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中华介入放射学电子杂志 ›› 2022, Vol. 10 ›› Issue (02) : 145 -151. doi: 10.3877/cma.j.issn.2095-5782.2022.02.005

基础研究

搭载达沙替尼的巨噬细胞膜囊泡用于缺血性脑卒中的治疗研究
张晓婷1, 张可1, 郭镜培1, 刘佳妮2, 周斌1,()   
  1. 1. 519000 广东珠海,中山大学附属第五医院介入医学中心;519000 广东珠海,中山大学附属第五医院脑血管病中心
    2. 广东省生物医学影像 重点实验室;广东省分子影像技术工程研究中心
  • 收稿日期:2022-04-07 出版日期:2022-05-25
  • 通信作者: 周斌
  • 基金资助:
    国家自然科学基金(82102164); 广东省自然科学基金(2019A1515011223); 珠海市科技计划医疗卫生项目(ZH22036201210058PWC)

Dasatinib-loaded macrophage membrane vesicles for the treatment of ischemic stroke

Xiaoting Zhang1, Ke Zhang1, Jingpei Guo1, Jiani Liu2, Bin Zhou1,()   

  1. 1. Department of Interventional Medicine, the Fifth Affiliated Hospital of Sun Yat-sen University, Guangdong Zhuhai 519000, China; Center of Cerebrovascular Disease, the Fifth Affiliated Hospital of Sun Yat-sen University, Guangdong Zhuhai 519000, China
    2. Guangdong Provincial Key Laboratory of Biomedical Imaging, the Fifth Affiliated Hospital of Sun Yat-sen University, Guangdong Zhuhai 519000, China; Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital of Sun Yat-sen University, Guangdong Zhuhai 519000, China
  • Received:2022-04-07 Published:2022-05-25
  • Corresponding author: Bin Zhou
引用本文:

张晓婷, 张可, 郭镜培, 刘佳妮, 周斌. 搭载达沙替尼的巨噬细胞膜囊泡用于缺血性脑卒中的治疗研究[J/OL]. 中华介入放射学电子杂志, 2022, 10(02): 145-151.

Xiaoting Zhang, Ke Zhang, Jingpei Guo, Jiani Liu, Bin Zhou. Dasatinib-loaded macrophage membrane vesicles for the treatment of ischemic stroke[J/OL]. Chinese Journal of Interventional Radiology(Electronic Edition), 2022, 10(02): 145-151.

目的

研究开发靶向缺血性大脑和跨血脑屏障的纳米载体,帮助达沙替尼(DAS)有效地输送到大脑,以减轻缺血性脑卒中(IS)后局部炎症反应和神经损伤。

方法

提取巨噬细胞膜构建搭载DAS的纳米囊泡。经尾静脉给药IS小鼠后,通过各器官组织切片HE染色分析载药囊泡的生物安全性。采用荧光标记载药囊泡,利用活体成像和免疫荧光分析载药囊泡的大脑靶向性和生物分布。对不同治疗处理组做神经功能评分、死亡率统计和神经细胞计数,评估载药囊泡的神经保护作用。

结果

载药囊泡在活体内具有良好的生物安全性,可快速高效靶向缺血侧脑组织内并被神经细胞摄取。对比单纯的DAS治疗,载药囊泡治疗可明显改善IS小鼠的神经功能,降低死亡率,减少神经细胞的凋亡。

结论

研究证实搭载DAS的巨噬细胞膜纳米囊泡可安全高效靶向缺血侧大脑递药,有效发挥抗炎和神经保护作用,可为改善IS后药物治疗提供新思路。

Objective

Aims to develop nanocarrier targeting the ischemic brain and the blood-brain barrier help deliver dasatinib (DAS) effectively to the brain, so as to alleviate local inflammatory response and neuronal damage after ischemic stroke (IS).

Methods

The macrophages membranes were extracted to construct DAS-loaded nanovesicles. The biosafety of DAS-loaded vesicles in IS mice was analyzed by HE staining in tissue sections of each organ. The DAS-loaded vesicles were labeled with fluorescence. Then, the brain targeting characteristic and biological distribution of DAS-loaded vesicles were analyzed by in vivo imaging and immunofluorescence. Neurological function score, mortality statistics and neuron count were performed in different treatment groups to evaluate the neuroprotective effect of DAS-loaded vesicles.

Results

DAS-loaded vesicles had good biosafety in vivo. They could rapidly and efficiently target ischemic brain tissue and be taken up by neuron. Compared with DAS, DAS-loaded vesicles significantly improved the neurological function of IS mice, reduced the mortality rate and neuronal apoptosis.

Conclusions

Our study confirmed that DAS-loaded macrophage membrane nanovesicles can safely and efficiently target the ischemic side of the brain, exert anti-inflammatory and neuroprotective effects. That provide new ideas for improving drug treatment after IS.

图1 利用RAW264.7细胞膜构建纳米载药囊泡1A:TEM观察DAS@CMVs的形态,图片的比例尺为200 μm;1B:NTA分析DAS@CMVs的粒径分布(n = 3)。
图2 尾静脉注射24 h的器官组织切片H&E染色(n = 3)(图片的比例尺为200 μm)
图3 DAS@CMVs在体内的大脑靶向性检测3A:pMCAO小鼠注射DAS@CMVs-Cy5后不同时间点进行IVIS活体荧光成像图片(n = 3);3B:免疫荧光检测发现PKH26标记的DAS@CMVs(红色)与脑组织中NeuN标记的神经细胞(绿色)共定位。图片的比例尺为20 μm,放大图的比例尺为5 μm。
图4 DAS@CMVs治疗可发挥有效的神经保护作用4A:Ludmila Belayev 12点评分;4B:Zea-Longa 5点评分;4C:各组小鼠的死亡率;4D:NeuN+细胞数量的定量分析。每组n = 3,数据以均数±标准差表示。与pMCAO组比较,*P < 0.05,**P < 0.01,***P < 0.001;各组间比较,#P < 0.05,###P < 0.001。
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