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

Objective: In this study, we aimed to develop an amino-terminal fragment(ATF) peptide-targeted liposome carrying β-elemene(ATF-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, and in 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 ATF-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: ATF-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. ATF-PEG-Lipo-β-E had better targeting efficiency and higher cytotoxicity than polyethylene glycol(PEG)ylated β-elemene liposomes(PEG-Lipo-β-E). DDP, combined with ATF-PEGLipo-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, the in 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 of β-elemene(β-E) to bladder cancer, and a combined strategy for bladder cancer treatment.