Riboflavin-modified lipo-polyplexes co-delivering CXCR4 siRNA and doxorubicin for treatment of highly metastatic cancer  

核黄素修饰的脂质复合纳米粒共递送CXCR4 siRNA和阿霉素治疗高转移性癌症

作　　者：Kaisen Li Rudong Wang Yiwei Peng Dawen Dong Xianrong Qi 李锴森;王如东;彭祎玮;董达文;齐宪荣(北京大学医学部药学院药剂学系,北京100191;北京大学医学部分子药剂学与新释药系统北京市重点实验室,北京100191;扬子江药业集团药物制剂新技术国家重点实验室,江苏225300)

机构地区：[1]Department of Pharmaceutics,School of Pharmaceutical Sciences,Peking University Health Science Center,Beijing 100191,China [2]Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System,School of Pharmaceutical Sciences,Peking University,Beijing 100191,China [3]State Key Laboratory of Advanced Pharmaceutical Formulation with High Technology,Yangtze River Pharmaceutical Group,Jiangsu 225300,China

出　　处：《Journal of Chinese Pharmaceutical Sciences》2021年第3期189-205,共17页中国药学（英文版）

基　　金：The National Nature Science Foundation of China(Grant No.81973258 and 81673365);State Key Laboratory of Advanced Pharmaceutical Formulation with High Technology in Yangtze River Pharmaceutical Group.

摘　　要：SDF-1/CXCR4 has been recognized as one of the most relevant chemokine signaling pathways to cancer metastasis,and siRNA targeting CXCR4 may provide potential improvements to treat those highly metastatic cancers,especially when combined with chemotherapy.In the present study,we constructed riboflavin-modified lipo-polyplexes to co-deliver CXCR4 siRNA and doxorubicin for cancer therapy.Doxorubicin was covalently conjugated to polyethyleneimine(PEI)with acid-cleavable hydrazine bond,and the obtained acid-sensitive conjugate was efficiently condensed with siRNA to form polyplexes,which were further coated with riboflavin-tailed lipid-membrane to prepare the lipo-polyplexes conveniently.Utilizing the fact that tumor cells overexpress riboflavin receptors,the riboflavin modification effectively enhanced uptake of lipo-polyplexes by tumor cells in a receptor-mediated manner.The riboflavin-modified lipo-polyplexes co-delivering CXCR4 siRNA and doxorubicin effectively decreased viability and invasiveness of tumor cells in vitro,and inhibited primary tumor growth and tumor metastasis in vivo.多项研究揭示SDF-1/CXCR4是与癌症转移最相关的趋化因子通路之一,因此靶向CXCR4的siRNA能够改善高转移性癌症治疗效果,尤其将其与化疗联合使用时潜力巨大。本研究中,我们构建了素修饰的脂质复合纳米粒,实现了对CXCR4 siRNA和阿霉素的共递送,用于癌症治疗。以酸性环境中可断裂的腙键,将阿霉素共价连接至聚乙烯亚胺(PEI),所得酸敏感性偶联物与siRNA紧密压缩形成聚合物纳米粒,进一步以尾端含核黄素的脂质薄膜对其进行包覆,制备了核黄素修饰的脂质复合纳米粒。利用肿瘤细胞高表达核黄素受体的事实,核黄素修饰有效增强了肿瘤细胞对脂质复合纳米粒的摄取。共包载CXCR4 siRNA和阿霉素的核黄素修饰脂质复合纳米粒在体外有效降低了肿瘤细胞的生存率和侵袭能力;在体内,抑制了原位肿瘤的生长,同时抑制了肿瘤转移。

关 键 词：RIBOFLAVIN Lipo-polyplexes CO-DELIVERY SIRNA DOXORUBICIN 

分 类 号：R944[医药卫生—药剂学]