Enhanced Treatment of Cerebral Ischemia-reperfusion Injury by Intelligent Nanocarriers through the Regulation of Neurovascular Units.
Enhanced Treatment of Cerebral Ischemia-reperfusion Injury by Intelligent Nanocarriers through the Regulation of Neurovascular Units.
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智能纳米载体通过调控神经血管单元增强对脑缺血 - 再灌注损伤的治疗效果。
DOI：
10.1016/j.actbio.2022.05.021
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发表时间：
2022-05
影响因子：
9.7
通讯作者：
Hongdan Lu;Shengnan Li;D. Dai;Qi Zhang;Zhiyi Min;Chuanzhou Yang;Shan Sun;Lu Ye;C. Teng;Xiang Cao;Haoyuan Yin;Lingyan Lv;Wei Lv;Hongliang Xin
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作者：
Hongdan Lu;Shengnan Li;D. Dai;Qi Zhang;Zhiyi Min;Chuanzhou Yang;Shan Sun;Lu Ye;C. Teng;Xiang Cao;Haoyuan Yin;Lingyan Lv;Wei Lv;Hongliang Xin
再灌注损伤是缺血性脑卒中致残和死亡的主要原因之一，药物开发主要集中在单神经元保护上。然而，脑缺血再灌注损伤后，神经血管单位（NVU）中的神经元、小胶质细胞和血管内皮细胞等多种细胞均发生了病理性改变，因此迫切需要开发一种能够全面保护参与NVU的多种细胞的药物递送系统。因此，我们构建了一种c（RGDyK）肽修饰的NF-κB抑制剂咖啡酸苯乙酯（CAPE）和活性氮（RNS）刺激响应性脂质体纳米载体（R-Lipo-CAPE），以靶向缺血损伤，然后重塑NVU以减轻脑缺血再灌注损伤的进展。R-Lipo-CAPE脂质体约为170 nm，ζ电位为-30.8 ± 0.2 mV。R-Lipo-CAPE的体外释放行为呈RNS-dependent模式。在体内研究中，短暂性大脑中动脉闭塞/再灌注（MCAO）模型小鼠经R-Lipo-CAPE治疗后，神经功能损害最小，脑组织损伤减少，梗死面积为13%，而生理盐水组和游离CAPE组分别为53%和38%。此外，缺血脑中的小胶质细胞在R-Lipo-CAPE处理后极化为组织修复M2表型。此外，R-Lipo-CAPE处理的小鼠显示出MMP-9的显著下调表达和紧密连接蛋白claudin-5的恢复表达。这一概念验证表明R-Lipo-CAPE是一种很有前途的通过调节神经血管单位来治疗脑缺血再灌注损伤的纳米药物。意义陈述基于脑缺血再灌注损伤机制的复杂性和治疗的困难性，对神经血管单位的整体调节已成为一个极其重要的靶点。然而，在靶向脑缺血再灌注损伤治疗中，很少有纳米药物被用于重塑神经血管单位。本研究设计了c（RGDyK）肽修饰的活性氮类（RNS）刺激响应性脂质体纳米载体，负载NF-κB抑制剂（CAPE），用于同时调控脑缺血再灌注损伤微环境中的各种细胞，以重塑神经血管单位。体外和体内实验结果表明，智能纳米载体通过减少神经元凋亡、调节小胶质细胞极化和修复血管内皮细胞，发挥病理信号刺激响应性药物释放、脑缺血再灌注损伤靶向性和神经血管单位重塑的能力。因此，智能脂质体药物传递系统在脑缺血再灌注损伤的治疗中是一种安全、有效的纳米药物。
Reperfusion injury is one of the major causes of disability and death caused by ischemic stroke, and drug development focuses mainly on single neuron protection. However, different kinds of cells in the neurovascular units (NVUs), including neurons, microglia and vascular endothelial cells, are pathologically changed after cerebral ischemia–reperfusion injury, resulting in an urgent need to develop a drug delivery system to comprehensively protect the kinds of cells involved in the NVU. Herein, we have constructed a c(RGDyK) peptide modified, NF-κB inhibitor caffeic acid phenethyl ester (CAPE)-loaded and reactive nitrogen species (RNS) stimuli-responsive liposomal nanocarrier (R-Lipo-CAPE) to target ischemic lesions and then remodel the NVU to reduce the progression of cerebral ischemia–reperfusion injury. The R-Lipo-CAPE liposomes were approximately 170 nm with a zeta potential of -30.8 ± 0.2 mV. Thein vitroCAPE release behavior from R-Lipo-CAPE showed an RNS-dependent pattern. Forin vivostudies, transient middle cerebral artery occlusion/reperfusion (MCAO) model mice treated with R-Lipo-CAPE had the least neurological impairment and decreased brain tissue damage, with an infarct area of 13%, compared with those treated with saline of 53% or free CAPE of 38%. Furthermore, microglia in the ischemic brain were polarized to the tissue-repairing M2 phenotype after R-Lipo-CAPE treatment. In addition, R-Lipo-CAPE-treated mice displayed a prominent down-regulated expression of MMP-9 and restored expression of the tight junction protein claudin-5. This proof-of-concept indicates that R-Lipo-CAPE is a promising nanomedicine for the treatment of cerebral ischemia–reperfusion injury through the regulation of neurovascular units.Statement of significanceBased on the complex mechanism and difficulty in treatment of cerebral ischemia-reperfusion injury, the overall regulation of neurovascular unit has become an extremely important target. However, little nanomedicine has been directed to remodel the neurovascular units in targeted cerebral ischemia-reperfusion injury therapy. Here, c(RGDyK) peptide modified reactive nitrogen species (RNS) stimuli-responsive liposomal nanocarrier loaded with a NF-κB inhibitor (CAPE), was designed to simultaneously regulate various cells in the microenvironment of cerebral ischemia-reperfusion injury to remodel the neurovascular units. Ourin vitroandin vivodata showed that the intelligent nanocarrier exerted the ability of pathological signal stimuli-responsive drug release, cerebral ischemia-reperfusion injury site targeting and neurovascular units remodeling through reducing neuron apoptosis, regulating microglia polarization and repairing vascular endothelial cell. Overall, the intelligent liposomal drug delivery system was a promising and safe nanomedicine in the perspective of cerebral ischemia-reperfusion injury treatment.