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

摘要 创伤性脑损伤是世界范围内导致死亡和残疾的主要原因之一，并伴随着 与急诊室就诊和住院相关的重大经济负担。氧化应激- 颅脑损伤后介导性继发性损伤是死亡率和长期损伤的重要危险因素。 脑外伤后，一系列的生物反应立即导致活性氧的产生增加。 物种(ROS)，通过脂质表现的后续病理生理事件的关键中介 过氧化(LPO)、蛋白质和DNA的氧化、神经炎症和神经变性。而当 技术和临床的进步改善了脑外伤患者的预后，有 目前尚无特效的神经保护疗法用于脑外伤相关继发性脑损伤的防治 与氧化应激相关的损伤。超级抗氧化剂、超氧化物歧化酶(SOD)和过氧化氢酶(Cat) 如果在术后不久给药，有可能减轻炎症的扩散和脑组织的损伤 一个TBI。然而，抗氧化剂的活性是短暂的，而且很快就会被清除，限制了基于 关于外源分娩。Pro运输公司正在开发一种抗氧化剂纳米颗粒(NP)递送系统，Pro- NP™，用于治疗颅脑损伤相关的继发性损伤，因为(1)目前没有有效的神经保护措施 针对颅脑损伤相关二次损伤的特定治疗；(2)先前的尝试因以下原因而未能成功临床翻译 无效的药物传递和滞留，以及意外的毒性；以及(3)超抗氧化剂，如超氧化物歧化酶和猫 在没有强大的药物输送系统的情况下，有效但短暂且迅速清除。拟议的研究将 通过提供能够(1)交付的交付系统Pro-NP™来解决并改进当前的方法 超级抗氧化剂持续存在，(2)在受损的大脑中迅速积累和保留，以及(3) 提高脑损伤恢复率。因此，本研究将为脑外伤后继发性脑损伤的治疗提供一种策略。 损害，这在目前的TBI治疗计划中是不可用的。 与目前的二次创伤性脑损伤治疗策略相比，普罗特斯的核心专利纳米技术， Pro-NP™，可提供具有生物活性的抗氧化酶，如超氧化物歧化酶和猫，具有持续释放和 增加了目标与受伤地点的交战。随着在损坏的环境中积累和保留的增加 大脑，负载抗氧化剂的前NP™，可以起到保护作用，防止生化传播 周围健康大脑的错乱，潜在地提供了比其他测试对象更大的优势 治疗。总体而言，这一阶段的STTRI项目将确定负载超氧化物歧化酶/CAT的前-NP™抑制的可行性 与颅脑损伤相关的继发性损伤的发生。此外，该项目将为第二阶段奠定基础 我们将研究前-NP™的药代动力学、生物分布和安全性。 颅脑损伤的治疗。

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.