Enzyme-loaded nanoparticles for neonatal neuroprotection

用于新生儿神经保护的载酶纳米粒子

• 批准号: 10194572
• 负责人: Elizabeth A Nance
• 金额: $ 22.21万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-16 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194572
• 关键词: Address; Adult; Affect; Anions; Antioxidants; Apoptotic; Asphyxia Neonatorum; Behavior; Biodistribution; Birth; Blood - brain barrier anatomy; Blood Circulation; Blood flow; Brain; Brain Injuries; Calcium; Calcium Channel; Cell Death; Cell membrane; Cerebral Palsy; Cessation of life; Child; Childhood; Curcumin; Data; Developed Countries; Dose; Electron Transport; Endotoxins; Enzymes; Epilepsy; Exposure to; Failure; Glutamates; Glycolates; Half-Life; Hydrogen Peroxide; Hypoxia; Hypoxic-Ischemic Brain Injury; Infant; Inflammation; Inflammatory; Injury; Intellectual functioning disability; Kinetics; Lipid Peroxidation; Lipopolysaccharides; Membrane; Mitochondria; Modeling; Morbidity - disease rate; N-Methyl-D-Aspartate Receptors; NADH dehydrogenase (ubiquinone); Nanotechnology; Neonatal; Neonatal Brain Injury; Neurodevelopmental Disability; Neurodevelopmental Impairment; Neurological outcome; Neuronal Injury; Newborn Infant; Outcome; Oxidative Stress; Oxygen; Pathologic; Peptides; Perinatal Brain Injury; Permeability; Peroxonitrite; Pharmaceutical Preparations; Polymers; Process; Production; Public Health; Rattus; Reactive Oxygen Species; Research; Rodent Model; Saline; Slice; Societies; Stroke; Superoxide Dismutase; Superoxides; Term Birth; Testing; Therapeutic; Time; Toxic effect; Visual impairment; Water; Work; antioxidant enzyme; base; catalase; clinically relevant; controlled release; cytokine; disability; efficacy evaluation; enzyme activity; ethylene glycol; excitotoxicity; glutathione peroxidase; hearing impairment; hypoxia neonatorum; improved; injured; mitochondrial dysfunction; mortality; mortality risk; nanomedicine; nanoparticle; natural hypothermia; neonatal brain; neonatal hypoxic-ischemic brain injury; neonate; neurobehavioral; neuropathology; neuroprotection; newborn brain injury; novel strategies; overexpression; perinatal period; peroxiredoxin; postnatal; stroke model; therapeutic nanoparticles; uptake

PROJECT SUMMARY/ABSTRACT Perinatal asphyxia (PA), where newborn infants suffer from a lack of oxygen and blood flow to the brain, is a leading cause of morbidity and mortality around the time of birth. PA in term infants, and the resulting neurodevelopmental sequelae such as intellectual disability, cerebral palsy, epilepsy, and hearing or vision impairment, result in a huge burden to society. Current therapies such as therapeutic hypothermia have a limited effect (15% reduction ins death or disability), and are not curative. We propose to develop an effective neuroprotective treatment using enzyme- loaded nanoparticles in a neonatal model of hypoxia-ischemic (HI) brain injury. Cellular oxidative stress often begins with the production of superoxide, for example, within the electron transport chain of dysfunctional mitochondria after HI brain injury. Superoxide is primarily scavenged by superoxide dismutase (SOD), catalyzing its dismutation anion to hydrogen peroxide,43 which is then converted to water and oxygen by catalase. The cooperative action of these multiple enzymes is crucial to the successful clearance of reactive oxygen species. For instance, while SOD overexpression is neuroprotective in a rodent model of adult stroke, it may exacerbate injury in the neonatal brain due to a relative under-expression of catalase, resulting in accumulation of hydrogen peroxide. Therefore, precisely-targeted and controlled co-delivery of cooperative antioxidant enzymes has significant potential for ameliorating oxidative stress in the setting of neonatal HI brain injury. Therefore, we will investigate the neuroprotective capability of combined catalase-loaded and SOD-loaded nanoparticles in a neonatal rodent model of term HI brain injury. The first aim focuses on determining the biodistribution and effective dose of SOD-loaded and catalase-loaded poly(lactic-co-glycolic)-poly(ethylene glycol) (PLGA-PEG) nanoparticles. The second aim will evaluate the efficacy of a combined delivery of SOD-loaded and catalase-loaded PLGA-PEG nanoparticles to determine the neuroprotective effects in newborn rats with HI in comparison to free drug and saline treated controls. This study is significant because it explores the potential of nanomedicine-based therapy for neuroprotection in a clinically-relevant model of neonatal HI, with implications for other perinatal brain injuries that share pathological hallmarks.

项目总结/摘要 围产期窒息（PA），新生儿缺氧和血流不足， 大脑是出生时发病和死亡的主要原因。足月儿PA， 以及由此产生的神经发育后遗症，如智力残疾，脑瘫， 癫痫和听力或视力受损，给社会造成巨大负担。当前疗法 例如治疗性低温具有有限效果（死亡或残疾减少15%）， 是没有疗效的我们建议开发一种有效的神经保护疗法，使用酶- 在缺氧-缺血性（HI）脑损伤的新生儿模型中，细胞氧化 压力通常始于超氧化物的产生，例如，在电子传递中 HI脑损伤后功能障碍的线粒体链。超氧化物主要由 超氧化物歧化酶（SOD），催化其歧化阴离子为过氧化氢，43 然后通过过氧化氢酶转化为水和氧气。这些多重的协同作用 酶对活性氧的成功清除至关重要。例如，虽然 SOD过表达在成年中风的啮齿动物模型中具有神经保护作用，它可能会加重损伤 在新生儿大脑中，由于过氧化氢酶的相对表达不足，导致 过氧化氢因此，精确定向和受控的合作药物的共同递送是必要的。 抗氧化酶具有改善氧化应激的显著潜力， 新生儿HI脑损伤。因此，我们将研究联合应用的神经保护能力。 图10是在足月HI脑损伤的新生啮齿动物模型中的负载过氧化氢酶的纳米颗粒和负载SOD的纳米颗粒的对比图。 第一个目标集中于确定SOD负载的生物分布和有效剂量， 负载过氧化氢酶的聚（乳酸-共-乙醇酸）-聚（乙二醇）（PLGA-PEG）纳米颗粒。的 第二个目的是评估SOD负载的和过氧化氢酶负载的组合递送的功效 PLGA-PEG纳米颗粒，以确定新生大鼠HI中的神经保护作用。 与游离药物和盐水处理的对照相比。这项研究意义重大，因为它探讨了 在临床相关模型中，基于纳米医学的神经保护疗法的潜力 新生儿HI，与其他围产期脑损伤的共同病理标志的影响。