影像指导纳米激动剂功能优化提高缺血性脑卒中神经保护疗效

Due to the delayed admission time, most of ischemic stroke patients in China missed the time-window for thrombolytic therapy. This project aims to develop a BBB permeable nanoagonist (NA) to improve the neuroprotective effect by blocking the “inflammatory response” that usually happens in the later stage of ischemia cascade. This NA is made up of the cerium oxide nanoparticle core (CeNP) and micellar coating that is self-assembled by amphiphilic monomers functionalized with adenosine A2A receptor (A2AR) agonist, ischemia targeting ligand and imaging reporter. NA first targets brain vessels in ischemic territories, up-regulates local BBB permeability via activation of endothelial A2AR, and finally inhibits inflammatory responses by activating A2AR expressed in neurons, astrocytes and lymphoid cells. Meanwhile, due to the enzymatic mimicking property of the CeNP core, this NP could efficiently eliminate the harmful reactive oxygen species over-produced in ischemic cascade evens. By non-invasively evaluating “BBB permeability”, “brain uptake of NA” and “nerve fiber bundle density and axonal remodeling” with magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT), it is possible to maximize the therapeutic efficacy and minimize the side-effects induced from non-specific BBB opening and A2AR over-signaling by fine tuning the particle size and the number of functional group labeled on the NA. Overall, this image-guided nanoagonist optimization strategy holds the promise of improving the therapeutic effect of ischemic stroke and accelerating the clinical translation of neuroprotecant candidates.

针对我国缺血性脑卒中病人入院时间滞后、溶栓治疗难以实施的普遍现状，本项目拟构建一类抑制脑缺血次急性期“炎性反应”的跨血脑屏障（BBB）纳米激动剂（NA）实现神经保护疗效。该NA由氧化铈核心（CeNP）和标记有腺苷A2A受体（A2AR）激动基团、靶向基团和影像基团的自组装胶束涂层构成。NA首先靶向脑缺血组织血管，激活内皮细胞A2AR开启BBB，入脑后激活神经/淋巴样细胞A2AR抑制缺血“炎性反应”，并通过CeNP拟酶效应消除炎症过程中产生的活性氧自由基。通过磁共振和单光子发射计算机断层成像实时监测“BBB通透性”、“NA靶向入脑效率”和“神经纤维束损伤恢复”关键事件，指导NA粒径及靶向、激动基团标记数目优化，在实现神经保护疗效最大化同时降低BBB无序开启和A2AR过度激活造成副作用。该影像指导纳米激动剂功能优化策略对提高缺血性脑卒中神经保护治疗疗效，促进神经保护药物临床转化均具有重要意义。

缺血性脑卒中占脑卒中发病率的80%。溶栓治疗是缺血性脑卒中治疗的首选方案，但由于治疗时间窗口短，仅有约5%患者受益于溶栓治疗。缺血部位过度炎性反应造成的二次伤害是脑卒中致死、致残的重要原因。本项目以小胶质细胞表型极化调控为抓手，在调控缺血部位炎性微环境方面取得进展，为绝大多数失去溶栓治疗机会病人提供了治疗新途径。（1）制备了一系列纳米酶，发现消除胞内过量生成的ROS能够抑制炎症信号通路NF-κB的活化，阻止小胶质细胞向促炎表型极化。（2）构建了特异性激活腺苷2A受体的激动胶束，其主动调控缺血部位血脑屏障通透性进入病灶，抑制PKA/NF-κB通路阻止小胶质细胞促炎极化，同时激活PKA/CREB通路促进小胶质细胞抑炎极化。该激动胶束还能够包载神经保护药物进一步提高疗效。项目围绕缺血性脑卒中炎性微环境调控科学问题，在药物跨血脑屏障靶向递送策略、小胶质细胞表型调控机制等方面取得积极成果。本工作还为炎性微环境相关脑疾病治疗提供了新机制和新方法。本项目共发表SCI收录论文9篇，其中3篇影响因子大于10分，8篇影响因子大于5分；获得4次国际会议口头报告邀请；培养博士研究生2名，硕士研究生4名。项目负责人获得2016年获得上海市青年科技英才称号。

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