用于自由基清除和检测的氧化铈/空腔介孔二氧化硅复合纳米体系的研究

Ischemic stroke is the second leading cause of death worldwide and scavenging excess free radicals in the brain is an important way to protect the neurons and brain tissues. This project will design and synthesize a new type of composite nanostructure based on ceria core/hollow mesoporous silica (hmSiO2) shell to overcome the drawbacks of traditional free radical scavengers, such as low brain uptake and radical scavenging efficiency, difficulty in learning about the efficiency. Fluorescein will be loaded in cavity as radical detector and targeting peptides will be conjugated on the surface to facilitate the crossing of the blood brain barrier (BBB). Such a nanocomposite can target cerebral infarction site, scavenge free radical efficiently and real time monitor the scavenging of free radical simultaneously. This project will employ the reverse microemusion and hot water etching process to construct CeO2@hmSiO2 composite nanostructure with tailored particle sizes, cavity size and shell-thickness, etc.. The biological effects will be systematically investigated. The capability of radical scavenging and detecting will be evaluated from in vitro to in vivo (ischemic stroke model), and the effects on shrinkage of brain infarct volume will also be studied. The launching of this project will play a significant role to neuroprotective therapy for ischemic stroke, and will pave the way for free radical-related diseases treatment in the coming future.

缺血性脑卒中是导致人类死亡的第二大疾病，清除脑内过量自由基是保护神经元、降低脑组织损伤的重要方法。本项目拟构建一种全新的CeO2颗粒/空腔介孔二氧化硅（hmSiO2）纳米复合结构，以克服传统自由基清除剂脑摄取率低，自由基清除效率有限且无法评价清除效率的难题。在空腔和颗粒表面分别嫁接感应自由基浓度的有机荧光素和穿越血脑屏障的靶向多肽，期望实现高效靶向脑梗塞位点、清除过量自由基、并实时可视化监控清除效率的多重目的。本项目拟采用反微乳液包裹和热水刻蚀工艺构建CeO2@hmSiO2复合纳米结构，调控其粒径、空腔大小和壁厚等关键结构参数；系统评价其细胞生物学效应；通过体外和体内缺血性脑卒中模型研究其自由基清除和实时检测性能，并考察其对缩小脑梗塞体积的作用。本项目的开展将对缺血性脑卒中的神经保护治疗具有重要意义，有望为治愈人类自由基过量相关疾病提供借鉴性研究思路和方法。

缺血性脑卒中是导致人类死亡的第二大疾病，清除脑内过量自由基是保护神经元、降低脑组织损伤的重要方法。本课题构建了一种全新的靶向载药纳米氧化铈材料体系，以克服传统自由基清除剂脑摄取率低，自由基清除效率有限且无法评价清除效率的难题。利用铈元素与羧基较强的配位力，在表面嫁接高分子PEG，从而改善生物相容性和生理毒性,增加超小颗粒在体内的血液循环时间；同时并联嫁接靶向配体ANG多肽，与脑微血管内皮细胞的LRP受体结合通过介导内吞的方式快速跨越血脑屏障达到病灶区，实现高效靶向脑梗塞位点及时清除自由基，缓解氧化应激引起的血脑屏障炎症性破坏等；最后借用嫁接的ANG/PEG有机大分子吸附性和分子间作用力在改性氧化铈中负载依达拉奉药物，避免自由基自由程过短，无法被氧化铈俘获，达到协同的高效治疗效果。本项目的开展对缺血性脑卒中的神经保护治疗具有重要意义，有望为治愈人类自由基过量相关疾病提供借鉴性研究思路和方法。