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），新生婴儿缺乏氧气和血液流向大脑的人，是一个 出生时期发病和死亡的主要原因。 pa是婴儿的，由此产生的 神经发育后遗症，例如智力障碍，脑瘫，癫痫和听力或视力 损害，给社会带来了巨大负担。当前疗法（例如治疗性体温过低）有限 效应（减少15％INS死亡或残疾），无法治愈。我们建议发展有效 在低氧 - 缺血（HI）脑的新生儿模型中使用酶的纳米颗粒进行神经保护治疗 受伤。细胞氧化应激通常始于例如在电子中的超氧化物的产生 HI脑损伤后线粒体功能失调的转运链。超氧主要被 超氧化物歧化酶（SOD），催化其拆卸的阴离子到过氧化氢，然后转换为43 通过过氧化氢酶进行水和氧气。这些多种酶的合作作用对成功至关重要 活性氧的清除。例如，尽管SOD过表达在啮齿动物中具有神经保护作用 成人中风的模型，由于相对表达的相对表达，可能会加剧新生儿大脑的损伤 过氧化氢酶，导致过氧化氢的积累。因此，精确的和受控的共同 合作抗氧化剂酶的递送具有重大的改善氧化应激的潜力 新生儿HI脑损伤的设置。因此，我们将研究合并的神经保护能力 在术语HI脑损伤的新生儿啮齿动物模型中，过氧化氢酶负载和SOD负载的纳米颗粒。第一个目标 专注于确定载有SOD和过氧化氢酶的聚（乳酸 - 乳糖）的生物分布和有效剂量 糖）-Poly（乙二醇）（PLGA-PEG）纳米颗粒。第二个目标将评估 加载了SOD负载和过氧化氢酶的PLGA-PEG纳米颗粒，以确定 与免费药物和盐水治疗的对照相比，新生大鼠的神经保护作用。这项研究 之所以重要，是因为它探讨了基于纳米医学的治疗在临床上 - 新生儿HI的相关模型，对共享病理的其他围产期脑损伤有影响 标志。

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