应激在血糖正常的中风中很重要，但在长时间的缺血和高血糖中，氧化应激的机制在数量上要大得多。 如果这些研究成功，我们将继续进行IND申请所需的额外临床前研究，用于中风的人体试验，作为对那些可能会有最坏结果的人的潜在治疗。