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Iron oxide nanoparticles inhibit tumour growth by inducing pro-inflammatory macrophage polarization in tumour tissues

Nature Nanotechnology volume 11, pages 986994 (2016) | Download Citation

Abstract

Until now, the Food and Drug Administration (FDA)-approved iron supplement ferumoxytol and other iron oxide nanoparticles have been used for treating iron deficiency, as contrast agents for magnetic resonance imaging and as drug carriers. Here, we show an intrinsic therapeutic effect of ferumoxytol on the growth of early mammary cancers, and lung cancer metastases in liver and lungs. In vitro, adenocarcinoma cells co-incubated with ferumoxytol and macrophages showed increased caspase-3 activity. Macrophages exposed to ferumoxytol displayed increased mRNA associated with pro-inflammatory Th1-type responses. In vivo, ferumoxytol significantly inhibited growth of subcutaneous adenocarcinomas in mice. In addition, intravenous ferumoxytol treatment before intravenous tumour cell challenge prevented development of liver metastasis. Fluorescence-activated cell sorting (FACS) and histopathology studies showed that the observed tumour growth inhibition was accompanied by increased presence of pro-inflammatory M1 macrophages in the tumour tissues. Our results suggest that ferumoxytol could be applied ‘off label’ to protect the liver from metastatic seeds and potentiate macrophage-modulating cancer immunotherapies.

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Acknowledgements

The authors acknowledge support from the National Institute of Health/National Cancer Institute (NIH/NCI), grant numbers R21CA156124 and R21CA176519, and the Department of Defense BCRP Era of Hope Scholar Expansion Award (BC10412). S.Z. was supported by the Stanford Cancer Imaging Training (SCIT) T32 fellowship programme. We also thank the Stanford Center for Innovation and In-Vivo Imaging (SCI 3) supported by the NCI Cancer Center (P30 CA124435–02) and NCI ICMIC (P50 CA114747) for providing the infrastructure for mouse imaging. G.H. was supported by a Swiss National Science Foundation Grant P-155336 (www.snf.ch) and the Novartis Foundation for Medical-Biological Research (www.stiftungmedbiol.novartis.com). In addition, we thank E. Misquez for her excellent administrative assistance throughout this project, D. Yang for assistance with cell culture and M. Winslow's laboratory (Stanford University) for their generous gift of the SCLC KP1-GFP-Luc cell lines.

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Affiliations

  1. Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, 725 Welch Road, Stanford, California 94305, USA

    • Saeid Zanganeh
    • , Ryan Spitler
    • , Olga Lenkov
    • , Hossein Nejadnik
    • , Michael Moseley
    •  & Heike Elisabeth Daldrup-Link
  2. Institute of Stem Cell Research and Regenerative Medicine, Stanford University, Stanford, California 94305, USA

    • Saeid Zanganeh
    • , Gregor Hutter
    • , Olga Lenkov
    • , Hossein Nejadnik
    •  & Heike Elisabeth Daldrup-Link
  3. Department of Neurosurgery, Stanford University, Stanford, California 94305, USA

    • Gregor Hutter
  4. Department of Medicine, Division of Cardiology, Stanford University, Stanford, California 94305, USA

    • Morteza Mahmoudi
  5. Department of Cell, Developmental & Cancer Biology, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon 97239, USA

    • Aubie Shaw
    •  & Lisa Marie Coussens
  6. Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University, Stanford, California 94305, USA

    • Jukka Sakari Pajarinen
    •  & Stuart Goodman
  7. Department of Pediatrics, Stanford University, Stanford, California 94305, USA

    • Heike Elisabeth Daldrup-Link

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Contributions

The study concept and design was developed by H.E.D.-L., L.M.C. and S.Z. The acquisition of data was performed by S.Z., R.S., G.H., M.Ma., S.G. and A.S. (cell experiments, tissue experiments and immunohistochemistry), S.Z., J.S.P., O.L. and H.N. (animal experiments), S.Z., O.L., M.Mo. (magnetic resonance imaging), and S.Z., G.H., A.S. (flow cytometry). All authors contributed to the analysis of the data and discussed the results. H.E.D.-L. and S.Z. wrote the manuscript. All authors edited the manuscript and approved the final version. Funding was obtained by H.E.D.-L. and all studies were supervised by H.E.D.-L.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Heike Elisabeth Daldrup-Link.

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DOI

https://doi.org/10.1038/nnano.2016.168

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