硫酸软骨素载药胶束靶向肿瘤细胞内高尔基体治疗肿瘤转移的初步研究  

Preliminary Study on Drug-Loaded Chondroitin Sulfate-Modified Micelles Targeting Golgi Apparatus in Tumor Cells for the Treatment of Tumor Metastasis

作　　者：周红利 李少宏 陈丹 赵婷 龚涛[1] 李佳[3] ZHOU Hong-li;LI Shao-hong;CHEN Dan;ZHAO Ting;GONG Tao;LI Jia(Key Laboratory of Drug Targeting and Delivery System of the Ministry of Education,West China School of Pharmacy,Sichuan University,Chengdu 610041,China;Chongqing Pharmaceutical(Group)Co.,Ltd,Chongqing 400010,China;West China Hospital of Stomatology,Sichuan University,Chengdu 610041,China)

机构地区：[1]四川大学华西药学院靶向药物与释药系统教育部重点实验室,成都610041 [2]重庆医药,集团)股份有限公司,重庆400010 [3]四川大学华西口腔医院,成都610041

出　　处：《四川大学学报（医学版）》2022年第4期619-625,共7页Journal of Sichuan University(Medical Sciences)

基　　金：国家自然科学基金(No.81872804)资助。

摘　　要：目的本研究旨在初步探究共载吡柔比星(pirarubicin,THP)与长春瑞宾(vinorelbine,VRL)的硫酸软骨素胶束(chondroitin sulfate-modified micelles,CSmicelles)的肿瘤细胞内高尔基体的靶向性及其体外抗肿瘤转移效果。方法采用流式细胞术考察小鼠乳腺癌细胞株4T1摄取CSmicelles情况及摄取机制;通过共定位实验对CSmicelles的高尔基体靶向性进行初步研究;采用GM130免疫荧光实验考察共载THP与VRL的CSmicelles(THP+VTL-CSmicelles)对高尔基体结构的影响;最后通过细胞划痕实验和Transwell迁移/侵袭实验对THP+VTL-CSmicelles的体外抗肿瘤转移效果进行初步评价。结果CSmicelles能显著增加药物的入胞能力,其细胞摄取途径为网格蛋白和小窝蛋白介导的内吞,为能量依赖性的主动转运,并具有良好的肿瘤细胞内高尔基体靶向性。THP+VTL-CSmicelles能破坏高尔基体结构,显著抑制肿瘤细胞的迁移和侵袭。结论THP+VTL-CSmicelles具有肿瘤细胞高尔基体靶向性,可发挥靶向效应,抑制肿瘤细胞转移。Objective To make preliminary exploration into the Golgi apparatus targeting of chondroitin sulfate-modified micelles(CSmicelles)co-loaded with pirarubicin(THP)and vinorelbine(VRL)in tumor cells,as well as their in vitro anti-tumor metastasis effect.Methods The cellular uptake efficiency and internalization mechanism of CSmicelles in 4T1 mouse breast cancer cell line were investigated by flow cytometry.Preliminary study of the Golgi apparatus targeting CSmicelles in tumor cells was conducted by co-localization experiment.Then,the effect of CSmicelles co-loaded with THP and VRL(THP+VTL-CSmicelles)on the structure of Golgi apparatus was investigated by GM130immunofluorescence experiment.Finally,the in vitro anti-tumor metastasis ability of THP+VTL-CSmicelles was evaluated by wound healing assay and Transwell migration/invasion assay.Results It was found that CSmicelles could significantly increase cellular uptake of drugs.CSmicelles were internalized into cells through clathrin-mediated and caveolin-mediated endocytosis,which was energy-dependent active transport and exhibited substantial ability of targeting Golgi apparatus in tumor cells.THP+VTL-CSmicelles could break down the structure of Golgi apparatus and significantly inhibit the migration and invasion of tumor cells.Conclusion THP+VTL-CSmicelles demonstrate high affinity towards Golgi apparatus in tumor cells,exert targeted effects and inhibit tumor cell metastasis,which provides a novel idea and method for the treatment of cancer metastasis.

关 键 词：高尔基体靶向 肿瘤转移 硫酸软骨素 胶束 长春瑞宾 

分 类 号：R943[医药卫生—药剂学]