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Iron oxide nanoclusters for T 1 magnetic resonance imaging of non-human primates

Abstract

Iron-oxide-based contrast agents for magnetic resonance imaging (MRI) had been clinically approved in the United States and Europe, yet most of these nanoparticle products were discontinued owing to failures to meet rigorous clinical requirements. Significant advances have been made in the synthesis of magnetic nanoparticles and their biomedical applications, but several major challenges remain for their clinical translation, in particular large-scale and reproducible synthesis, systematic toxicity assessment, and their preclinical evaluation in MRI of large animals. Here, we report the results of a toxicity study of iron oxide nanoclusters of uniform size in large animal models, including beagle dogs and the more clinically relevant macaques. We also show that iron oxide nanoclusters can be used as T 1 MRI contrast agents for high-resolution magnetic resonance angiography in beagle dogs and macaques, and that dynamic MRI enables the detection of cerebral ischaemia in these large animals. Iron oxide nanoclusters show clinical potential as next-generation MRI contrast agents.

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Fig. 1: Characterization and biocompatibility evaluation of the PEG–IONCs.
Fig. 2: MRA of a beagle dog and a macaque using PEG–IONCs.
Fig. 3: Dynamic susceptibility contrast perfusion-weighted imaging using PEG–IONCs in a beagle dog with cerebral ischaemia.
Fig. 4: Left cerebral ischaemia in a macaque.

References

  1. 1.

    Michalet, X. et al. Quantum dots for live cells, in vivo imaging, and diagnostics. Science 307, 538–544 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Nam, J. M., Thaxton, C. S. & Mirkin, C. A. Nanoparticle-based bio-bar codes for the ultrasensitive detection of proteins. Science 301, 1884–1886 (2003).

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Chou, L. Y. T., Zagorovsky, K. & Chan, W. C. W. DNA assembly of nanoparticle superstructures for controlled biological delivery and elimination. Nat. Nanotech. 9, 148–155 (2014).

    CAS  Article  Google Scholar 

  4. 4.

    Howes, P. D., Chandrawati, R. & Stevens, M. M. Colloidal nanoparticles as advanced biological sensors. Science 346, 1247390 (2014).

    Article  PubMed  Google Scholar 

  5. 5.

    Maggiorella, L. et al. Nanoscale radiotherapy with hafnium oxide nanoparticles. Future Oncol. 8, 1167–1181 (2012).

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Libutti, S. K. et al. Phase I and pharmacokinetic studies of CYT-6091, a novel PEGylated colloidal gold-rhTNF nanomedicine. Clin. Cancer Res. 16, 6139–6149 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Zhao, Y. Z. et al. Bioengineered magnetoferritin nanoprobes for single-dose nuclear-magnetic resonance tumor imaging. ACS Nano 10, 4184–4191 (2016).

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Lee, H., Sun, E., Ham, D. & Weissleder, R. Chip-NMR biosensor for detection and molecular analysis of cells. Nat. Med. 14, 869–874 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Zhang, C. et al. Magnesium silicide nanoparticles as a deoxygenation agent for cancer starvation therapy. Nat. Nanotech. 12, 378–386 (2017).

    CAS  Article  Google Scholar 

  10. 10.

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

    CAS  Article  Google Scholar 

  11. 11.

    Ghosh, D. et al. M13-templated magnetic nanoparticles for targeted in vivo imaging of prostate cancer. Nat. Nanotech. 7, 677–682 (2012).

    CAS  Article  Google Scholar 

  12. 12.

    Etoc, F. et al. Subcellular control Rac-GTPase signalling by magnetogenetic manipulation inside living cells. Nat. Nanotech. 8, 193–198 (2013).

    CAS  Article  Google Scholar 

  13. 13.

    Chan, K. W. Y. et al. MRI-detectable pH nanosensors incorporated into hydrogels for in vivo sensing of transplanted-cell viability. Nat. Mater. 12, 268–275 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Kircher, M. F. et al. A brain tumor molecular imaging strategy using a new triple-modality MRI-photoacoustic-Raman nanoparticle. Nat. Med. 18, 829–834 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Chapman, S. et al. Nanoparticles for cancer imaging: the good, the bad, and the promise. Nano Today 8, 454–460 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Lewin, M. et al. Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells. Nat. Biotechnol. 18, 410–414 (2000).

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Bulte, J. W. M. et al. Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells. Nat. Biotechnol. 19, 1141–1147 (2001).

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Cho, M. H. et al. A magnetic switch for the control of cell death signalling in in vitro and in vivo systems. Nat. Mater. 11, 1038–1043 (2012).

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Lee, J. H. et al. Exchange-coupled magnetic nanoparticles for efficient heat induction. Nat. Nanotech. 6, 418–422 (2011).

    CAS  Article  Google Scholar 

  20. 20.

    Gao, J. H., Gu, H. W. & Xu, B. Multifunctional magnetic nanoparticles: design, synthesis, and biomedical applications. Acc. Chem. Res. 42, 1097–1107 (2009).

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Della Rocca, J., Liu, D. M. & Lin, W. B. Nanoscale metal-organic frameworks for biomedical imaging and drug delivery. Acc. Chem. Res. 44, 957–968 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Lee, N. et al. Iron oxide based nanoparticles for multimodal imaging and magnetoresponsive therapy. Chem. Rev. 115, 10637–10689 (2015).

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Long, M. J. C., Pan, Y., Lin, H. C., Hedstrom, L. & Xu, B. Cell compatible trimethoprim-decorated iron oxide nanoparticles bind dihydrofolate reductase for magnetically modulating focal adhesion of mammalian cells. J. Am. Chem. Soc. 133, 10006–10009 (2011).

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Pan, Y., Du, X. W., Zhao, F. & Xu, B. Magnetic nanoparticles for the manipulation of proteins and cells. Chem. Soc. Rev. 41, 2912–2942 (2012).

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Issadore, D. et al. Self-assembled magnetic filter for highly efficient immunomagnetic separation. Lab Chip 11, 147–151 (2011).

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Min, Y. Z., Caster, J. M., Eblan, M. J. & Wang, A. Z. Clinical translation of nanomedicine. Chem. Rev. 115, 11147–11190 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Lee, N. & Hyeon, T. Designed synthesis of uniformly sized iron oxide nanoparticles for efficient magnetic resonance imaging contrast agents. Chem. Soc. Rev. 41, 2575–2589 (2012).

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Arami, H., Khandhar, A., Liggitt, D. & Krishnan, K. M. In vivo delivery, pharmacokinetics, biodistribution and toxicity of iron oxide nanoparticles. Chem. Soc. Rev. 44, 8576–8607 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Balakrishnan, V. S. et al. Physicochemical properties of ferumoxytol, a new intravenous iron preparation. Eur. J. Clin. Invest. 39, 489–496 (2009).

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Yilmaz, A., Rosch, S., Yildiz, H., Klumpp, S. & Sechtem, U. First multiparametric cardiovascular magnetic resonance study using ultrasmall superparamagnetic iron oxide nanoparticles in a patient with acute myocardial infarction: new vistas for the clinical application of ultrasmall superparamagnetic iron oxide. Circulation 126, 1932–1934 (2012).

    Article  PubMed  Google Scholar 

  31. 31.

    Penfield, J. G. & Reilly, R. F. What nephrologists need to know about gadolinium. Nat. Clin. Pract. Nephrol. 3, 654–668 (2007).

    Article  PubMed  Google Scholar 

  32. 32.

    White, G. W., Gibby, W. A. & Tweedle, M. F. Comparison of Gd(DTPA-BMA) (Omniscan) versus Gd(HP-DO3A) (ProHance) relative-to gadolinium retention in human bone tissue by inductively coupled plasma mass spectroscopy. Invest. Radiol. 41, 272–278 (2006).

    Article  PubMed  Google Scholar 

  33. 33.

    Kanda, T. et al. Gadolinium-based contrast agent accumulates in the brain even in subjects without severe renal dysfunction: evaluation of autopsy brain specimens with inductively coupled plasma mass spectroscopy. Radiology 276, 228–232 (2015).

    Article  PubMed  Google Scholar 

  34. 34.

    Ghazani, A. A. et al. Molecular characterization of scant lung tumor cells using iron-oxide nanoparticles and micro-nuclear magnetic resonance. Nanomedicine 10, 661–668 (2014).

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Shao, H. L. et al. Magnetic nanoparticles and microNMR for diagnostic applications. Theranostics 2, 55–65 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Shao, H. L., Yoon, T. J., Liong, M., Weissleder, R. & Lee, H. Magnetic nanoparticles for biomedical NMR-based diagnostics. Beilstein J. Nanotechnol. 1, 142–154 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Issadore, D. et al. Miniature magnetic resonance system for point-of-care diagnostics. Lab Chip 11, 2282–2287 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Ghazani, A. A., Castro, C. M., Gorbatov, R., Lee, H. & Weissleder, R. Sensitive and direct detection of circulating tumor cells by multimarker µ-nuclear magnetic resonance. Neoplasia 14, 388–395 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    De Vries, I. J. M. et al. Magnetic resonance tracking of dendritic cells in melanoma patients for monitoring of cellular therapy. Nat. Biotechnol. 23, 1407–1413 (2005).

    Article  PubMed  Google Scholar 

  40. 40.

    Valencia, P. M., Farokhzad, O. C., Karnik, R. & Langer, R. Microfluidic technologies for accelerating the clinical translation of nanoparticles. Nat. Nanotech. 7, 623–629 (2012).

    CAS  Article  Google Scholar 

  41. 41.

    Cheng, Z. L., Al Zaki, A., Hui, J. Z., Muzykantov, V. R. & Tsourkas, A. Multifunctional nanoparticles: cost versus benefit of adding targeting and imaging capabilities. Science 338, 903–910 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Yoon, T. J., Lee, H., Shao, H. L., Hilderbrand, S. A. & Weissleder, R. Multicore assemblies potentiate magnetic properties of biomagnetic nanoparticles. Adv. Mater. 23, 4793–4797 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Yoon, T. J., Lee, H., Shao, H. L. & Weissleder, R. Highly magnetic core-shell nanoparticles with a unique magnetization mechanism. Angew. Chem. Int. Ed. 50, 4663–4666 (2011).

    CAS  Article  Google Scholar 

  44. 44.

    Park, J. et al. Ultra-large-scale syntheses of monodisperse nanocrystals. Nat. Mater. 3, 891–895 (2004).

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Laurent, S. et al. Magnetic iron oxide nanoparticles: synthesis, stabilization, vectorization, physicochemical characterizations, and biological applications. Chem. Rev. 108, 2064–2110 (2008).

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Choi, H. S. et al. Renal clearance of quantum dots. Nat. Biotechnol. 25, 1165–1170 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Jiang, W., Kim, B. Y. S., Rutka, J. T. & Chan, W. C. W. Nanoparticle-mediated cellular response is size-dependent. Nat. Nanotech. 3, 145–150 (2008).

    CAS  Article  Google Scholar 

  48. 48.

    Choi, H. S. et al. Design considerations for tumour-targeted nanoparticles. Nat. Nanotech. 5, 42–47 (2010).

    CAS  Article  Google Scholar 

  49. 49.

    Ye, L. et al. A pilot study in non-human primates shows no adverse response to intravenous injection of quantum dots. Nat. Nanotech. 7, 453–458 (2012).

    CAS  Article  Google Scholar 

  50. 50.

    Yan, G. M. et al. Genome sequencing and comparison of two nonhuman primate animal models, the cynomolgus and Chinese rhesus macaques. Nat. Biotechnol. 29, 1019–1023 (2011).

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Kim, B. H. et al. Large-scale synthesis of uniform and extremely small-sized iron oxide nanoparticles for high-resolution T 1 magnetic resonance imaging contrast agents. J. Am. Chem. Soc. 133, 12624–12631 (2011).

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Boles, M. A., Ling, D., Hyeon, T. & Talapin, D. V. The surface science of nanocrystals. Nat. Mater. 15, 141–153 (2016).

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Na, H. B. et al. Versatile PEG-derivatized phosphine oxide ligands for water-dispersible metal oxide nanocrystals. Chem. Commun. 5167–5169 (2007).

  54. 54.

    Rowe, R. C., Sheskey, P. J. & Quinn, M. E. Handbook of Pharmaceutical Excipients 6th edn (Pharmaceutical Press, London, UK, and American Pharmacists Association, Washington, USA, 2009).

  55. 55.

    Van der Meel, R., Vehmeijer, L. J. C., Kok, R. J., Storm, G. & van Gaal, E. V. B. Ligand-targeted particulate nanomedicines undergoing clinical evaluation: current status. Adv. Drug Deliv. Rev. 65, 1284–1298 (2013).

    Article  PubMed  Google Scholar 

  56. 56.

    Stirland, D. L., Nichols, J. W., Miura, S. & Bae, Y. H. Mind the gap: a survey of how cancer drug carriers are susceptible to the gap between research and practice. J. Control. Release 172, 1045–1064 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Ling, D., Lee, N. & Hyeon, T. Chemical synthesis and assembly of uniformly sized iron oxide nanoparticles for medical applications. Acc. Chem. Res. 48, 1276–1285 (2015).

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Wang, Y.-X. J. Superparamagnetic iron oxide based MRI contrast agents: current status of clinical application. Quant. Imaging Med. Surg 1, 35–40 (2011).

    PubMed  PubMed Central  Google Scholar 

  59. 59.

    Chen, R. et al. Parallel comparative studies on mouse toxicity of oxide nanoparticle- and gadolinium-based T 1 MRI contrast agents. ACS Nano 9, 12425–12435 (2015).

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Saleem, K. S. & Logothetis, N. K. A Combined MRI and Histology Atlas of the Rhesus Monkey Brain in Stereotaxic Coordinates 1st edn (Academic Press, London, UK, 2007).

  61. 61.

    Varallyay, C. G. et al. Dynamic MRI using iron oxide nanoparticles to assess early vascular effects of antiangiogenic versus corticosteroid treatment in a glioma model. J. Cereb. Blood Flow Metab. 29, 853–860 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Kim, S. G. et al. Cerebral blood volume MRI with intravascular superparamagnetic iron oxide nanoparticles. NMR Biomed. 26, 949–962 (2013).

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Coelho, O. R., Rickers, C., Kwong, R. Y. & Jerosch-Herold, M. MR myocardial perfusion imaging. Radiology 266, 701–715 (2013).

    Article  Google Scholar 

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Acknowledgements

T.H. and S.H.C. acknowledge financial support from the Research Center Program of the Institute for Basic Science (IBS-R006-D1) in Korea. Y.L., D.-H.Z., D.L. and L.Z. acknowledge financial support from the National Key Research and Development Program of China (2016YFA0203600), National Natural Science Foundation of China (51572067, 21501039, 51503180, 31370983, 81401518, 31430028 and 5161101036), Fundamental Research Funds for the Central Universities (2015HGCH0009), Anhui Province Funds for Distinguished Young Scientists (1508085J08), Natural Science Foundation of Anhui Province (1708085ME114) and Young Top-Notch Talent Support Scheme at Anhui Medical University.

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T.H., S.H.C., D.-H.Z., Y.L., D.L., Y.-J.X. and G.-b.Z. conceived the idea and designed the experiments. T.H., S.H.C. and D.-H.Z. supervised the research. Y.L., D.L., B.H.K., H.C., J.K. and N.L. processed the samples. D.-H.Z., T.W., Y.Z., J.-C.H. and L.Z. worked on the macaque breeding. G.-b.Z. and M.-q.W. worked on the cerebral ischaemia model. Y.-J.X., Y.L., D.L., N.L. and S.H.C. investigated the MR performance. T.W., Y.Z., L.Z. and H.-Q.W. processed the biocompatibility evaluation. Y.-D.W., L.D., F.L. and B.Y. performed the biodistribution and pharmacokinetic study in vivo. X.-T.H. performed the pathological analysis. Y.L., D.L., M.J.H., Y.-J.X., G.-b.Z., N.L., T.H., S.H.C. and D.-H.Z. wrote the paper. All authors analysed and discussed the results.

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Correspondence to Seung Hong Choi or Taeghwan Hyeon or Duo-Hong Zou.

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Lu, Y., Xu, YJ., Zhang, Gb. et al. Iron oxide nanoclusters for T 1 magnetic resonance imaging of non-human primates. Nat Biomed Eng 1, 637–643 (2017). https://doi.org/10.1038/s41551-017-0116-7

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