Enzyme-loaded nanoparticles for neonatal neuroprotection

项目摘要/摘要 围产期窒息(PA)是一种新生儿缺氧和脑供血不足的疾病。 出生时发病和死亡的主要原因。足月儿的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 损害，给社会造成了巨大的负担。目前的治疗方法，如治疗性低温治疗， 效果(死亡或残疾减少15%)，而且不能治愈。我们建议开发一种有效的 酶纳米粒在新生儿缺氧缺血性脑损伤模型中的神经保护作用 受伤。细胞氧化应激通常始于超氧化物的产生，例如，在电子中 缺氧缺血性脑损伤后功能障碍的线粒体运输链。超氧化物主要由以下物质清除 超氧化物歧化酶(SOD)，催化其歧化阴离子生成过氧化氢，43然后转化为过氧化氢 通过过氧化氢酶转化为水和氧气。这些多个酶的协同作用是成功的关键 清除活性氧物种。例如，虽然在啮齿动物中过量表达超氧化物歧化酶具有神经保护作用 在成人卒中模型中，由于相对表达不足，可能会加重新生儿脑损伤 过氧化氢酶，导致过氧化氢的积累。因此，精准定向和受控的联合 协同抗氧化酶的交付具有显著改善脑内氧化应激的潜力 新生儿缺氧缺氧性脑损伤的背景。因此，我们将研究联合应用的神经保护能力。 过氧化氢酶纳米颗粒和超氧化物歧化酶纳米颗粒在新生儿缺氧缺血性脑损伤模型中的应用。第一个目标 重点测定了负载超氧化物歧化酶和过氧化氢酶的聚乳酸-共聚物的生物分布和有效剂量。 乙醇酸-聚乙二醇(PLGA-PEG)纳米粒子。第二个目标是评估一种 负载超氧化物歧化酶和过氧化氢酶的聚乙二醇纳米粒的联合给药研究 缺氧缺血性脑病新生大鼠神经保护作用与游离药物和生理盐水对照组的比较。本研究 意义重大，因为它探索了基于纳米药物的治疗在临床上用于神经保护的潜力- 新生儿缺氧缺血性脑病的相关模型及其对其他具有相同病理特征的围产期脑损伤的启示 这是个标志。

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.