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Two-way magnetic resonance tuning and enhanced subtraction imaging for non-invasive and quantitative biological imaging

Nature Nanotechnology volume 15, pages 482–490 (2020)Cite this article

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Abstract

Distance-dependent magnetic resonance tuning (MRET) technology enables the sensing and quantitative imaging of biological targets in vivo, with the advantage of deep tissue penetration and fewer interactions with the surroundings as compared with those of fluorescence-based Förster resonance energy transfer. However, applications of MRET technology in vivo are currently limited by the moderate contrast enhancement and stability of T1-based MRET probes. Here we report a new two-way magnetic resonance tuning (TMRET) nanoprobe with dually activatable T1 and T2 magnetic resonance signals that is coupled with dual-contrast enhanced subtraction imaging. This integrated platform achieves a substantially improved contrast enhancement with minimal background signal and can be used to quantitatively image molecular targets in tumours and to sensitively detect very small intracranial brain tumours in patient-derived xenograft models. The high tumour-to-normal tissue ratio offered by TMRET in combination with dual-contrast enhanced subtraction imaging provides new opportunities for molecular diagnostics and image-guided biomedical applications.

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Scheme 1
Fig. 1: TMRET nanoprobes and the T1/T2 dual-quenching properties, as well as the mechanism.
Fig. 2: Illustration of the mechanism of T1 and T2 quenching and recovery in the TMRET nanoprobe.
Fig. 3: The dual responsiveness of T1 and T2 MR signals of DCM@P–Mn–SPIO compared with different levels of GSH in cells.
Fig. 4: The relationship between the MRI relaxation rates and the concentrations of the molecular target of TMRET.
Fig. 5: In vivo MRI of tumours using DCM@P–Mn–SPIO.
Fig. 6: In vivo applications of TMRET probe with DESI technique on orthotopic brain tumours.
Fig. 7: Application of TMRET nanotechnology and DESI on a pH-responsive POP@P–Mn–SPIO.

Data availability

The data that support the plots within this paper and other findings of this study are available from the corresponding author upon reasonable request.

Code availability

The subtraction imaging was obtained in MATLAB R2013b software by using the following commands:

A = imread (‘D:T1WI’); B = imread (‘D: T2WI’); C = imsubtract (A, B); J = imcomplement c;

J, subtraction images of the T1- and T2-weighted imaging.

The last step involved the antiphase processing of subtraction images using MATLAB R2013b software.

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Acknowledgements

We thank financial support from the National Institutes of Health (NIH)/National Cancer Institute (R01CA199668), NIH/Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD086195), UC Davis Comprehensive Cancer Center Support Grant (CCSG) awarded by the National Cancer Institute (NCI P30CA093373) and National Science Foundation (NSF) (ECCS-1611424 and ECCS-1933527). The acquisition of a magnetic property measurements system (MPMS3) at Georgetown University was supported by the NSF (DMR-1828420).

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Author notes

  1. These authors contributed equally: Zhongling Wang, Xiangdong Xue.

Authors and Affiliations

  1. Department of Radiology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China

    Zhongling Wang & Na Tang

  2. Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA, USA

    Zhongling Wang, Xiangdong Xue, Hongwei Lu, Yixuan He, Ye Yuan, Courtney A. Dreyer, Kit S. Lam, Jeffrey H. Walton & Yuanpei Li

  3. Department of Radiology, First Affiliated Hospital of Soochow University, Suzhou, China

    Ziwei Lu

  4. Department of Physics, University of California, Davis, CA, USA

    Zhijie Chen, Nicholas Curro & Kai Liu

  5. Department of Physics, Georgetown University, Washington, DC, USA

    Zhijie Chen & Kai Liu

  6. Department of Materials Science and Engineering, University of Tennessee, Knoxville, TS, USA

    Lizabeth Quigley & Dustin A. Gilbert

  7. Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis, Sacramento, CA, USA

    Kit S. Lam & Tzu-yin Lin

  8. UC Davis NMR Facility, Davis, CA, USA

    Jeffrey H. Walton

  9. Department of Biomedical Engineering, University of California Davis, Davis, CA, USA

    Angelique Y. Louie

  10. Department of Radiology, Stanford University, Palo Alto, CA, USA

    Katherine W. Ferrara

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  1. Zhongling Wang
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Contributions

Y.L., X.X. and Z.W. conceived the idea and designed the TMRET nanoprobe. Z.W. conducted most of the experiments, X.X. assisted with some of the experiments. X.X. and Z.W. analysed the data. X.X. led the revisions of the manuscript. H.L. worked on the POP materials and animal experiments. Y.H. assisted with the animal studies. Z.W. and Z.L. conducted the DESI process. Z.C., L.Q., N.C., D.A.G., X.X. and K.L. performed the magnetic characterization and assisted with the explanation of T2 quench mechanism. Y.Y. assisted with the MRI studies. N.T. assisted with the MRI data analysis. T.L. assisted with the design and data analysis of biological experiments. K.S.L., A.Y.L. and K.W.F. provided valuable suggestions on the project methodology. X.X., Y.L. and Z.W. wrote the paper and all the authors commented on the manuscript. Y.L. supervised the project.

Corresponding author

Correspondence to Yuanpei Li.

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Competing interests

Y.L., X.X. and Z.W. are the co-inventors on the pending patent application filed by the Regents of the University of California on the TMRET nanotechnology and DESI.

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Peer review information Nature Nanotechnology thanks Jeff Bulte, John Waterton and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Wang, Z., Xue, X., Lu, H. et al. Two-way magnetic resonance tuning and enhanced subtraction imaging for non-invasive and quantitative biological imaging. Nat. Nanotechnol. 15, 482–490 (2020). https://doi.org/10.1038/s41565-020-0678-5

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