Mitochondrion-targeted supramolecular "nano-boat" simultaneously inhibiting dual energy metabolism for tumor selective and synergistic chemo-radiotherapy

• Published in: Theranostics Vol. 12; no. 3; pp. 1286 - 1302
• Main Authors: Gao, Jie, Wang, Zhilong, Guo, Qingxiang, Tang, Huan, Wang, Zhongyan, Yang, Cuihong, Fan, Huirong, Zhang, Wenxue, Ren, Chunhua, Liu, Jianfeng
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher Pty Ltd 2022; Ivyspring International Publisher
• Subjects: Apoptosis; Boats; Cancer therapies; Cell Line, Tumor; Chemoradiotherapy; Cytochrome; Drug delivery systems; Energy; Energy Metabolism; Hydrogels; Metabolism; Microscopy; Mitochondria - metabolism; Oxidative Phosphorylation; Peptides; Radiation therapy; Reactive Oxygen Species - metabolism; Research Paper; cancer metabolism; selective killing; mitochondrion-targeted; peptide self-assembly; radio-sensitization
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.67543

Tumor energy metabolism has been a well-appreciated target of cancer therapy; however, the metabolism change of cancer cells between oxidative phosphorylation and glycolysis poses a challenge to the above. In this study, we constructed an innovative mitochondrion-targeted supramolecular "nano-boat" based on peptide self-assembly for tumor combined chemo-radiotherapy by simultaneously inhibiting the dual energy metabolism. A lipophilic self-assembled peptide and a positively charged cyclen were integrated to fabricate a brand new mitochondrion-targeted nano-platform for the first time. The indices of mitochondrial dysfunction including mitochondrial membrane potential, apoptosis proteins expression and ultrastructure change were evaluated using a JC-1 probe, western blotting and biological transmission electron microscopy, respectively. Energy metabolism assays were conducted on a Seahorse XF24 system by detecting the oxygen consumption rate and the glycolytic proton efflux rate. The radio-sensitization effect was investigated by colony formation, the comet assay, and γ-H2AX staining. The supramolecular "nano-boat" could selectively kill cancer cells by much higher enrichment and reactive oxygen species generation than those in normal cells. In the cancer cells treated with the supramolecular "nano-boat", the dysfunctional morphological changes of the mitochondrial ultrastructure including swelling and pyknosis were evidently observed, and the endogenous mitochondrial apoptosis pathway was effectively triggered by abundant of cytochrome C leaking out. Concurrently, the dual metabolic pathways of glycolysis and oxidative phosphorylation were severely inhibited. More importantly, the supramolecular "nano-boat" displayed an excellent radio-sensitization effect with a sensitization enhancement ratio value as high as 2.58, and hence, efficiently combining radiotherapy yielded an enhanced chemo-radiotherapy effect. Our study demonstrated that the rationally designed peptide-based "nano-boat" could efficiently induce cancer cell apoptosis by the energy metabolism inhibition involving multiple pathways, which may provide the motivation for designing novel and universal mitochondria-targeted drug delivery systems for cancer therapy.