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Ferritin-based targeted delivery of arsenic to diverse leukaemia types confers strong anti-leukaemia therapeutic effects

Nature Nanotechnology volume 16, pages 1413–1423 (2021)Cite this article

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Abstract

Trivalent arsenic (AsIII) is an effective agent for treating patients with acute promyelocytic leukaemia, but its ionic nature leads to several major limitations like low effective concentrations in leukaemia cells and substantial off-target cytotoxicity, which limits its general application to other types of leukaemia. Here, building from our clinical discovery that cancerous cells from patients with different leukaemia forms featured stable and strong expression of CD71, we designed a ferritin-based As nanomedicine, As@Fn, that bound to leukaemia cells with very high affinity, and efficiently delivered cytotoxic AsIII into a large diversity of leukaemia cell lines and patient cells. Moreover, As@Fn exerted strong anti-leukaemia effects in diverse cell-line-derived xenograft models, as well as in a patient-derived xenograft model, in which it consistently outperformed the gold standard, showing its potential as a precision treatment for a variety of leukaemias.

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Fig. 1: High expression of CD71 by leukaemia cells in patients with diverse types and courses of leukaemia.
Fig. 2: Preparation of As@Fn nanomedicine and profile of specific receptor-mediated uptake, effective release and cytotoxicity in vitro.
Fig. 3: Specific binding and cytotoxicity assessments of As@Fn as applied to diverse leukaemia cell lines and clinical samples.
Fig. 4: Targeting ability assessments of As@Fn to leukaemia cells in vivo.
Fig. 5: In vivo anti-leukaemia effects in HL-60 (AML) engrafted xenografts.
Fig. 6: Potent anti-leukaemia activity in an ALL-PDX model.

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Data availability

The main data supporting the results in this study are available within the paper and Supplementary Information. The raw and analysed datasets generated during the study are too large to be publicly shared, yet they are available for research purposes from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (U2001224, 21821005, 21725301, 21821004, 51622211), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB29040303), the National Key R&D Program of China (2017YFA0207900), the Open Funding Project of the State Key Laboratory of Biochemical Engineering (2012KF-03), Guangzhou Regenerative Medicine and Health Guangdong Laboratory (2018GZR110105014), the Natural Science Foundation of Guangdong Province (2018B030311042) and the Beijing Outstanding Young Scientist Program (BJJWZYJH01201914430039). D.M. acknowledges support from the Tencent Foundation through the XPLORER PRIZE.

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Author notes

  1. These authors contributed equally: Changlong Wang, Wei Zhang, Yanjie He.

Authors and Affiliations

  1. State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, P. R. China

    Changlong Wang, Shuang Wang, Feng Li, Hua Yue, Wei Wei & Guanghui Ma

  2. School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing, P. R. China

    Changlong Wang, Feng Li, Wei Wei & Guanghui Ma

  3. Beijing National Laboratory for Molecular Engineering, College of Chemistry and Molecular Engineering and College of Engineering, and BIC-ESAT, Peking University, Beijing, P. R. China

    Wei Zhang, Zirui Gao, Chaochao Zhao & Ding Ma

  4. Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, P. R. China

    Yanjie He, Siyao Yu, Yuxing Hu & Yuhua Li

  5. Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, Beijing, P. R. China

    Liyuan Liu & Hui Li

  6. School of Physical Sciences and CAS Key Laboratory of Vacuum Sciences, University of Chinese Academy of Sciences, Beijing, P. R. China

    Jinan Shi & Wu Zhou

  7. Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, P. R. China

    Yuhua Li

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Contributions

W.W., G.M., D.M. and Y.L. conceived and designed the study; W. Zhang, C.W. and C.Z. constructed the nanomedicine and performed in vitro experiments; C.W., Y. He, S.Y. and W.W. analysed the clinical samples; Z.G., W. Zhou and J.S. conducted high-resolution aberration-corrected electron microscope analysis; H.L. and L.L. contributed to quantum mechanical calculations; C.W. performed in vivo experiments on CDX models; C.W., Y. He and Y. Hu conducted leukaemia supression efficiency analysis on PDX model; S.W., F.L. and H.Y. helped with the animal experiments and facilitated the data and file processing; W.W. and C.W. wrote the manuscript; and W.W., G.M., D.M. and Y.L. further revised the manuscript.

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Correspondence to Yuhua Li, Wei Wei, Guanghui Ma or Ding Ma.

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Peer review information Nature Nanotechnology thanks Monica Guzman and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Wang, C., Zhang, W., He, Y. et al. Ferritin-based targeted delivery of arsenic to diverse leukaemia types confers strong anti-leukaemia therapeutic effects. Nat. Nanotechnol. 16, 1413–1423 (2021). https://doi.org/10.1038/s41565-021-00980-7

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