Stimuli-responsive combination therapy of cisplatin and Nrf2 siRNA for improving antitumor treatment of osteosarcoma

查看全文 作　　者：Ting-Ting [1]Gu;Chengjun [2]Li;Yurui [1]Xu;Lei [1]Zhang;Xue [1]Shan;Xinyu [1]Huang;Leilei [1]Guo;Kerong [1]Chen;Xiaojian [3]Wang;Haixiong [1]Ge;Xinghai [1,4]Ning 机构地区：[1]National Laboratory of Solid State Microstructures,College of Engineering and Applied Sciences,Nanjing University,Nanjing,210093,China;[2]Jinling Hospital,Department of Orthopedics,School of medicine,Nanjing University,Nanjing,210002,China;[3]Institute of advanced synthesis,Nanjing Tech University,Nanjing,210093,China;[4]Chemstry and Biomedicine Innovation Center(ChemBIC),Nanjing University,Nanjing,210093,China 出　　处：《Nano Research》索引2020年第13卷第3期,共8页 基　　金：This work was supported by the National Key Research and Development Program of China(No.2019YFA0802800);the Key Research and Development Program of Jiangsu Provincial Department of Science and Technology of China(No.BE2019002);the Medical Key Young Talents Programs of Jiangsu Province(No.QNRC2016915);the“The Six Top Talents”of Jiangsu Province(No.WSW-112);the Fundamental Research Funds for the Central Universities(No.021314380120);the National Key Research and Development Program of China(No.2018YFB1105400);National Natural Science Foundation of China(No.21708019);Natural Science Foundation of Jiangsu(No.BK20170987). 摘　　要：Cisplatin is a widely applied therapeutics for the treatment of osteosarcoma.However,its clinical applications have been hindered due to low efficacy and bioavailability,and particularly frequent emergence of reactive oxygen species(ROS)-decrease induced drug resistance.The transcription factor NF-E2-related factor 2(Nrf2)is increased in cancer patients and induces poor outcome in osteosarcoma treatment,making it a novel target to improve the efficacy of chemotherapy.Herein,a hyaluronidase-responsive multi-layer liposome(HLCN)for co-delivery of cisplatin and Nrf2 siRNA(siNrf2)is developed.It is composed of Vpr52-96 modified liposome covered with hyaluronic acid(HA).HLCN selectively accumulates in osteosarcoma by targeting tumor-specific CD44,and can be degraded by endosomal hyaluronidase to generate cationic liposome,which promotes the endosomal escape of Vpr52-96,cisplatin and siNrf2.HLCN can effectively decrease Nrf2 level,promote ROS generation,activate itochondrial apoptotic pathway,and consequently enhance anticancer efficacy of cisplatin.Particularly,HLCN shows high cytotoxicity to osteosarcoma cells with an IC50 value of about 1µM,which is four-fold lower than liposomal cisplatin(IC504µM),indicating that Nrf2 silence can significantly improve cisplatin sensitivity in cancer cells.Importantly,HLCN can remarkably inhibit tumor growth in the xenograft osteosarcoma mice with minimal systemic adverse effects.Therefore,this novel stimuli-responsive combination therapy of cisplatin and siNrf2 provides a promising strategy for the treatment of osteosarcoma. 关 键 词：stimuli-responsive liposome NF-E2-related factor 2(Nrf2)siRNA(siNrf2) reactive oxygen species(ROS) OSTEOSARCOMA combination therapy