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

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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Figure 1: Combining ferumoxytol and macrophages leads to cancer cell apoptosis through the Fenton reaction.
Figure 2: Iron oxide nanoparticles inhibit tumour growth.
Figure 3: Ferumoxytol causes in vivo M1 macrophage polarization.
Figure 4: Systemic delivery of ferumoxytol inhibits liver and lung metastases.
Figure 5: Pretreatment with ferumoxytol inhibits development of liver metastases.
Figure 6: Ferumoxytol alters macrophage polarization in hepatic metastasis in vivo.

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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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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.

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Correspondence to Heike Elisabeth Daldrup-Link.

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Zanganeh, S., Hutter, G., Spitler, R. et al. Iron oxide nanoparticles inhibit tumour growth by inducing pro-inflammatory macrophage polarization in tumour tissues. Nature Nanotech 11, 986–994 (2016). https://doi.org/10.1038/nnano.2016.168

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