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Magnetoferritin nanoparticles for targeting and visualizing tumour tissues

Nature Nanotechnology volume 7, pages 459–464 (2012)Cite this article

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An Addendum to this article was published on 05 December 2012

A Corrigendum to this article was published on 05 December 2012

An Addendum to this article was published on 06 November 2012

This article has been updated

Abstract

Engineered nanoparticles have been used to provide diagnostic1,2,3, therapeutic4,5 and prognostic information6,7 about the status of disease. Nanoparticles developed for these purposes are typically modified with targeting ligands (such as antibodies8,9,10, peptides11,12 or small molecules13) or contrast agents14,15,16 using complicated processes and expensive reagents. Moreover, this approach can lead to an excess of ligands on the nanoparticle surface, and this causes non-specific binding17,18,19,20 and aggregation of nanoparticles18,19,20, which decreases detection sensitivity17,18,19,20. Here, we show that magnetoferritin nanoparticles (M-HFn) can be used to target and visualize tumour tissues without the use of any targeting ligands or contrast agents. Iron oxide nanoparticles are encapsulated inside a recombinant human heavy-chain ferritin (HFn) protein shell, which binds to tumour cells that overexpress transferrin receptor 1 (TfR1). The iron oxide core catalyses the oxidation of peroxidase substrates in the presence of hydrogen peroxide to produce a colour reaction that is used to visualize tumour tissues. We examined 474 clinical specimens from patients with nine types of cancer and verified that these nanoparticles can distinguish cancerous cells from normal cells with a sensitivity of 98% and specificity of 95%.

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Figure 1: Preparation and characterization of M-HFn nanoparticles.
Figure 2: HFn binds specifically to TfR1 in cancer cells.
Figure 3: M-HFn nanoparticle staining of tumour tissues.
Figure 4: Cancer diagnosis in clinical specimens using M-HFn nanoparticles.

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Change history

  • 22 October 2012

    Editorial note: A potential breach of our editorial policies has emerged following the publication of this paper. Yongxin Pan and Changqian Cao, who are listed as contributing authors, have declared no knowledge of the submission of the paper, and their disagreement with its publication. They have pointed out several errors in the description of the synthesis and characterization of the magnetoferritin nanoparticles used in the study. We take breaches of editorial policies very seriously and have therefore informed the listed authors' institutions and the Chinese Academy of Sciences.

  • 27 November 2012

    Editorial note: Following an investigation by the Chinese Academy of Sciences under the directive of Professor Chunli Bai, the investigating committee consisting of Professor Tao Xu, Professor Rixiang Zhu, Professor Jinghui Guo and Professor Ruiming Xu concluded that, owing to lack of communication between the authors, the original paper published online on 17 June 2012 contained errors but the central findings of the paper remain valid. The authors have reconciled their opinions and relevant sections of the paper have now been corrected through a Corrigendum.

  • 27 November 2012

    In the version of this Letter originally published, Fig. 1a was incorrect and in Fig. 1c the wrong TEM image was used. In the Supplementary Information, one of the authors was not mentioned in the author list: Lina Song has now been added. In the section 'Preparation and characterization of M-HFn particles' the column used for size-exclusion chromatography was incorrect: it should have been 'Sepharose 6B'. The synthesis procedure for M-HFn nanoparticles was incorrect: it should have read 'HFn protein shells were used as a reaction template to synthesize iron oxide nanoparticles according to the method reported by Cao et al.2 with some modification. The solution of 50 ml 100 mM NaCl with HFn (1 mg ml−1) was added to the reaction vessel, synthesized at 65 °C and pH 8.5. Fe(II) (25 mM (NH4)2Fe(SO4)2•6H2O) and stoichiometric equivalents (1:3 H2O2:Fe2+) of freshly prepared H2O2 (8.33 mM) were added. Fe(II) was added in a rate of 100 Fe/(protein min) using a dosing device (800 Dosino) connected with 842 Titrando. After theoretical 5000 Fe/ protein cage were added to the reaction vessel, the reaction was continued for another 5 min. Finally, 200 μl of 300 mM sodium citrate was added to chelate any free iron. The synthesized magnetite-containing HFn (M-HFn) nanoparticles were centrifuged and purified through size exclusion chromatography to remove the aggregated nanoparticles. The concentration of M-HFn nanoparticles was assumed to be the same as that of HFn protein and was determined using a BCA protein assay kit (Pierce). Purified M-HFn nanoparticles were obtained with a yield of about 75%.' Reference 2 was incorrect and should have read Cao, C. Q. et al. Magnetic characterization of noninteracting, randomly oriented, nanometer-scale ferrimagnetic particles. J. Geophys. Res. 115, B07103 (2010). The aforementioned errors did not affect the main conclusions of the paper. These errors have now been corrected in the HTML and PDF versions.

  • 05 December 2012

    Nature Nanotechnology 7, 459–464 (2012); published online 17 June 2012; corrected after print 22 October 2012; corrected after print 27 November 2012. In the version of this Letter originally published, Fig. 1a was incorrect and in Fig. 1c the wrong TEM image was used, they should have appeared as shown below.

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Acknowledgements

This work was partially supported by grants from the National Science and Technology Major Project (2012ZX10002009-016), the Knowledge Innovation Program of the Chinese Academy of Sciences (KJCX2-YW-M15), 973 Program (2011CB933500, 2012CB934003), and the National Defense Science and Technology Innovation Fund of Chinese Academy of Sciences (CXJJ-11-M61).

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Authors and Affiliations

  1. Key Laboratory of Protein and Peptide Pharmaceutical, National Laboratory of Biomacromolecules, CAS-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, 100101, China

    Kelong Fan, Di Lu, Dongling Yang, Jing Feng, Lina Song, Minmin Liang & Xiyun Yan

  2. Paleomagnetism and Geochronology Laboratory, Key Laboratory of the Earth's Deep Interior, Institute of Geology and Geophysics, Chinese Academy of Sciences, Beijing, 100029, China

    Changqian Cao & Yongxin Pan

Authors
  1. Kelong Fan
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  4. Di Lu
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Contributions

M.L. conceived and designed the experiments. K.F. and M.L. performed the experiments. M.L. and X.Y. reviewed, analysed and interpreted the data. C.C. and Y.P. synthesized the nanoparticles. D.L., D.Y., J.F. and L.S. cultured the cancer cells. M.L. wrote the paper. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Minmin Liang or Xiyun Yan.

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Fan, K., Cao, C., Pan, Y. et al. Magnetoferritin nanoparticles for targeting and visualizing tumour tissues. Nature Nanotech 7, 459–464 (2012). https://doi.org/10.1038/nnano.2012.90

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