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

Nature Nanotechnology volume 14, pages 379–387 (2019)Cite this article

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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.

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

References

  1. Weinberg, S. E. & Chandel, N. S. Targeting mitochondria metabolism for cancer therapy. Nat. Chem. Biol. 11, 9–15 (2015).

    Article  CAS  Google Scholar 

  2. Sena, L. A. & Chandel, N. S. Physiological roles of mitochondrial reactive oxygen species. Mol. Cell 48, 158–167 (2012).

    Article  CAS  Google Scholar 

  3. Shadel, G. S. & Horvath, T. L. Mitochondrial ROS signaling in organismal homeostasis. Cell 163, 560–569 (2015).

    Article  CAS  Google Scholar 

  4. Willems, P. H., Rossignol, R., Dieteren, C. E., Murphy, M. P. & Koopman, W. J. Redox homeostasis and mitochondrial dynamics. Cell. Metab. 22, 207–218 (2015).

    Article  CAS  Google Scholar 

  5. Sabharwal, S. S. & Schumacker, P. T. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles’ heel? Nat. Rev. Cancer 14, 709–721 (2014).

    Article  CAS  Google Scholar 

  6. Dickinson, B. C. & Chang, C. J. Chemistry and biology of reactive oxygen species in signaling or stress responses. Nat. Chem. Biol. 7, 504–511 (2011).

    Article  CAS  Google Scholar 

  7. Wallace, D. C. Mitochondria and cancer. Nat. Rev. Cancer 12, 685–698 (2012).

    Article  CAS  Google Scholar 

  8. Baulies, A. et al. The 2-oxoglutarate carrier promotes liver cancer by sustaining mitochondrial GSH despite cholesterol loading. Redox Biol. 14, 164–177 (2018).

    Article  CAS  Google Scholar 

  9. Gorrini, C., Harris, I. S. & Mak, T. W. Modulation of oxidative stress as an anticancer strategy. Nat. Rev. Drug Discov. 12, 931–947 (2013).

    Article  CAS  Google Scholar 

  10. Chen, G., Chen, Z., Hu, Y. & Huang, P. Inhibition of mitochondrial respiration and rapid depletion of mitochondrial glutathione by β-phenethyl isothiocyanate: mechanisms for anti-leukemia activity. Antioxid. Redox Sign. 15, 2911–2921 (2011).

    Article  CAS  Google Scholar 

  11. Trachootham, D., Alexandre, J. & Huang, P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat. Rev. Drug Discov. 8, 579–591 (2009).

    Article  CAS  Google Scholar 

  12. Liu, L. et al. Generation of subnanometric platinum with high stability during transformation of a 2D zeolite into 3D. Nat. Mater. 16, 132–138 (2017).

    Article  CAS  Google Scholar 

  13. Yao, S. et al. Atomic-layered Au clusters on α-MoC as catalysts for the low-temperature water-gas shift reaction. Science 357, 389–393 (2017).

    Article  CAS  Google Scholar 

  14. Liu, P. et al. Photochemical route for synthesizing atomically dispersed palladium catalysts. Science 352, 797–800 (2016).

    Article  CAS  Google Scholar 

  15. Zhang, Z. et al. Thermally stable single atom Pt/m-Al2O3 for selective hydrogenation and CO oxidation. Nat. Commun. 8, 16100 (2017).

    Article  CAS  Google Scholar 

  16. Yang, X.-F. et al. Single-atom catalysts: a new frontier in heterogeneous catalysis. Acc. Chem. Res. 46, 1740–1748 (2013).

    Article  CAS  Google Scholar 

  17. Ma, X., Gong, N., Zhong, L., Sun, J. & Liang, X.-J. Future of nanotherapeutics: targeting the cellular sub-organelles. Biomaterials 97, 10–21 (2016).

    Article  CAS  Google Scholar 

  18. Zhang, C. J. et al. Mechanism-guided design and synthesis of a mitochondria-targeting artemisinin analogue with enhanced anticancer activity. Angew. Chem. Int. Ed. 128, 13974–13978 (2016).

    Article  Google Scholar 

  19. Ka, H. et al. Cinnamaldehyde induces apoptosis by ROS-mediated mitochondrial permeability transition in human promyelocytic leukemia HL-60 cells. Cancer Lett. 196, 143–152 (2003).

    Article  CAS  Google Scholar 

  20. Grönbeck, H., Curioni, A. & Andreoni, W. Thiols and disulfides on the Au(111) surface: the headgroup–gold interaction. J. Am. Chem. Soc. 122, 3839–3842 (2000).

    Article  Google Scholar 

  21. Chen, F., Li, X., Hihath, J., Huang, Z. & Tao, N. Effect of anchoring groups on single-molecule conductance: comparative study of thiol-, amine-, and carboxylic-acid-terminated molecules. J. Am. Chem. Soc. 128, 15874–15881 (2006).

    Article  CAS  Google Scholar 

  22. Miller, J. et al. The effect of gold particle size on Au–Au bond length and reactivity toward oxygen in supported catalysts. J. Catal. 240, 222–234 (2006).

    Article  CAS  Google Scholar 

  23. Liu, J. Catalysis by supported single metal atoms. ACS Catal. 7, 34–59 (2016).

    Article  Google Scholar 

  24. Frenkel, A. I., Hills, C. W. & Nuzzo, R. G. A view from the inside: complexity in the atomic scale ordering of supported metal nanoparticles. J. Phys. Chem. B 105, 12689–12703 (2001).

    Article  CAS  Google Scholar 

  25. Oberli, L., Monot, R., Mathieu, H., Landolt, D. & Buttet, J. Auger and X-ray photoelectron spectroscopy of small Au particles. Surf. Sci. 106, 301–307 (1981).

    Article  CAS  Google Scholar 

  26. Wang, X. et al. Glutathione-triggered ‘off–on’ release of anticancer drugs from dendrimer-encapsulated gold nanoparticles. J. Am. Chem. Soc. 135, 9805–9810 (2013).

    Article  CAS  Google Scholar 

  27. Hu, Q., Gao, M., Feng, G. & Liu, B. Mitochondria-targeted cancer therapy using a light-up probe with aggregation-induced-emission characteristics. Angew. Chem. Int. Ed. 53, 14225–14229 (2014).

    Article  CAS  Google Scholar 

  28. Han, D. C. et al. 2′-Benzoyloxycinnamaldehyde induces apoptosis in human carcinoma via reactive oxygen species. J. Biol. Chem. 279, 6911–6920 (2004).

    Article  CAS  Google Scholar 

  29. Kim, B. et al. Dual acid-responsive micelle-forming anticancer polymers as new anticancer therapeutics. Adv. Funct. Mater. 23, 5091–5097 (2013).

    Article  CAS  Google Scholar 

  30. Deng, C., Jiang, Y., Cheng, R., Meng, F. & Zhong, Z. Biodegradable polymeric micelles for targeted and controlled anticancer drug delivery: promises, progress and prospects. Nano Today 7, 467–480 (2012).

    Article  CAS  Google Scholar 

  31. Shan, X., Jones, D. P., Hashmi, M. & Anders, M. Selective depletion of mitochondrial glutathione concentrations by (R,S)-3-hydroxy-4-pentenoate potentiates oxidative cell death. Chem. Res. Toxicol. 6, 75–81 (1993).

    Article  CAS  Google Scholar 

  32. Marí, M. et al. Mechanism of mitochondrial glutathione-dependent hepatocellular susceptibility to TNF despite NF-κB activation. Gastroenterology 134, 1507–1520 (2008).

    Article  Google Scholar 

  33. Esterbauer, H., Schaur, R. J. & Zollner, H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic. Biol. Med. 11, 81–128 (1991).

    Article  CAS  Google Scholar 

  34. Hinman, A., Chuang, H.-H., Bautista, D. M. & Julius, D. TRP channel activation by reversible covalent modification. Proc. Natl Acad. Sci. USA 103, 19564–19568 (2006).

    Article  CAS  Google Scholar 

  35. Ma, X. et al. Colloidal gold nanoparticles induce changes in cellular and subcellular morphology. ACS Nano 11, 7807–7820 (2017).

    Article  CAS  Google Scholar 

  36. Green, D. R. & Reed, J. C. Mitochondria and apoptosis. Science 281, 1309–1311 (1998).

    Article  CAS  Google Scholar 

  37. Higuchi, Y. Chromosomal DNA fragmentation in apoptosis and necrosis induced by oxidative stress. Biochem. Pharmacol. 66, 1527–1535 (2003).

    Article  CAS  Google Scholar 

  38. Smiley, S. T. et al. Intracellular heterogeneity in mitochondrial membrane potentials revealed by a J-aggregate-forming lipophilic cation JC-1. Proc. Natl Acad. Sci. USA 88, 3671–3675 (1991).

    Article  CAS  Google Scholar 

  39. Alavian, K. N. et al. Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FO ATP synthase. Nat. Cell Biol. 13, 1224–1233 (2011).

    Article  CAS  Google Scholar 

  40. Schulte, A. & Schuhmann, W. Single-cell microelectrochemistry. Angew. Chem. Int. Ed. 46, 8760–8777 (2007).

    Article  CAS  Google Scholar 

  41. Maluccio, M. & Covey, A. Recent progress in understanding, diagnosing, and treating hepatocellular carcinoma. CA Cancer J. Clin. 62, 394–399 (2012).

    Article  Google Scholar 

  42. Altekruse, S. F., Henley, S. J., Cucinelli, J. E. & McGlynn, K. A. Changing hepatocellular carcinoma incidence and liver cancer mortality rates in the United States. Am. J. Gastroenterol. 109, 542–553 (2014).

    Article  Google Scholar 

  43. Gao, H. et al. High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response. Nat. Med. 21, 1318–1325 (2015).

    Article  CAS  Google Scholar 

  44. Lin, S., Lin, C., Lin, C., Hsu, C. & Chen, Y. Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less. Gut. 54, 1151–1156 (2005).

    Article  CAS  Google Scholar 

  45. Germani, G. et al. Clinical outcomes of radiofrequency ablation, percutaneous alcohol and acetic acid injection for hepatocelullar carcinoma: a meta-analysis. J. Hepatol. 52, 380–388 (2010).

    Article  CAS  Google Scholar 

  46. Livraghi, T. et al. Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection. Radiology 197, 101–108 (1995).

    Article  CAS  Google Scholar 

  47. Zheng, M. et al. Integrating oxaliplatin with highly luminescent carbon dots: an unprecedented theranostic agent for personalized medicine. Adv. Mater. 26, 3554–3560 (2014).

    Article  CAS  Google Scholar 

  48. Crooks, R. M., Zhao, M., Sun, L., Chechik, V. & Yeung, L. K. Dendrimer-encapsulated metal nanoparticles: synthesis, characterization, and applications to catalysis. Acc. Chem. Res. 34, 181–190 (2001).

    Article  CAS  Google Scholar 

  49. Yuan, L., Lin, W., Xie, Y., Chen, B. & Song, J. Development of a ratiometric fluorescent sensor for ratiometric imaging of endogenously produced nitric oxide in macrophage cells. Chem. Commun. 47, 9372–9374 (2011).

    Article  CAS  Google Scholar 

  50. Ravel, B. & Newville, M. ATHENA, ARTEMIS, HEPHAESTUS: data analysis for X-ray absorption spectroscopy using IFEFFIT. J. Synchrotron. Radiat. 12, 537–541 (2005).

    Article  CAS  Google Scholar 

  51. Tan, X. et al. The influence of dissolved Si on Ni precipitate formation at the kaolinite water interface: kinetics, DRS and EXAFS analysis. Chemosphere 173, 135–142 (2017).

    Article  CAS  Google Scholar 

  52. Price, S. W., Rhodes, J. M., Calvillo, L. & Russell, A. E. Revealing the details of the surface composition of electrochemically prepared Au@Pd core@shell nanoparticles with in situ EXAFS. J. Phys. Chem. C 117, 24858–24865 (2013).

    Article  CAS  Google Scholar 

  53. Noh, J. et al. Amplification of oxidative stress by a dual stimuli-responsive hybrid drug enhances cancer cell death. Nat. Commun. 6, 6907 (2015).

    Article  CAS  Google Scholar 

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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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Authors and Affiliations

  1. Laboratory of Controllable Nanopharmaceuticals, Chinese Academy of Sciences (CAS) Center for Excellence in Nanoscience and CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing, China

    Ningqiang Gong, Xiaowei Ma, Xiaoxia Ye, Xiaoai Chen, Shuaidong Huo, Tingbin Zhang, Shizhu Chen, Xixue Hu, Yaling Gan & Xing-Jie Liang

  2. Department of Chemistry, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, China

    Ningqiang Gong, Xucong Teng & Jinghong Li

  3. University of Chinese Academy of Sciences, Beijing, China

    Ningqiang Gong & Xing-Jie Liang

  4. Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, China

    Qunfang Zhou & Jie Yu

  5. School of Environment and Chemical Engineering, North China Electric Power University, Beijing, China

    Xiaoli Tan

  6. School of Physical Science and Technology, Shanghai Tech University, Shanghai, China

    Shengkun Yao & Huaidong Jiang

  7. Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding, China

    Shizhu Chen

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Contributions

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.

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Correspondence to Jinghong Li or Xing-Jie Liang.

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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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