Carbon-dot-supported atomically dispersed gold as a mitochondrial oxidative stress amplifier for cancer treatment

Abstract

Mitochondrial redox homeostasis, the balance between reactive oxygen species and antioxidants such as glutathione, plays critical roles in many biological processes, including biosynthesis and apoptosis, and thus is a potential target for cancer treatment. Here, we report a mitochondrial oxidative stress amplifier, MitoCAT-g, which consists of carbon-dot-supported atomically dispersed gold (CAT-g) with further surface modifications of triphenylphosphine and cinnamaldehyde. We find that the MitoCAT-g particles specifically target mitochondria and deplete mitochondrial glutathione with atomic economy, thus amplifying the reactive oxygen species damage caused by cinnamaldehyde and finally leading to apoptosis in cancer cells. We show that imaging-guided interventional injection of these particles potently inhibits tumour growth in subcutaneous and orthotopic patient-derived xenograft hepatocellular carcinoma models without adverse effects. Our study demonstrates that MitoCAT-g amplifies the oxidative stress in mitochondria and suppresses tumour growth in vivo, representing a promising agent for anticancer applications.

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Fig. 1: Design of a mitochondrial oxidative stress amplifier (MitoCAT-g) for cancer treatment.
Fig. 2: Synthesis and characterization of CAT-g.
Fig. 3: Intracellular distribution of MitoCAT-g in HepG-2 cells.
Fig. 4: MitoCAT-g amplifies mitochondrial oxidative stress in HepG-2 cancer cells.
Fig. 5: MitoCAT-g amplifies oxidative stress and suppresses tumour growth in a subcutaneous tumour model.
Fig. 6: MitoCAT-g amplifies oxidative stress and induces an enhanced antitumour effect in orthotopic hepatic PDX tumours.

Data availability

All relevant data during the study are available from the corresponding authors upon request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (NSFC) (grants nos. 21327806, 21621003, 21235004, 31630027, 31430031, 31600808 and 31225009), the NSFC-German Research Foundation (DFG) project 31761133013 and the ‘Strategic Priority Research Program’ from the Chinese Academy of Sciences (XDA09030301). The authors acknowledge support from the BL14W1 station of the Shanghai Synchrotron Radiation Facility.

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N.G., J.L. and X.-J.L. conceived and designed the experiments. N.G., X.M., X.Y., Q.Z., S.H., T.Z. and S.C. performed the experiments. N.G., X.Y., X.C., X.Tan, S.Y., T.Z., J.Y., H.J., J.L. and X.-J.L. analysed the results. N.G., X.Teng, X.H., Y.G., J.L. and X.-J.L. wrote the manuscript. J.L. and X.-J.L. supervised the entire project.

Corresponding authors

Correspondence to Jinghong Li or Xing-Jie Liang.

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The authors declare no competing interests.

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Journal peer review information Nature Nanotechnology thanks Jose Fernandez-Checa, Chun Li and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Gong, N., Ma, X., Ye, X. et al. Carbon-dot-supported atomically dispersed gold as a mitochondrial oxidative stress amplifier for cancer treatment. Nat. Nanotechnol. 14, 379–387 (2019). https://doi.org/10.1038/s41565-019-0373-6

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