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


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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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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Authors and Affiliations



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.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Supplementary Figs. 1–26 and Tables 1–4.

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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).

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