Nanoparticle-mediated reduction of oxidative stress for the treatment of traumatic brain injury

项目摘要/摘要 创伤性脑损伤(TBI)是45岁以下人群致残和死亡的主要原因 全世界每年约有1000万新病例。TBI的影响可能是严重的，包括 神经认知、身体和心理社会功能障碍。仍有大量未得到满足的需求需要开发 避免颅脑损伤造成长期损害的策略。脑外伤的初发期描述的是即刻神经元 全球质量效应造成的挫伤或缺氧造成的损害。继发性损伤后来通过 再灌注损伤、迟发性皮质水肿、血脑屏障(BBB)破坏等机制，以及 局部电解质失衡。这些干扰会导致活性氧物种(ROS)、钙 释放、谷氨酸毒性、脂质过氧化(LP)和线粒体功能障碍导致恶性阳性 渐进性氧化应激介导的神经变性和神经炎症的反馈回路。是这样的 继发性损伤可能发生在最初假定的损伤部位附近的大脑，产生意外的扩散 受伤后几个月的损伤区。 以治疗继发性脑损伤为目标，ROS清除剂和LP产物抑制剂已成为 越来越受欢迎。然而，仍然没有有效的治疗方案表明结果有所改善。 在一项大型的多中心III期试验中，这可能部分归因于在 大脑。我们的总体目标是使用ROS和LP产品减少颅脑损伤的长期继发性损伤阶段 反应性纳米颗粒(NPs)可以快速积聚并保留在受损组织中，以减少损伤后的 创伤性氧化应激。我们之前已经开发出多功能的反应性NPs，可以帮助进行成像 在损伤中的分布，并导致小鼠神经炎症和神经行为缺陷的减少 全脑损伤模型。 我们假设，NP介导的减少脑损伤中的氧化应激将减少长期损害和 提高复苏率。这是基于ROS和LP表现出的临床前疗效的科学前提 产物抑制剂以及NP在TBI中的积累和保留。为了解决我们的假设，我们将完善 并优化我们的模块化、图像引导的NPs，以最大限度地提高受损大脑中的摄取和保留 在目标1中，我们将研究NP介导的脑损伤对小鼠脑损伤的影响。 减少创伤后氧化应激对继发性损伤的扩散将为我们提供一种治疗方法 索引这些NPs，然后在目标3中测试神经行为结果。这项建议充分利用了 纳米技术的进展，促进了治疗和成像脑损伤的新方法的发展。如果 如果成功，这些NPs可以被进一步开发用于其他涉及进行性疾病的病理 神经炎症和神经变性。

PROJECT SUMMARY/ABSTRACT Traumatic brain injury (TBI) is the leading cause of disability and death in people under 45 with approximately 10 million new cases each year worldwide. The effects of TBI can be severe, including neurocognitive, physical, and psychosocial impairment. There remains a significant unmet need to develop strategies to avoid long-term damage from TBI. The primary phase of TBI describes immediate neuronal damage from contusions or oxygen deprivation caused by global mass effect. Secondary injury occurs later via such mechanisms as reperfusion injury, delayed cortical edema, blood-brain barrier (BBB) breakdown, and local electrolyte imbalance. These disturbances result in increased reactive oxygen species (ROS), calcium release, glutamate toxicity, lipid peroxidation (LP), and mitochondrial dysfunction that lead to a vicious positive feedback loop of progressive oxidative stress-mediated neurodegeneration and neuroinflammation. Such secondary injury may occur in brain adjacent to the site of initial supposed injury, yielding unexpected spread of the zone of damage over months post-injury. With the goal of treating secondary brain injury, ROS scavengers and LP product inhibitors have become increasingly popular. However, there are still no effective treatment options demonstrating improved outcome in a large, multi-center Phase III trial, which can be partially attributed to poor delivery to and retention in the brain. Our overall goal is to reduce the long-term secondary injury phase of TBI using ROS and LP product reactive nanoparticles (NPs) that can quickly accumulate and be retained in damaged tissue to reduce post- traumatic oxidative stress. We have previously developed multifunctional, reactive NPs that aid in imaging distribution within the injury and result in reduced neuroinflammation and neurobehavioral deficits in a mouse model of TBI. We hypothesize that NP-mediated reduction oxidative stress in TBI will reduce long-term damage and improve recovery. This is based on the scientific premise of preclinical efficacy shown with ROS and LP product inhibitors as well as NP accumulation and retention in a TBI. To address our hypothesis, we will refine and optimize our modular, image-guided NPs to maximize uptake and retention within damaged brain in a controlled cortical impact mouse model of TBI in Aim 1. In Aim 2, we will study the effects of NP-mediated reduction in post-traumatic oxidative stress on the spread of secondary injury that will provide us a therapeutic index for these NPs and, and then in Aim 3 test neurobehavioral outcome. This proposal capitalizes on advances in nanotechnology that facilitate the development of novel approaches to treat and image TBI. If successful, these NPs could be further developed for other pathologies that involve progressive neuroinflammation and neurodegeneration.