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《天津医科大学学报》[ISSN:1006-8147/CN:12-1259/R]

卷:

27卷

期数:

2021年03期

页码:

229-233

栏目:

基础医学

出版日期:

2021-05-30

文章信息/Info

Title:

Tumor-derived exosomes mediate targeted therapy in hepatocellular carcinoma mice

文章编号:

1006-8147(2021)03-0229-05

作者:

张杨; 游阿彬; 齐寒; 张缘; 左冰峰; 尹海芳

天津医科大学基础医学院细胞生物学系，天津 300070

Author(s):

ZHANG Yang;  YOU A-bin;  QI Han;  ZHANG Yuan;  ZUO Bing-feng;  YIN Hai-fang

Department of Cell Biology，School of Basic Medical Sciences，Tianjin Medical University，Tianjin 300070，China

关键词:

肝细胞癌; 外泌体; 化疗药物; 靶向治疗

Keywords:

hepatocellular carcinoma; exosomes; chemotherapeutics; targeted therapy

分类号:

Q291

DOI:

-

文献标志码:

A

摘要:

目的：在小鼠肝癌皮下瘤模型中探究肝癌靶向肽介导负载甲氨蝶呤（MTX）的肝癌细胞来源外泌体（tumor-derived exosome-TEX）的抗肿瘤效果及不良反应。方法：利用超速离心法收集负载MTX的小鼠肝癌细胞来源的外泌体（TEXMTX）；利用外泌体特异锚定短肽CP05将肝癌靶向肽SP94修饰在TEXMTX表面，活体成像检测靶向肽修饰的TEXMTX能否高效靶向肝癌组织；通过尾静脉注射荷瘤鼠，评估该靶向肽修饰的TEXMTX的抑瘤效果，同时检测治疗后各组小鼠血生化指标及组织形态学染色，评估该药物生物安全性。结果：负载MTX并不影响外泌体的基本结构和形态特征； SP94可将TEXMTX高效靶向运输到肿瘤部位；在皮下抑瘤实验中，与PBS组相比，SP94-CP05-TEXMTX能够显著抑制小鼠肝癌皮下瘤的生长（t=5.811，P＜0.01），与MTX组和TEXMTX组相比，SP94-CP05-TEXMTX组肿瘤体积也显著减小（t=2.573、3.152，均P＜0.05）；血生化指标和病理指标显示，与PBS组相比， MTX组和TEXMTX组小鼠血清谷草转氨酶水平显著升高（t=7.084、5.260，均P＜0.05）。与MTX组和TEXMTX组相比，SP94-CP05-TEXMTX组小鼠谷草转氨酶水平显著下降（t=6.241、4.955，均P＜0.05）；SP94-CP05-TEXMTX组与MTX组相比，小鼠血清肌酸激酶水平也显著下降（t=5.073，P＜0.05）。结论：肝癌靶向肽修饰的TEXMTX可将MTX靶向运输到肝细胞癌组织，有效抑制肿瘤生长，提高化疗药物的生物安全性。

Abstract:

Objective: To investigate the anti-tumor and adverse reactions of hepatocellular carcinoma（HCC）-targeting peptide modified tumor-derived exosomes（TEX） loaded with methotrexate（MTX） cargoes in a mouse model of subcutaneous HCC. Methods: Tumor-derived exosomes（TEXMTX） loaded with methotrexate was collected by ultracentrifugation. HCC-targeting peptides SP94 were modified on TEXMTX by using exosomal-specific anchoring peptide CP05. In vivo imaging was used to detect whether targeting peptide-modified TEXMTX could efficiently target HCC tissues. The tumor-bearing mice were injected through the tail vein to compare the anti-tumor effects of TEXMTX in each group. At the same time， the blood biochemical indexes and histomorphological staining of each group after treatment were detected to assess the biological safety of the drug. Results: Loading MTX did not affect the basic structure and morphological characteristics of exosomes. TEXMTX modified with SP94 improved the delivery efficiency of chemotherapy drugs into targeted HCC tumor tissue. In the subcutaneous tumor suppression experiment， compared with the PBS group， SP94-CP05-TEXMTX could significantly inhibit the growth of liver cancer subcutaneous tumors in mice（t=5.811，P＜0.01）. Compared with the MTX group and the TEXMTX group， the tumor volume in the SP94-CP05-TEXMTX group was also significantly reduced（t=2.573，3.152， both P＜0.05）. Blood biochemical indicators and pathological indicators showed that compared with the PBS group， the serum aspartate aminotransferase levels of mice in the MTX group and TEXMTX group were significantly increased（t=7.084， 5.260， both P＜0.05）. Compared with the MTX group and the TEXMTX group， the level of aspartate aminotransferase in mice of the SP94-CP05-TEXMTX group decreased significantly（t=6.241，4.955，both P＜0.05）. Compared with the MTX group， the SP94-CP05-TEXMTX group also showed a significant decrease in serum creatine kinase levels（t=5.073，P＜0.05）. Conclusion: HCC-targeting peptide modified TEXMTX can target MTX to hepatocellular carcinoma tissues， effectively inhibit the tumor growth， and improve the biological safety of chemotherapy drugs.

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备注/Memo

备注/Memo:

基金项目 天津市教委科研计划项目(2017KJ222)
作者简介 张杨(1994-)，男，硕士在读，研究方向：外泌体与肿瘤免疫治疗；
通信作者：尹海芳，E-mail：haifangyin@tmu.edu.cn；左冰峰，E-mail：zuobingfeng@tmu.edu.cn。

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更新日期/Last Update: 2021-05-30