Antioxidant enzyme-loaded Pro-NP for treatment of TBI.

用于治疗 TBI 的抗氧化酶 Pro-NP。

• 批准号: 10079980
• 负责人: Forrest M Kievit
• 金额: $ 25.99万
• 依托单位: PROTRANSIT NANOTHERAPY, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10079980
• 关键词: Acute; Address; Animals; Antioxidants; Attenuated; Biochemical; Biodistribution; Biological; Brain; Brain Injuries; Brain imaging; Cause of Death; Clinical; DNA; Data; Development; Dose; Drug Delivery Systems; Drug Kinetics; Economic Burden; Emergency department visit; Event; Foundations; Hospitalization; Hour; Human; Impairment; Individual; Inflammation; Injury; Interruption; Kinetics; Legal patent; Lipid Peroxidation; Magnetic Resonance Imaging; Mediating; Mediator of activation protein; Monitor; Mus; Nanotechnology; Nerve Degeneration; Oxidative Stress; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Prevention; Process; Production; Proteins; Reactive Oxygen Species; Recovery; Research; Risk Factors; Safety; Site; Small Business Technology Transfer Research; Superoxide Dismutase; System; TBI treatment; Testing; Therapeutic; Time; Tissues; Toxic effect; Translations; Traumatic Brain Injury; Traumatic Brain Injury recovery; Treatment Efficacy; antioxidant enzyme; base; brain tissue; catalase; clinical translation; confocal imaging; disability; drug efficacy; drug testing; improved; improved outcome; mortality; mouse model; nanoparticle; nanoparticle delivery; neuroinflammation; novel therapeutic intervention; oxidation; preclinical study; prevent; protective effect; response; treatment planning

ABSTRACT Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide and comes with a significant economic burden associated with emergency room visits and hospitalizations. Oxidative stress- mediated secondary injury post-TBI is a considerable risk factor for mortality and long-term impairment. Immediately following TBI, a cascade of biological responses leads to increased production of reactive oxygen species (ROS), a critical mediator of the subsequent pathophysiological events that manifest through lipid peroxidation (LPO), oxidation of proteins and DNA, neuroinflammation, and neurodegeneration. While technological and clinical advancements have improved the outcome for individuals suffering from TBI, there is currently no effective neuroprotective therapy specific for the prevention and treatment of TBI-related secondary injury associated with oxidative stress. Super antioxidants, superoxide dismutase (SOD), and catalase (Cat) have the potential to attenuate the spread of inflammation and brain tissue damage if administered shortly after a TBI. However, the activity of antioxidants is short-lived and rapidly cleared, limiting therapeutic strategies based on exogenous delivery. ProTransit is developing an antioxidant-loaded nanoparticles (NP) delivery system, Pro- NP™, for the treatment of TBI-related secondary injury, as (1) there is currently no effective neuroprotective therapy specific for TBI-related secondary damage; (2) prior attempts have failed clinical translation due to ineffectual drug delivery and retention, and unintended toxicity; and (3) super antioxidants like SOD and Cat are effective but short-lived and rapidly cleared without a robust drug delivery system. The proposed research will address and improve upon current approaches by providing a delivery system, Pro-NP™ that can (1) deliver super antioxidants in a sustained manner, (2) rapidly accumulate and be retained in the damaged brain, and (3) improve TBI recovery. Thus, this proposal will provide a therapeutic strategy for TBI-related secondary brain damage, which is not available through current TBI treatment plans. In contrast with current secondary TBI therapeutic strategies, Protransit’s core patented nanotechnology, Pro-NP™, can deliver biologically active antioxidant enzymes, like SOD and Cat, with sustained release and increased target engagement with the site of injury. With increased accumulation and retention in a damaged brain, antioxidant-loaded Pro-NP™, can exert a protective effect and prevent the spread of biochemical derangements to surrounding healthy brain, potentially providing a significant advantage over other tested therapies. Overall, this Phase I STTR project will determine the feasibility of SOD/Cat-loaded Pro-NP™ to inhibit the development of secondary injury related to TBI. Further, this project will lay the foundation for a Phase II STTR in which we will investigate the pharmacokinetics, biodistribution, and safety profile of Pro-NP™ for the treatment of TBI.

抽象的 创伤性脑损伤 (TBI) 是全世界死亡和残疾的主要原因之一，并且伴随着 与急诊室就诊和住院治疗相关的重大经济负担。 TBI 后介导的继发性损伤是死亡和长期损伤的重要危险因素。 TBI 发生后，一系列生物反应会导致活性氧产生增加 物种（ROS），通过脂质表现出来的后续病理生理事件的关键介质 过氧化 (LPO)、蛋白质和 DNA 氧化、神经炎症和神经变性。 技术和临床进步改善了 TBI 患者的治疗结果， 目前尚无有效的神经保护疗法专门用于预防和治疗 TBI 相关继发性脑损伤 与氧化应激相关的损伤。 如果在服用后不久服用，有可能减轻炎症的蔓延和脑组织损伤 然而，抗氧化剂的活性是短暂的并且很快被清除，限制了基于的治疗策略。 ProTransit 正在开发一种负载抗氧化剂的纳米颗粒 (NP) 递送系统 Pro- NP™，用于治疗TBI相关的继发性损伤，因为（1）目前尚无有效的神经保护剂 (2) 先前的尝试因以下原因而失败的临床转化 无效的药物输送和保留以及意外的毒性；(3) SOD 和 Cat 等超级抗氧化剂 如果没有强大的药物输送系统，该研究将有效但短暂且迅速清除。 通过提供交付系统 Pro-NP™ 来解决和改进当前的方法，该系统可以 (1) 交付 超级抗氧化剂以持续的方式，（2）迅速积累并保留在受损的大脑中，（3） 因此，该提案将为 TBI 相关的次级大脑提供治疗策略。 目前的 TBI 治疗计划无法提供这种损害。 与目前的二次 TBI 治疗策略相比，Protransit 的核心专利纳米技术， Pro-NP™，可以提供具有生物活性的抗氧化酶，如 SOD 和 Cat，具有持续释放和 增加目标与受伤部位的接触，增加受损部位的积累和保留。 含有抗氧化剂的Pro-NP™，可以对大脑发挥保护作用，防止生化物质的传播 对周围健康大脑的紊乱，可能比其他测试提供显着优势 总体而言，该第一阶段 STTR 项目将确定加载 SOD/Cat 的 Pro-NP™ 抑制的可行性。 此外，该项目将为第二阶段奠定基础。 STTR，其中我们将研究 Pro-NP™ 的药代动力学、生物分布和安全性概况 TBI 的治疗。