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An ATF24 peptide-functionalized β-elemene-nanostructured lipid carrier combined with cisplatin for bladder cancer treatment

引用

Cancer Biology & Medicine 2020年第3期17卷 676-692页

作者： Bingtao Zhai Peng Chen Wengang Wang Shuiping Liu Jiao Feng Ting Duan Yu Xiang Ruonan Zhang Mingming Zhang Xuemeng Han Xiaying Chen Qiujie Li Guohua Li Ying Liu Xingxing Huang Wenzheng Zhang Ting Pan Lili Yan Ting Jin Tian Xie Xinbing Sui Department of Medical Oncology the Affiliated Hospital of Hangzhou Normal UniversityCollege of MedicineHangzhou Normal UniversityHangzhou 310018China Key Laboratory of Elemene Class Anti-cancer Chinese Medicine of Zhejiang Provinee and Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province Hangzhou Normal UniversityHangzhou 310018China College of Pharmacy Chengdu University of Traditional Chinese MedicineChengdu 611137China Department of Medical Oncology Sir Run Run Shaw HospitalZhejiang UniversityHangzhou 310016China

Objective:In this study,we aimed to develop an amino-terminal fragment(ATF)peptide-targeted liposome carryingβ-elemene(ATF24-PEG-Lipo-β-E)for targeted delivery into urokinase plasminogen activator receptor-overexpressing bladder cancer cells combined with cisplatin(DDP)for bladder cancer treatment.Methods:The liposomes were prepared by ethanol injection and high-pressure microjet homogenization.The liposomes were characterized,and the drug content,entrapment efficiency,andin vitro release were studied.The targeting efficiency was investigated using confocal microscopy,ultra-fast liquid chromatography,and an orthotopic bladder cancer model.The effects of ATF24-PEG-Lipo-β-E combined with DDP on cell viability and proliferation were evaluated by a Cell Counting Kit-8(CCK-8)assay,a colony formation assay,and cell apoptosis and cell cycle analyses.The anticancer effects were evaluated in a KU-19-19 bladder cancer xenograft model.Results:ATF24-PEG-Lipo-β-E had small and uniform sizes(~79 nm),high drug loading capacity(~5.24 mg/mL),high entrapment efficiency(98.37±0.95%),and exhibited sustained drug release behavior.ATF24-PEG-Lipo-β-E had better targeting efficiency and higher cytotoxicity than polyethylene glycol(PEG)ylatedβ-elemene liposomes(PEG-Lipo-β-E).DDP,combined with ATF24-PEG-Lipo-β-E,exerted a synergistic effect on cellular apoptosis and cell arrest at the G2/M phase,and these effects were dependent on the caspase-dependent pathway and Cdc25C/Cdc2/cyclin B1 pathways.Furthermore,thein vivo antitumor activity showed that the targeted liposomes effectively inhibited the growth of tumors,using the combined strategy.Conclusions:The present study provided an effective strategy for the targeted delivery ofβ-elemene(β-E)to bladder cancer,and a combined strategy for bladder cancer treatment.

关键词： uPAR β-elemene active targeting liposome bladder cancer DDP

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