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A hepatocyte-targeting nanoparticle for enhanced hepatobiliary magnetic resonance imaging

Nature Biomedical Engineering volume 7, pages 221–235 (2023)Cite this article

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Abstract

Hepatobiliary magnetic resonance imaging (MRI) can inform the diagnosis of liver tumours in patients with liver cirrhosis and hepatitis. However, its clinical utility has been hampered by the lack of sensitive and specific contrast agents, partly because hepatocyte-specific nanoparticles, regardless of their surface ligands, are readily sequestered by Kupffer cells. Here we show, in rabbits, pigs and macaques, that the performance of hepatobiliary MRI can be enhanced by an ultrasmall nanoparticle composed of a manganese ferrite core (3 nm in diameter) and poly(ethylene glycol)-ethoxy-benzyl surface ligands binding to hepatocyte-specific transmembrane metal and anion transporters. The nanoparticle facilitated faster, more sensitive and higher-resolution hepatobiliary MRI than the clinically used contrast agent gadoxetate disodium, a substantial enhancement in the detection rate (92% versus 48%) of early-stage liver tumours in rabbits, and a more accurate assessment of biliary obstruction in macaques. The nanoparticle’s performance and biocompatibility support the further translational development of liver-specific MRI contrast agents.

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Fig. 1: Design of hepatocyte-specific MnFe2O4-EOB-PEG nanoparticle-based CAs for hepatobiliary MRI.
Fig. 2: In vitro hepatocyte affinity evaluation of MnFe2O4-EOB-PEG.
Fig. 3: In vivo hepatocyte-specific MRI and safety evaluation in pigs.
Fig. 4: MR detection of liver tumours in rabbits.
Fig. 5: Hepatobiliary tract imaging in macaques.

Data availability

The main data supporting the findings of this study are available within the paper and its Supplementary Information. The raw and analyzed datasets are too large to be readily shared publicly but can be made available from the corresponding author on reasonable request. Source data are provided with this paper.

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Acknowledgements

We acknowledge the financial support provided by the National Key R&D Program of China (2021YFA1201401 to H.F.), the National Natural Science Foundation of China (82150301 to H.F., 81971586 to Y.G., 81871417 to J.J., 82072063 to X.L., 22072115 to M.P. and 31901003 to X.L.), the Shaanxi Province Funds for Distinguished Young Scholars (2019JC-27 to H.F.), the Sichuan Science and Technology Program (2020YFS0050 to Y.G.), the Guangdong Natural Science Foundation (2018A030313919 to J.J.), the Shaanxi Natural Science Foundation (2021JQ-459 to H.Z.) and the China Postdoctoral Science Foundation (2019M653719 to H.Z.). We also acknowledge A. Li (Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education, College of Chemistry and Materials Science, Northwest University) for assistance in the theoretical calculations and helpful discussion.

Author information

Author notes

  1. These authors contributed equally: Huan Zhang, Yingkun Guo, Ju Jiao.

Authors and Affiliations

  1. Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi’an, Shaanxi, China

    Huan Zhang, Ying Qiu, Yuqing Miao, Yuan He, Mingli Peng, Yaoyu Wang & Haiming Fan

  2. Department of Radiology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China

    Yingkun Guo & Ke Xu

  3. Department of Nuclear Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

    Ju Jiao

  4. Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    Zhenlin Li & Chunchao Xia

  5. State Key Laboratory of Oncology in South China, Imaging Diagnosis and Interventional Center, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China

    Li Li & Jing Cai

  6. Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an, Shaanxi, China

    Xiaoli Liu & Haiming Fan

  7. College of Physics, Northwest University, Xi’an, Shaanxi, China

    Ce Zhang

  8. Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Boon-Huat Bay

  9. Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China

    Shijie Song & Yanlian Yang

  10. University of Chinese Academy of Sciences, Beijing, China

    Shijie Song & Yanlian Yang

Authors
  1. Huan Zhang
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  2. Yingkun Guo
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Contributions

H.F., H.Z., Y.G. and J.J. conceived and designed the experiments. H.Z., Y.Q., Y.M., Z.L., C.X., L.L., J.C., K.X. and S.S. performed the experiments. H.F., H.Z., Y.H., X.L., C.Z., Y.Y., M.P. and Y.W. analyzed the results. H.Z., Y.G., J.J., Y.H., B.-H.B. and H.F. wrote the manuscript. H.F. supervised the entire project. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Haiming Fan.

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Extended data

Extended Data Fig. 1 Comparison of MnFe2O4-EOB-PEG and Gd-EOB-DTPA for the detection of small liver tumours.

a, Representative MnFe2O4-EOB-PEG and Gd-EOB-DTPA enhanced MRI of rabbit’s liver using the starvibe sequence. One rabbit was randomly implanted 5 pieces of VX2 tumours in liver. All five tumours were detected using the MnFe2O4-EOB-PEG, the tumour 4 and tumour 5 were absent on the Gd-EOB-DTPA-enhanced MRI. b, Histopathological detection of the liver VX2 tumours with sizes of 3.72 mm × 2.47 mm (tumour 1), 3.62 mm × 3.29 mm (tumour 2), 3.88 mm × 2.17 mm (tumour 3), 2.35 mm × 2.60 mm (tumour 4) and 3.13 mm × 1.82 mm (tumour 5), respectively. Scale bar, 1 mm.

Extended Data Fig. 2

Dynamic liver MRI using MnFe2O4-EOB-PEG and gadoxetate disodium in macaque monkeys.

Supplementary information

Supplementary Information

Supplementary figures and tables.

Reporting Summary

Supplementary Video 1

Dynamic time-resolved magnetic resonance angiography in a rabbit using an angio-twist sequence after bolus injection of MnFe2O4-EOB-PEG at a dose of 3 mg (Fe+Mn) kg−1 body weight.

Source data

Source Data Fig. 1

Unprocessed western blots.

Source Data Fig. 2

Unprocessed western blots.

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Zhang, H., Guo, Y., Jiao, J. et al. A hepatocyte-targeting nanoparticle for enhanced hepatobiliary magnetic resonance imaging. Nat. Biomed. Eng 7, 221–235 (2023). https://doi.org/10.1038/s41551-022-00975-2

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