Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

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.

References

  1. Liu, G. L. et al. A nanoplasmonic molecular ruler for measuring nuclease activity and DNA footprinting. Nat. Nanotechnol. 1, 47–52 (2006).

    Article  CAS  Google Scholar 

  2. Nguyen, A. W. & Daugherty, P. S. Evolutionary optimization of fluorescent proteins for intracellular FRET. Nat. Biotechnol. 23, 355–360 (2005).

    Article  CAS  Google Scholar 

  3. Sönnichsen, C., Reinhard, B. M., Liphardt, J. & Alivisatos, A. P. A molecular ruler based on plasmon coupling of single gold and silver nanoparticles. Nat. Biotechnol. 23, 741–745 (2005).

    Article  Google Scholar 

  4. Ma, Y. et al. A FRET sensor enables quantitative measurements of membrane charges in live cells. Nat. Biotechnol. 35, 363–370 (2017).

    Article  CAS  Google Scholar 

  5. Schuler, B., Lipman, E. A. & Eaton, W. A. Probing the free-energy surface for protein folding with single-molecule fluorescence spectroscopy. Nature 419, 743–747 (2002).

    Article  CAS  Google Scholar 

  6. Rizzo, M. A., Springer, G. H., Granada, B. & Piston, D. W. An improved cyan fluorescent protein variant useful for FRET. Nat. Biotechnol. 22, 445–449 (2004).

    Article  CAS  Google Scholar 

  7. Biskup, C., Zimmer, T. & Benndorf, K. FRET between cardiac Na+ channel subunits measured with a confocal microscope and a streak camera. Nat. Biotechnol. 22, 220–224 (2004).

    Article  CAS  Google Scholar 

  8. Jares-Erijman, E. A. & Jovin, T. M. FRET imaging. Nat. Biotechnol. 21, 1387–1395 (2003).

    Article  CAS  Google Scholar 

  9. Choi, J. S. et al. Distance-dependent magnetic resonance tuning as a versatile MRI sensing platform for biological targets. Nat. Mater. 16, 537–542 (2017).

    Article  CAS  Google Scholar 

  10. Mizukami, S. et al. Paramagnetic relaxation-based 19F MRI probe to detect protease activity. J. Am. Chem. Soc. 130, 794–795 (2008).

    Article  CAS  Google Scholar 

  11. Mura, S., Nicolas, J. & Couvreur, P. Stimuli-responsive nanocarriers for drug delivery. Nat. Mater. 12, 991–1003 (2013).

    Article  CAS  Google Scholar 

  12. Hong, R. et al. Glutathione-mediated delivery and release using monolayer protected nanoparticle carriers. J. Am. Chem. Soc. 128, 1078–1079 (2006).

    Article  CAS  Google Scholar 

  13. Tam, N. C. M. et al. Porphyrin–lipid stabilized gold nanoparticles for surface enhanced Raman scattering based imaging. Bioconj. Chem. 23, 1726–1730 (2012).

    Article  CAS  Google Scholar 

  14. Lovell, J. F. et al. Porphysome nanovesicles generated by porphyrin bilayers for use as multimodal biophotonic contrast agents. Nat. Mater. 10, 324–332 (2011).

    Article  CAS  Google Scholar 

  15. Xue, X. et al. Trojan horse nanotheranostics with dual transformability and multifunctionality for highly effective cancer treatment. Nat. Commun. 9, 3653 (2018).

    Article  Google Scholar 

  16. Zhou, Z. et al. T1–T2 dual-modal magnetic resonance imaging: from molecular basis to contrast agents. ACS Nano 11, 5227–5232 (2017).

    Article  CAS  Google Scholar 

  17. Santra, S. et al. Gadolinium-encapsulating iron oxide nanoprobe as activatable NMR/MRI contrast agent. ACS Nano 6, 7281–7294 (2012).

    Article  CAS  Google Scholar 

  18. Mørup, S., Hansen, M. F. & Frandsen, C. Magnetic interactions between nanoparticles. Beilstein J. Nanotechnol. 1, 182–190 (2010).

    Article  Google Scholar 

  19. Köseoğlu, Y., Yıldız, F., Kim, D. K., Muhammed, M. & Aktaş, B. EPR studies on Na-oleate coated Fe3O4 nanoparticles. Phys. Status Solidi C 1, 3511–3515 (2004).

    Article  Google Scholar 

  20. Kuch, W. et al. Three-dimensional noncollinear antiferromagnetic order in single-crystalline FeMn ultrathin films. Phys. Rev. Lett. 92, 017201 (2004).

    Article  Google Scholar 

  21. Webb, M. R., Ash, D. E., Leyh, T. S., Trentham, D. R. & Reed, G. H. Electron paramagnetic resonance studies of Mn(ii) complexes with myosin subfragment 1 and oxygen 17-labeled ligands. J. Biol. Chem. 257, 3068–3072 (1982).

    CAS  Google Scholar 

  22. Bulte, J. W., Brooks, R. A., Moskowitz, B. M., Bryant, L. H. Jr. & Frank, J. A. Relaxometry and magnetometry of the MR contrast agent MION-46L. Magn. Reson. Med. 42, 379–384 (1999).

    Article  CAS  Google Scholar 

  23. Li, Y. et al. Probing of the assembly structure and dynamics within nanoparticles during interaction with blood proteins. ACS Nano 6, 9485–9495 (2012).

    Article  CAS  Google Scholar 

  24. Li, Y. et al. Well-defined, reversible disulfide cross-linked micelles for on-demand paclitaxel delivery. Biomaterials 32, 6633–6645 (2011).

    Article  CAS  Google Scholar 

  25. Li, Y., Xiao, K., Zhu, W., Deng, W. & Lam, K. S. Stimuli-responsive cross-linked micelles for on-demand drug delivery against cancers. Adv. Drug Deliv. Rev. 66, 58–73 (2014).

    Article  CAS  Google Scholar 

  26. Maeda, H. et al. Effective treatment of advanced solid tumors by the combination of arsenic trioxide and l-buthionine-sulfoximine. Cell Death Differ. 11, 737–746 (2004).

    Article  CAS  Google Scholar 

  27. Pileblad, E., Magnusson, T. & Fornstedt, B. Reduction of brain glutathione by l‐buthionine sulfoximine potentiates the dopamine‐depleting action of 6‐hydroxydopamine in rat striatum. J. Neurochem. 52, 978–980 (1989).

    Article  CAS  Google Scholar 

  28. Zheng, X. et al. Successively activatable ultrasensitive probe for imaging tumour acidity and hypoxia. Nat. Biomed. Eng. 1, 0057 (2017).

    Article  CAS  Google Scholar 

  29. Hori, S. S., Tummers, W. S. & Gambhir, S. S. Cancer diagnostics: on-target probes for early detection. Nat. Biomed. Eng. 1, 0062 (2017).

    Article  CAS  Google Scholar 

  30. Li, Y. et al. A smart and versatile theranostic nanomedicine platform based on nanoporphyrin. Nat. Commun. 5, 4712 (2014).

    Article  CAS  Google Scholar 

  31. Kato, J. et al. Disulfide cross-linked micelles for the targeted delivery of vincristine to B-cell lymphoma. Mol. Pharm. 9, 1727–1735 (2012).

    Article  CAS  Google Scholar 

  32. Xiao, K. et al. Disulfide cross-linked micelles of novel HDAC inhibitor thailandepsin A for the treatment of breast cancer. Biomaterials 67, 183–193 (2015).

    Article  CAS  Google Scholar 

  33. Wang, Z. et al. Active targeting theranostic iron oxide nanoparticles for MRI and magnetic resonance-guided focused ultrasound ablation of lung cancer. Biomaterials 127, 25–35 (2017).

    Article  CAS  Google Scholar 

  34. Zhang, Z. et al. Facile synthesis of folic acid-modified iron oxide nanoparticles for targeted MR imaging in pulmonary tumor xenografts. Mol. Imaging Biol. 18, 569–578 (2016).

    Article  CAS  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

Authors

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.

Ethics declarations

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.

Additional information

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.

Supplementary information

Supplementary Information

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

Reporting Summary

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41565-020-0678-5

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research