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

Nature Biomedical Engineering volume 1, pages 637–643 (2017)Cite this article

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.

For the past 20 years, various inorganic nanoparticles have been extensively investigated for the treatment and diagnosis of major diseases1,2,3,4,5,6,7,8,9. Among them, magnetic nanoparticles have been widely studied for their biomedical applications to targeted imaging in vivo10,11,12,13,14,15, tracking of stem cells16,17, magneto-control of subcellular signalling pathways18, magnetic hyperthermia19, magnetoresponsive therapy20,21,22 and magnetic separation23,24,25. Several kinds of superparamagnetic iron oxide nanoparticles (SPIOs), including ferumoxide and ferucarbotran, have been clinically approved as T 2 magnetic resonance imaging (MRI) contrast agents in the United States and Europe26. These SPIOs exhibit a T 2 contrast effect from the magnetic inhomogeneity induced by their strong magnetic moment22,27. However, their extensive clinical uses are limited by several disadvantages. Most importantly, the intrinsic dark signal produced by T 2 contrast agents can be confused with other hypointense regions such as air, haemorrhage, calcification, metal deposition and blood clots. Furthermore, the ‘blooming effect’, which is caused by the high magnetic moment, exaggerates the size of the imaged area, blurring the image22,27. Consequently, T 1 contrast agents are more desirable than T 2 agents for accurate high-resolution imaging, and these first-generation SPIO-based T 2 MRI contrast agents have shown greatly limited clinical utility. Moreover, some SPIOs have been associated with severe adverse effects including anaphylactic shock, which has ultimately led to their discontinuation in the clinic26,28. In 2009, a safe ultrasmall SPIO formulation, ferumoxytol, which has an iron oxide core of around 7 nm in diameter, a hydrodynamic diameter of around 20 nm and a carboxymethyldextran coating, was approved by the United States Food and Drug Administration (FDA) to serve as a high-dose intravenous iron preparation for patients suffering from iron deficiency29. This clinically approved formulation was successfully used for magnetic resonance angiography (MRA) of the aorta in a patient with acute myocardial infarction30. Meanwhile, the first FDA-approved gadolinium-based contrast agents (GBCAs) have been clinically used for nearly 30 years. Nevertheless, there remains strong demand for clinically applicable alternatives to the current standard of GBCAs because of their several disadvantages in clinical settings. GBCAs are generally excreted quickly through urine, preventing their use in high-resolution imaging applications that require a long scan time27. Furthermore, they are known to exhibit toxic side effects, including nephrogenic systemic fibrosis caused by leached free Gd3+ ions in patients with renal-function impairment31. Moreover, it has been confirmed that gadolinium accumulates in human bone32 and even brain33 after repeat exposure to linear GBCAs for magnetic resonance (MR) diagnosis, and that it remains in these organs for many years. In guidelines by the American College of Radiology Committee on Drugs and Contrast Media updated in 2015, GBCAs were classified into three groups by the reported number of nephrogenic systemic-fibrosis cases, whereas the European Society for Urological Radiology classifies GBCAs according to the level of nephrogenic systemic-fibrosis-associated risk. As a result, there remains strong demand for clinically applicable alternatives to the current standard of GBCAs, and more attention should be paid to the development of iron oxide nanoparticle-based MRI contrast agents34.

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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.

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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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Author notes

  1. Yang Lu, Yun-Jun Xu, Guo-bing Zhang and Daishun Ling contributed equally to this work.

Authors and Affiliations

  1. Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, 08826, Republic of Korea

    Yang Lu, Michael J. Hackett, Byung Hyo Kim, Hogeun Chang, Jonghoon Kim, Nohyun Lee, Seung Hong Choi & Taeghwan Hyeon

  2. School of Chemical and Biological Engineering, and Institute of Chemical Processes, Seoul National University, Seoul, 08826, Republic of Korea

    Yang Lu, Michael J. Hackett, Byung Hyo Kim, Hogeun Chang, Jonghoon Kim, Nohyun Lee & Taeghwan Hyeon

  3. School of Chemistry and Chemical Engineering, Hefei University of Technology, Hefei, 230009, China

    Yang Lu, Ya-Dong Wu & Liang Dong

  4. Department of Radiology, Anhui Provincial Hospital, Hefei, 230001, China

    Yun-Jun Xu

  5. The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230022, China

    Guo-bing Zhang, Ming-quan Wang, Li Zhang & Hui-Qin Wen

  6. Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China

    Daishun Ling, Fangyuan Li & Bo Yang

  7. Key Laboratory of Biomedical Engineering of the Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, 310058, China

    Daishun Ling & Fangyuan Li

  8. Department of Dental Implant Centre, Stomatologic Hospital and College, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei, 230032, China

    Yong Zhou, Tao Wu, Jia-Cai He & Duo-Hong Zou

  9. Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China

    Xin-Tian Hu

  10. School of Advanced Materials Engineering, Kookmin University, Seoul, 02727, Republic of Korea

    Nohyun Lee

  11. Department of Radiology, Seoul National University Hospital, and the Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul, 03080, Republic of Korea

    Seung Hong Choi

  12. Second Dental Clinic, Ninth People’s Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai Key Laboratory of Stomatology, National Clinical Research Center of Stomatology, Shanghai, 200001, P. R. China

    Duo-Hong Zou

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  1. Yang Lu
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Contributions

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, 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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