脑梗死溶栓治疗使血管再通后会出现无复流现象，意味着细胞能量代谢耗竭时即使恢复血流也不能得以挽救，pH值代表的细胞代谢水平比脑血流量能更准确的定义可挽救的半暗带。在前期合成的尿激酶纳米凝胶的基础上，我们提出假说：以特定pH值作为靶点控制药物释放于半暗带区，能够实现药物靶向干预。本研究拟采用pH敏感微电极绘制大鼠大脑中动脉缺血再灌注模型梗死核心周围组织pH变化梯度图。依靠核磁共振选取脑血流量降低且弥散像正常部位，明确脑梗死后半暗带区的pH值变化范围。在此基础上制备相应pH值敏感的PEG-尿激酶纳米凝胶，经脑梗死大鼠颈内动脉注射，观察其对脑梗死体积、神经功能评分的影响。以caspase-9和NMDA受体为指标明确尿激酶靶向治疗对神经元损伤的影响。通过对血脑屏障通透通透性、紧密连接蛋白claudin-5及基质金属蛋白酶表达的检测明确尿激酶靶向治疗对血脑屏障的作用。这将为急性脑梗死的治疗开拓新的方向

Even when blood flow is restored after thrombolysis, there is sometimes no-flow phenomenon in cerebral infarction. The fate of ischemic cell is determined by energy state rather than cerebral blood flow. The pH value will be more appropreite for identification of salvageble penumbra. In our previous work, urokinase was allosteric through crosslinking with PEG.Our hypothesis is that pH sensitive PEG-urokinase nanogels can be released in the penumbra resulting in targeting therapy.In this study pH sensitive microelectrode will be introduced into ischemic brain tissue to evaluate the tissue pH value. A pH gradient map can be drawn.We will choose PWI/DWI mismatch region on MRI and identify the pH value of ischemic penumbra. We will synthesis pH sensitive PEG-urokinase nanogels according to pH value of the penumbra. The nanogels will be injected through internal carotid artery. Cerebral infarction volume and neurological deficit will be evaluated. Improvement of neurotoxicity will be investigated through the expression of caspase-9 and NMDA receptor. Improvement of BBB injury will be investigated through BBB permeability, expression of claudin-5 and matrix metalloproteinases.This brings a new direction for the treatment of ischemic stroke.