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Combination of fucoidan-based magnetic nanoparticles and immunomodulators enhances tumour-localized immunotherapy

Abstract

Checkpoint immunotherapy that inhibits tumour immune evasion has demonstrated significant clinical success. However, the therapeutic response is limited to certain patient populations, and immunotoxicity as well as autoimmunity have compromised the therapeutic benefits. Here, we report on an inherently therapeutic fucoidan–dextran-based magnetic nanomedicine (IO@FuDex3) conjugated with a checkpoint inhibitor (anti-PD-L1) and T-cell activators (anti-CD3 and anti-CD28). IO@FuDex3 can repair the immunosuppressive tumour microenvironment by reinvigorating tumour-infiltrating lymphocytes, while targeting the nanomedicine via magnetic navigation to the tumour to minimize off-target effects. Treatment that combines IO@FuDex3 and magnetic navigation reduces the occurrence of adverse events and extends the median survival from 32 to 63 days with less than 1 per cent dose compared with soluble anti-PD-L1. Thus, we demonstrate the potential of integrating anti-PD-L1 and T-cell activators as a form of inherently therapeutic nanomedicine to augment the therapeutic index of combination checkpoint immunotherapy.

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Fig. 1: Characterization of IO@FuDex.
Fig. 2: Targeting ability and cell association behaviour of various IO@FuDex formulations to either 4T1 cells or CD8+ T cells.
Fig. 3: Magnetic navigation amplifies nanomedicine accumulation in the tumour.
Fig. 4: Tumour inhibition and anti-metastatic capacity of various IO@FuDex formulations in 4T1 and CT-26 tumour model.
Fig. 5: Changes in TILs and cytokines at four weeks after tumour inoculation.
Fig. 6: Systemic effects and irAEs assessments.

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Acknowledgements

The authors thank Taiwan’s Ministry of Science and Technology for research grants from: MOST105-2314-B-009-001-MY3; MOST105-2221-E-009-024-MY3; MOST106-2221-E-009-065-MY3; MOST105-2314-B-039-011-MY3; MOST2628-B-039-009-MY3; and China Medical University Hospital (CMU104-S-10, CMU104-S-15-03 and DMR-104-054, DMR-106-070). The authors would like to thank N.-T. Tsou and S.-S. Chien for computer simulation support.

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C.-S.C. conceived the idea and designed the materials. S.-Y.C. designed the project and directed the research. W.-C.S., C.-H.H. and Y.-J.L. contributed to the design of the in vivo studies. Y.-H.L and H.-W.C. performed the materials analysis. C.-S.C., Y.-J.L., C.-H.H., W.-C.S. and R.L. interpreted the data. C.-S.C. wrote the manuscript with the help of S.-Y.C., C.-H.H., W.-C.S. and R.L. All authors discussed the results.

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Correspondence to Chia-Hung Hsieh or Woei-Cherng Shyu or San-Yuan Chen.

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Chiang, CS., Lin, YJ., Lee, R. et al. Combination of fucoidan-based magnetic nanoparticles and immunomodulators enhances tumour-localized immunotherapy. Nature Nanotech 13, 746–754 (2018). https://doi.org/10.1038/s41565-018-0146-7

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