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

项目总结/摘要 创伤性脑损伤（TBI）是45岁以下人群残疾和死亡的主要原因， 全球每年约有1000万新病例。TBI的影响可能很严重，包括 神经认知、身体和心理社会障碍。仍然有一个重大的未满足的需要， 避免TBI造成长期损害的策略。TBI的原发相描述了直接神经元损伤， 挫伤或整体质量效应导致的缺氧造成的损伤。继发性损伤发生在以后， 诸如再灌注损伤、迟发性皮质水肿、血脑屏障（BBB）破坏以及 局部电解质失衡。这些干扰导致活性氧（ROS）、钙离子（Ca ~（2+））和钙离子（Ca ~（2+））增加。 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 进行性氧化应激介导的神经变性和神经炎症的反馈回路。等 继发性损伤可能发生在最初假定损伤部位附近的脑中，产生意外的扩散 在受伤后的几个月里， 以治疗继发性脑损伤为目标，ROS清除剂和LP产物抑制剂已成为治疗继发性脑损伤的有效药物。 越来越受欢迎。然而，仍然没有有效的治疗方案显示改善的结果 在一项大型、多中心III期试验中，这可能部分归因于药物输送和保留不良。 个脑袋我们的总体目标是使用ROS和LP产品减少TBI的长期继发性损伤阶段 反应性纳米颗粒（NP），可以快速积累并保留在受损组织中，以减少后 创伤性氧化应激我们以前已经开发了多功能，反应性纳米粒子，有助于成像 分布在损伤内，并导致小鼠神经炎症和神经行为缺陷减少 TBI模型 我们假设NP介导的减少TBI中的氧化应激将减少长期损伤， 改善恢复。这是基于ROS和LP显示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，我们将改进 并优化我们的模块化，图像引导的纳米粒子，以最大限度地吸收和保留在受损的大脑中， Aim 1中TBI的对照皮质撞击小鼠模型。在目标2中，我们将研究NP介导的 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 指标，然后在目标3测试神经行为结果。该提案利用了 纳米技术的进步促进了治疗和成像TBI的新方法的开发。如果 成功的，这些纳米颗粒可以进一步发展为其他病理，涉及进行性 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.