融合蛋白anti-EGFR-iRGD修饰的红细胞外囊泡联合siRNA靶向抑制三阴性乳腺癌恶性进程  

Targeted inhibition of triple-negative breast cancer by fusion protein anti-EGFR-iRGD modified extracellular vesicles of red blood cells combined with siRNA

作　　者：韦雪妮 杨忠慧[1] 黄吉 陈国梅[1] 成昌娟 WEI Xueni;YANG Zhonghui;HUANG Ji;CHEN Guomei;CHENG Changjuan(Department of Pharmacy,Suzhou University Affiliated Taicang Hospital(the First People's Hospital of Taicang),Jiangsu Taicang 215400,China)

机构地区：[1]苏州大学附属太仓医院(太仓市第一人民医院)药剂科,江苏太仓215400

出　　处：《现代肿瘤医学》2024年第17期3197-3205,共9页Journal of Modern Oncology

基　　金：江苏省苏州市科技发展计划(民生科技-医疗卫生应用基础研究)项目(编号:SYSD2020172)。

摘　　要：目的:通过红细胞来源的细胞外囊泡(red blood cell-derived extracellular vesicles,RBCEVs)构建靶向递送系统以提高对三阴性乳腺癌(triple-negative breast cancer,TNBC)恶性进程的抑制效率。方法:采用脂质插入法将融合蛋白anti-抗人表皮生长因子受体(epidermal growth factor receptor,EGFR)-iRGD多肽结合至RBCEVs膜表面以构建生物相容性药物递送系统。通过电穿孔方式使连环蛋白β1(Catenin Beta 1,CTNNB1)-siRNA有效装载至anti-EGFR-iRGD-RBCEVs。进一步验证anti-EGFR-iRGD-si-CTNNB1-RBCEVs对TNBC增殖、迁移的影响及对上皮间充质转化相关蛋白表达的调控。结果:anti-EGFR-iRGD-si-CTNNB1-RBCEVs在120 h内具有较高血清稳定性,并且可有效防止RNA酶对CTNNB1-siRNA的降解。另外,该复合物可显著提高si-CTNNB1对TNBC细胞中CTNNB1基因及β-catenin蛋白的抑制作用并抑制TNBC细胞的增殖、迁移能力,下调Snail、Vimentin、N-cadherin并促进E-cadherin蛋白的表达。结论:该研究通过构建融合蛋白anti-EGFR-iRGD修饰的RBCEVs联合siRNA靶向抑制TNBC恶性进程,这将为治疗整合素α_(v)β_(3)高表达的TNBC提供更有利治疗方式。Objective:To develop a targeted delivery system using red blood cell-derived extracellular vesicles(RBCEVs) to enhance the inhibitory efficiency against triple-negative breast cancer(TNBC).Methods:The fusion protein anti-epidermal growth factor receptor(EGFR)-iRGD peptide was incorporated into the membrane surface of RBCEVs using lipid insertion method to construct a biocompatible drug delivery system.Catenin Beta 1(CTNNB1) siRNA was effectively loaded onto anti-EGFR-iRGD-RBCEVs through electroporation.The inhibitory effects of anti-EGFR-iRGD-si-CTNNB1-RBCEVs on TNBC proliferation and migration were further examined,along with their regulation of epithelial-mesenchymal transition(EMT)-related protein expression.Results:The anti-EGFR-iRGD-si-CTNNB1-RBCEVs complex demonstrated high serum stability within 120 h and effectively prevented degradation of siRNA by RNAases.Moreover,this complex significantly enhanced the inhibitory effect of si-CTNNB1 on both the CTNNB1 gene and protein in TNBC cells,suppressing of TNBC proliferation and migration.The expression of Snail,Vimentin,and N-cadherin proteins was downregulated,while the expression of E-cadherin protein was promoted.Conclusion:This study demonstrates the targeted inhibition of TNBC cells using fusion protein anti-EGFR-iRGD modified RBCEVs in combination with siRNA.These findings provide a promising therapeutic approach for reating TNBC with high expression of integrin α_(v)β_(3).

关 键 词：红细胞来源的细胞外囊泡 三阴性乳腺癌 SIRNA 上皮间充质转化 脂质插入法 连环蛋白β1 

分 类 号：R737.9[医药卫生—肿瘤]