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

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.

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.

References

  1. Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2019. CA Cancer J. Clin. 69, 7–34 (2019).

    Google Scholar 

  2. Miller, K. D. et al. Cancer treatment and survivorship statistics, 2019. CA Cancer J. Clin. 69, 363–385 (2019).

    Google Scholar 

  3. Lhermitte, L. et al. Automated database-guided expert-supervised orientation for immunophenotypic diagnosis and classification of acute leukemia. Leukemia 32, 874–881 (2018).

    CAS  Google Scholar 

  4. Bassan, R. & Hoelzer, D. Modern therapy of acute lymphoblastic leukemia. J. Clin. Oncol. 29, 532–543 (2011).

    Google Scholar 

  5. Nabhan, C. & Rosen, S. T. Chronic lymphocytic leukemia: a clinical review. J. Am. Med. Assoc. 312, 2265–2276 (2014).

    Google Scholar 

  6. Short, N. J. et al. Advances in the treatment of acute myeloid leukemia: new drugs and new challenges. Cancer Discov. 10, 506–525 (2020).

    CAS  Google Scholar 

  7. Lo-Coco, F. et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N. Engl. J. Med. 369, 111–121 (2013).

    CAS  Google Scholar 

  8. Zhang, X. W. et al. Arsenic trioxide controls the fate of the PML-RARα oncoprotein by directly binding PML. Science 328, 240–243 (2010).

    CAS  Google Scholar 

  9. Chen, G. Q. et al. In vitro studies on cellular and molecular mechanisms of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia: As2O3 induces NB4 cell apoptosis with downregulation of Bcl-2 expression and modulation of PML-RAR alpha/PML proteins. Blood 88, 1052–1061 (1996).

    CAS  Google Scholar 

  10. Wang, X. et al. Arsenene: a potential therapeutic agent for acute promyelocytic leukaemia cells by acting on nuclear proteins. Angew. Chem. Int. Ed. 59, 5151–5158 (2020).

    CAS  Google Scholar 

  11. Yedjou, C., Tchounwou, P., Jenkins, J. & McMurray, R. Basic mechanisms of arsenic trioxide (ATO)-induced apoptosis in human leukemia (HL-60) cells. J. Hematol. Oncol. 3, 28 (2010).

    Google Scholar 

  12. Chen, H. M. et al. Lipid encapsulation of arsenic trioxide attenuates cytotoxicity and allows for controlled anticancer drug release. J. Am. Chem. Soc. 128, 13348–13349 (2006).

    CAS  Google Scholar 

  13. Qian, C. et al. Suppression of pancreatic tumor growth by targeted arsenic delivery with anti-CD44v6 single chain antibody conjugated nanoparticles. Biomaterials 34, 6175–6184 (2013).

    CAS  Google Scholar 

  14. Dilda, P. J. et al. Insight into the selectivity of arsenic trioxide for acute promyelocytic leukemia cells by characterizing Saccharomyces cerevisiae deletion strains that are sensitive or resistant to the metalloid. Int. J. Biochem. Cell Biol. 40, 1016–1029 (2008).

    CAS  Google Scholar 

  15. Emadi, A. & Gore, S. D. Arsenic trioxide — an old drug rediscovered. Blood Rev. 24, 191–199 (2010).

    CAS  Google Scholar 

  16. Sahu, G. R. & Jena, R. K. Significance of intracellular arsenic trioxide for therapeutic response in acute promyelocytic leukemia. Am. J. Hematol. 78, 113–116 (2005).

    CAS  Google Scholar 

  17. Davila, M. L. et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci. Transl. Med. 6, 224Rra25 (2014).

    Google Scholar 

  18. Grupp, S. A. et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509–1518 (2013).

    CAS  Google Scholar 

  19. Bielamowicz, K. et al. Trivalent CAR T cells overcome interpatient antigenic variability in glioblastoma. Neurooncol. 20, 506–518 (2018).

    CAS  Google Scholar 

  20. Zhou, Y. et al. Advances in the molecular pathobiology of B-lymphoblastic leukemia. Hum. Pathol. 43, 1347–1362 (2012).

    CAS  Google Scholar 

  21. Fry, T. J. et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat. Med. 24, 20–28 (2018).

    CAS  Google Scholar 

  22. Qin, H. Y. et al. Preclinical development of bivalent chimeric antigen receptors targeting both CD19 and CD22. Mol. Ther. Oncolytics 11, 127–137 (2018).

    CAS  Google Scholar 

  23. Zah, E., Lin, M. Y., Silva-Benedict, A., Jensen, M. C. & Chen, Y. Y. T Cells expressing CD19/CD20 bispecific chimeric antigen receptors prevent antigen escape by malignant B cells. Cancer Immunol. Res. 4, 639–641 (2016).

    Google Scholar 

  24. Peng, Y. et al. Smart human-serum-albumin-As2O3 nanodrug with self-amplified folate receptor-targeting ability for chronic myeloid leukemia treatment. Angew. Chem. Int. Ed. 56, 10845–10849 (2017).

    CAS  Google Scholar 

  25. Ellison, P. A. et al. Intrinsic and stable conjugation of thiolated mesoporous silica nanoparticles with radioarsenic. ACS Appl. Mater. Interfaces 9, 6772–6781 (2017).

    CAS  Google Scholar 

  26. Zhang, K. et al. An extracellular pH-driven targeted multifunctional manganese arsenite delivery system for tumor imaging and therapy. Biomater. Sci. 7, 2480–2490 (2019).

    CAS  Google Scholar 

  27. Li, L. et al. Binding and uptake of H-ferritin are mediated by human transferrin receptor-1. Proc. Natl Acad. Sci. USA 107, 3505–3510 (2010).

    CAS  Google Scholar 

  28. Montemiglio, L. C. et al. Cryo-EM structure of the human ferritin–transferrin receptor 1 complex. Nat. Commun. 10, 1121 (2019).

    Google Scholar 

  29. Fan, K. et al. Ferritin nanocarrier traverses the blood brain barrier and kills glioma. ACS Nano 12, 4105–4115 (2018).

    CAS  Google Scholar 

  30. Ding, F. et al. Enhancing the chemotherapeutic efficacy of platinum prodrug nanoparticles and inhibiting cancer metastasis by targeting iron homeostasis. Nanoscale Horiz. 5, 999–1015 (2020).

    CAS  Google Scholar 

  31. Kawabata, H. Transferrin and transferrin receptors update. Free Radic. Biol. Med. 133, 46–54 (2019).

    CAS  Google Scholar 

  32. Lyons, V. J., Helms, A. & Pappas, D. The effect of protein expression on cancer cell capture using the human transferrin receptor (CD71) as an affinity ligand. Anal. Chim. Acta 1076, 154–161 (2019).

    CAS  Google Scholar 

  33. Fan, K. et al. Magnetoferritin nanoparticles for targeting and visualizing tumour tissues. Nat. Nanotechnol. 7, 459–464 (2012).

    CAS  Google Scholar 

  34. Liang, M. et al. H-ferritin-nanocaged doxorubicin nanoparticles specifically target and kill tumors with a single-dose injection. Proc. Natl Acad. Sci. USA 111, 14900–14905 (2014).

    CAS  Google Scholar 

  35. Douglas, T. et al. Synthesis and structure of an iron(III) sulfide–ferritin bioinorganic nanocomposite. Science 269, 54–57 (1995).

    CAS  Google Scholar 

  36. Sun, C. J. et al. Controlling assembly of paired gold clusters within apoferritin nanoreactor for in vivo kidney targeting and biomedical imaging. J. Am. Chem. Soc. 133, 8617–8624 (2011).

    CAS  Google Scholar 

  37. Wang, W. et al. Dual-targeting nanoparticle vaccine elicits a therapeutic antibody response against chronic hepatitis B. Nat. Nanotechnol. 15, 406–416 (2020).

    CAS  Google Scholar 

  38. Meldrum, F. C., Heywood, B. R. & Mann, S. Magnetoferritin: in vitro synthesis of a novel magnetic protein. Science 257, 522–523 (1992).

    CAS  Google Scholar 

  39. Meldrum, F. C., Wade, V. J., Nimmo, D. L., Heywood, B. R. & Mann, S. Synthesis of inorganic nanophase materials in supramolecular protein cages. Nature 349, 684–687 (1991).

    CAS  Google Scholar 

  40. Dilda, P. J. & Hogg, P. J. Arsenical-based cancer drugs. Cancer Treat. Rev. 33, 542–564 (2007).

    CAS  Google Scholar 

  41. Spuches, A. M., Kruszyna, H. G., Rich, A. M. & Wilcox, D. E. Thermodynamics of the As(III)-thiol interaction: arsenite and monomethylarsenite complexes with glutathione, dihydrolipoic acid, and other thiol ligands. Inorg. Chem. 44, 2964–2972 (2005).

    CAS  Google Scholar 

  42. Pozzi, C. et al. Iron binding to human heavy-chain ferritin. Acta Crystallogr. D Biol. Crystallogr. 71, 1909–1920 (2015).

    CAS  Google Scholar 

  43. Hutter, J., Iannuzzi, M., Schiffmann, F. & VandeVondele, J. CP2K: atomistic simulations of condensed matter systems. Wires Comput. Mol. Sci. 4, 15–25 (2014).

    CAS  Google Scholar 

  44. Becke, A. D. Density-functional exchange-energy approximation with correct asymptotic-behavior. Phys. Rev. A 38, 3098–3100 (1988).

    CAS  Google Scholar 

  45. Goedecker, S., Teter, M. & Hutter, J. Separable dual-space Gaussian pseudopotentials. Phys. Rev. B 54, 1703–1710 (1996).

    CAS  Google Scholar 

  46. Grimme, S. Accurate description of van der Waals complexes by density functional theory including empirical corrections. J. Comput. Chem. 25, 1463–1473 (2004).

    CAS  Google Scholar 

Download references

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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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.

Corresponding authors

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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Supplementary Figs. 1–32, Table 1 and Methods.

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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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