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: 10391787
• 负责人: Elizabeth A Nance
• 金额: $ 3.11万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-03 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10391787
• 关键词: Adult; Anions; Asphyxia Neonatorum; Biodistribution; Birth; Blood flow; Brain; Brain Injuries; Cerebral Palsy; Cessation of life; Child; Childhood; Dose; Electron Transport; Enzymes; Epilepsy; Hydrogen Peroxide; Hypoxia; Hypoxic-Ischemic Brain Injury; Infant; Injury; Intellectual functioning disability; Mitochondria; Modeling; Morbidity - disease rate; Neonatal; Neonatal Brain Injury; Neurodevelopmental Disability; Newborn Infant; Oxidative Stress; Oxygen; Pathologic; Perinatal Brain Injury; Pharmaceutical Preparations; Polymers; Production; Public Health; Rattus; Reactive Oxygen Species; Research; Rodent Model; Saline; Societies; Stroke; Superoxide Dismutase; Superoxides; Therapeutic; Time; Visual impairment; Water; antioxidant enzyme; base; catalase; clinically relevant; disability; efficacy evaluation; ethylene glycol; hearing impairment; hypoxia neonatorum; mortality; nanomedicine; nanoparticle; natural hypothermia; neonatal brain; neonatal hypoxic-ischemic brain injury; neonate; neuroprotection; overexpression; therapeutic nanoparticles

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.

项目摘要/摘要 围产期窒息（PA），新生儿遭受缺氧和血液流向大脑，是一种 在出生时发病和死亡的主要原因。早产儿，以及由此产生的 神经发育后遗症，如智力残疾、脑瘫、癫痫、听力或视力 损害，给社会造成巨大负担。目前的治疗方法，如治疗性低温， 效果（死亡或残疾减少15%），但不能治愈。我们建议制定一个有效的 在缺氧缺血（HI）脑的新生模型中使用酶负载纳米颗粒的神经保护治疗 损伤细胞氧化应激通常始于超氧化物的产生，例如，在电子 HI脑损伤后功能障碍的线粒体转运链。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然后将其转化为 转化为水和氧气。这些多种酶的协同作用对于成功地 清除活性氧。例如，虽然SOD过表达在啮齿动物中具有神经保护作用， 在成年人中风模型中，它可能会加重新生儿脑损伤，因为 过氧化氢酶，导致过氧化氢的积累。因此，精确的目标和控制的共同， 协同抗氧化酶的传递对于改善氧化应激具有显著的潜力， 新生儿HI脑损伤的设置。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 着重于确定SOD负载和过氧化氢酶负载的聚乳酸-co-的生物分布和有效剂量。 乙醇酸）-聚（乙二醇）（PLGA-PEG）纳米颗粒。第二个目标是评估一种 SOD-负载和过氧化氢酶负载的PLGA-PEG纳米颗粒的组合递送，以确定 与游离药物和盐水处理的对照相比，HI新生大鼠的神经保护作用。本研究 是重要的，因为它探索了纳米医学为基础的治疗在临床神经保护的潜力， 新生儿HI的相关模型，对其他围产期脑损伤的影响， 特征

项目成果

Data Management Schema Design for Effective Nanoparticle Formulation for Neurotherapeutics.

神经治疗有效纳米颗粒配方的数据管理模式设计。

• DOI: 10.1002/aic.17459
• 发表时间: 2021
• 期刊: AIChE journal. American Institute of Chemical Engineers
• 作者: Helmbrecht,Hawley;Xu,Nuo;Liao,Rick;Nance,Elizabeth
• 通讯作者: Nance,Elizabeth

Neonatal Pharmacokinetics and Biodistribution of Polymeric Nanoparticles and Effect of Surfactant.

• DOI: 10.3390/pharmaceutics15041176
• 发表时间: 2023-04-07
• 期刊: Pharmaceutics
• 影响因子: 5.4
• 作者: Xu N;Wong M;Balistreri G;Nance E
• 通讯作者: Nance E