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Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress tumour growth

Nature Nanotechnology volume 11, pages 977–985 (2016)Cite this article

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Abstract

The design of cancer-targeting particles with precisely tuned physicochemical properties may enhance the delivery of therapeutics and access to pharmacological targets. However, a molecular-level understanding of the interactions driving the fate of nanomedicine in biological systems remains elusive. Here, we show that ultrasmall (<10 nm in diameter) poly(ethylene glycol)-coated silica nanoparticles, functionalized with melanoma-targeting peptides, can induce a form of programmed cell death known as ferroptosis in starved cancer cells and cancer-bearing mice. Tumour xenografts in mice intravenously injected with nanoparticles using a high-dose multiple injection scheme exhibit reduced growth or regression, in a manner that is reversed by the pharmacological inhibitor of ferroptosis, liproxstatin-1. These data demonstrate that ferroptosis can be targeted by ultrasmall silica nanoparticles and may have therapeutic potential.

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Figure 1: αMSH-PEG-C′-dot particles and their localization to lysosomal networks.
Figure 2: αMSH-PEG-C′ dot particles induce cell death in amino-acid-deprived conditions.
Figure 3: αMSH-PEG-C′ dot particle-induced cell death is not apoptosis, necroptosis or autosis.
Figure 4: Ferroptosis is the underlying mechanisms of αMSH particle-induced cell death.
Figure 5: αMSH-PEG-C′ dots induce cell death in different types of cancer cells.
Figure 6: αMSH-PEG-C′ dots inhibit tumour growth in 786-O and HT-1080 xenograft models.

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Acknowledgements

This study was funded by grants from the National Institutes of Health (R01GM111350 to M.O.; 1R01CA161280-01A1 to M.B. and U.W.; 1U54 CA199081-01 to M.B. and U.W.; R01GM113013 and R01CA166413 to X.J.; Sloan Kettering Institute Core Grant P30 CA008748CCSG and the Benjamin Friedman Research Fund to M.O.). Peptide synthesis was conducted by the University of Missouri Structural Biology Core.

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  1. Michelle S. Bradbury and Michael Overholtzer: These authors contributed equally to this work

Authors and Affiliations

  1. Cell Biology Program, Sloan Kettering Institute for Cancer Research, New York, 10065, New York, USA

    Sung Eun Kim, Michelle Riegman, Minghui Gao, Xuejun Jiang & Michael Overholtzer

  2. BCMB Allied Program, Weill Cornell Medical College, New York, 10065, New York, USA

    Sung Eun Kim, Xuejun Jiang & Michael Overholtzer

  3. Department of Radiology, Sloan Kettering Institute for Cancer Research, New York, 10065, New York, USA

    Li Zhang, Feng Chen, Mohan Pauliah & Michelle S. Bradbury

  4. Department of Materials Science & Engineering, Cornell University, Ithaca, 14853, New York, USA

    Kai Ma, Melik Ziya Turker & Ulrich Wiesner

  5. Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, 85764, Germany

    Irina Ingold & Marcus Conrad

  6. Tri-Institutional Laboratory of Comparative Pathology, The Rockefeller University, Sloan Kettering Institute for Cancer Research, Weill Cornell Medical College, New York, 10065, New York, USA

    Sebastien Monette

  7. Department of Epidemiology and Biostatistics, Sloan Kettering Institute for Cancer Research, New York, 10065, New York, USA

    Mithat Gonen

  8. Department of Medical Physics, Sloan Kettering Institute for Cancer Research, New York, 10065, New York, USA

    Pat Zanzonico

  9. Department of Biochemistry, University of Missouri, Columbia, 65211, Missouri, USA

    Thomas Quinn

  10. Molecular Pharmacology Program, Sloan Kettering Institute for Cancer Research, New York, 10065, New York, USA

    Michelle S. Bradbury

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  1. Sung Eun Kim
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Contributions

Product preparation was performed by K.M., T.Q. and M.Z.T., experimental design by S.E.K., M.O., M.S.B., K.M., L.Z., M.Go., X.J., P.Z., S.M., F.C., T.Q. and U.W., data acquisition by S.E.K., L.Z., K.M., M.Z.T., M.Go., X.J., M.P., F.C., S.M., M.S.B., M.O., I.I., M.C. and M.R., data analysis and interpretation by S.E.K., M.O., M.S.B., K.M., M.P., F.C., P.Z., M.Ga., S.M., L.Z., U.W., I.I., M.C. and M.R., and preparation of the manuscript by S.E.K., M.O., M.S.B., M.Go., P.Z., K.M., S.M., T.Q. and U.W. All authors discussed the results and implications and commented on the manuscript.

Corresponding authors

Correspondence to Michelle S. Bradbury or Michael Overholtzer.

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Competing interests

The authors have filed an international patent application PCT/US16/34351.

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Kim, S., Zhang, L., Ma, K. et al. Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress tumour growth. Nature Nanotech 11, 977–985 (2016). https://doi.org/10.1038/nnano.2016.164

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