脑是机体中对高原缺氧最敏感的器官，目前尚无理想高原缺氧脑损伤防治药物。课题组前期研究发现氮氧自由基HPN对高原缺氧损伤具有保护作用，但是其分子量小、活性高、代谢快，缺乏靶向性。为了提高其对高原缺氧脑损伤的保护效果，本项目首次以线粒体和脑部炎症损伤为作用靶点，设计合成以三苯基膦阳离子（TPP+）为线粒体靶向基团的HPN衍生物（Mito-HPN），并将其负载于Angiopep-2（ANG）和AMD3100共修饰的PLGA纳米载体中。利用载体提高HPN稳定性，ANG将载体递送至脑组织，AMD3100引导载体至炎症损伤部位，最终通过TPP+将HPN富集于线粒体内。该多级靶向递药系统预期能够增强HPN治疗效果，降低给药剂量，减少毒副作用。本研究还将综合采用蛋白质组学、生物信息学以及靶分子功能验证技术，阐明HPN对高原缺氧脑损伤的保护作用机制，为氮氧自由基的开发利用和高原缺氧防护药物研发提供新的思路。

Brain is highly vulnerable to high-altitude hypoxia due to its high oxygen consumption and less antioxidant enzymes. There were no ideal medicines for prevention and treatment of brain injury induced by high-altitude hypoxia until now. Our previous study found that HPN has protective effects on injury induced by high-altitude hypoxia, but HPN is characterized as low molecular weight, high activity, fast metabolism and lack of targeting. In order to improve the protective effect of HPN on brain injury induced by high altitude hypoxia, we designed a serious of mitochondria-targeted derivatives of HPN(Mito-HPN) by linking HPN with triphenylphosphonium cation(TPP+) and constructed a dual targeting PLGA nanoparticle modified with both angiopep-2(ANG) and AMD3100 for loading Mito-HPN using mitochondria and brain inflammation as target. PLGA nanoparticle can improve the stability of HPN. ANG can deliver PLGA nanoparticle to brain, while AMD3100 further lead PLGA nanoparticle in inflammation region with high expression of CXCR4. Finally, TPP+ make the HPN accumulated in mitochondria. We hope that this multi-targeted drug delivery system will enhance the activity, reduce the dosage and decrease side effects of HPN. In addition, the protective effect mechanism and molecular target of HPN against brain injury induced by high-altitude hypoxia were evaluated using proteomics, bioinformatics and the technology of functional verification of target molecules. This study will provide new ideas for development and utilization of nitronyl nitroxide as well as the research of high altitude hypoxia injuries prevention drugs.