A magnetic resonance tuning sensor for the MRI detection of biological targets

Abstract

Sensors that detect specific molecules of interest in a living organism can be useful tools for studying biological functions and diseases. Here, we provide a protocol for the construction of nanosensors that can noninvasively detect biologically important targets with magnetic resonance imaging (MRI). The key operating principle of these sensors is magnetic resonance tuning (MRET), a distance-dependent phenomenon occurring between a superparamagnetic quencher and a paramagnetic enhancer. The change in distance between the two magnetic components modulates the longitudinal (T1) relaxivity of the enhancer. In this MRET sensor, distance variation is achieved by interactive linkers that undergo binding, cleavage, or folding/unfolding upon their interaction with target molecules. By the modular incorporation of suitable linkers, the MRET sensor can be applied to a wide range of targets. We showcase three examples of MRET sensors for enzymes, nucleic acid sequences, and pH. This protocol comprises three stages: (i) chemical synthesis and surface modification of the quencher, (ii) conjugation with interactive linkers and enhancers, and (iii) MRI sensing of biological targets. The entire procedure takes up to 3 d.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Schematic illustration of a magnetic resonance tuning (MRET) sensor.
Fig. 2: Schematic illustration of the experimental workflow.
Fig. 3: The quencher and its magnetic properties.
Fig. 4: Enhancer and its MRI contrast effects.
Fig. 5: Quencher synthesis.
Fig. 6: Surface modification of the quencher with DMSA.
Fig. 7: Purification of an MRET sensor by a MACS column (Step 22A(v) and (vi)).
Fig. 8: Three different types of MRET sensors.

References

  1. 1.

    Sonnichsen, 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 

  2. 2.

    Yun, C. S. et al. Nanometal surface energy transfer in optical rulers, breaking the FRET barrier. J. Am. Chem. Soc. 127, 3115–3119 (2005).

    CAS  Article  Google Scholar 

  3. 3.

    Medintz, I. L. et al. Self-assembled nanoscale biosensors based on quantum dot FRET donors. Nat. Mater. 2, 630–638 (2003).

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    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).

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Ntziachristos, V. Going deeper than microscopy: the optical imaging frontier in biology. Nat. Methods 7, 603–614 (2010).

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Glenn, D. R. et al. Single-cell magnetic imaging using a quantum diamond microscope. Nat. Methods 12, 736–U161 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    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).

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Tu, C., Osborne, E. A. & Louie, A. Y. Activatable T 1 and T 2 magnetic resonance imaging contrast agents. Ann. Biomed. Eng. 39, 1335–1348 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Davies, G. L., Kramberger, I. & Davis, J. J. Environmentally responsive MRI contrast agents. Chem. Commun. 49, 9704–9721 (2013).

    CAS  Article  Google Scholar 

  10. 10.

    Stuber, M. et al. Positive contrast visualization of iron oxide-labeled stem cells using inversion-recovery with on-resonant water suppression (IRON). Magn. Reson. Med. 58, 1072–1077 (2007).

    Article  Google Scholar 

  11. 11.

    Kobayashi, H. & Choyke, P. L. Target-cancer-cell-specific activatable fluorescence imaging probes: rational design and in vivo applications. Acc. Chem. Res. 44, 83–90 (2011).

    CAS  Article  Google Scholar 

  12. 12.

    Shi, H. et al. Activatable aptamer probe for contrast-enhanced in vivo cancer imaging based on cell membrane protein-triggered conformation alteration. Proc. Natl. Acad. Sci. USA 108, 3900–3905 (2011).

    CAS  Article  Google Scholar 

  13. 13.

    Vogel, S. S., van der Meer, B. W. & Blank, P. S. Estimating the distance separating fluorescent protein FRET pairs. Methods 66, 131–138 (2014).

    CAS  Article  Google Scholar 

  14. 14.

    Ozerdem, U. & Hargens, A. R. A simple method for measuring interstitial fluid pressure in cancer tissues. Microvasc. Res. 70, 116–120 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Arami, H., Khandhar, A., Liggitt, D. & Krishnan, K. M. In vivo delivery, pharmacokinetics, biodistribution and toxicity of iron oxide nanoparticles. Chem. Soc. Rev. 44, 8576–8607 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Wei, H. et al. Exceedingly small iron oxide nanoparticles as positive MRI contrast agents. Proc. Natl. Acad. Sci. USA 114, 2325–2330 (2017).

    CAS  Article  Google Scholar 

  17. 17.

    Shin, T. H., Choi, Y., Kim, S. & Cheon, J. Recent advances in magnetic nanoparticle-based multi-modal imaging. Chem. Soc. Rev. 44, 4501–4516 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Caravan, P., Ellison, J. J., McMurry, T. J. & Lauffer, R. B. Gadolinium(iii) chelates as MRI contrast agents: structure, dynamics, and applications. Chem. Rev. 99, 2293–2352 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Shin, T. H. et al. T 1 and T 2 dual-mode MRI contrast agent for enhancing accuracy by engineered nanomaterials. ACS Nano 8, 3393–3401 (2014).

    CAS  Article  Google Scholar 

  20. 20.

    Choi, J.-s et al. Self-confirming “AND” logic nanoparticles for fault-free MRI. J. Am. Chem. Soc. 132, 11015–11017 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    House, M. J. et al. Correlation of proton transverse relaxation rates (R2) with iron concentrations in postmortem brain tissue from alzheimer’s disease patients. Magn. Reson. Med. 57, 172–180 (2007).

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Jang, J. T. et al. Critical enhancements of mri contrast and hyperthermic effects by dopant-controlled magnetic nanoparticles. Angew. Chem. Int. Ed. Engl. 48, 1234–1238 (2009).

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Lee, H., Shin, T. H., Cheon, J. & Weissleder, R. Recent developments in magnetic diagnostic systems. Chem. Rev. 115, 10690–10724 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Song, H. T. et al. Surface modulation of magnetic nanocrystals in the development of highly efficient magnetic resonance probes for intracellular labeling. J. Am. Chem. Soc. 127, 9992–9993 (2005).

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Lee, J.-H. et al. Artificially engineered magnetic nanoparticles for ultra-sensitive molecular imaging. Nat. Med. 13, 95–99 (2007).

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Huh, Y. M. et al. In vivo magnetic resonance detection of cancer by using multifunctional magnetic nanocrystals. J. Am. Chem. Soc. 127, 12387–12391 (2005).

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Hagberg, G. E. & Scheffler, K. Effect of r1 and r2 relaxivity of gadolinium-based contrast agents on the T 1-weighted MR signal at increasing magnetic field strengths. Contrast Media Mol. Imaging. 8, 456-465, (2013).

  28. 28.

    Rockwood, C. A., Green, D. P. & Bucholz, R. W. Rockwood and Green’s Fractures in Adults 7th edn, 443 (Wolters Kluwer Health/Lippincott Williams & Wilkins, Philadelphia, 2010).

  29. 29.

    Bonevich, J. E. & Wolfgang, K. H. NIST-NCL Joint Assay Protocol, pcc-7: Measuring the Size of Nanoparticles Using Transmission Electron Microscopy (National Institute of Standards and Technology, Gaithersburg, MD, 2010).

  30. 30.

    Rowlands, N. & Burgess, S. Energy dispersive analysis in the TEM. Mater. Today 12, 46–48 (2010).

    Article  Google Scholar 

  31. 31.

    Qiao, L. et al. Standardizing size- and shape-controlled synthesis of monodisperse magnetite (Fe3O4) nanocrystals by identifying and exploiting effects of organic impurities. ACS Nano 11, 6370–6381 (2017).

    CAS  Article  Google Scholar 

  32. 32.

    Jonsson, A., Hjalmarsson, C., Falk, P. & Ivarsson, M. L. Levels of matrix metalloproteinases differ in plasma and serum—aspects regarding analysis of biological markers in cancer. Br. J. Cancer 115, 703–706 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Kim, B. H. et al. Large-scale synthesis of uniform and extremely small-sized iron oxide nanoparticles for high-resolution T 1 magnetic resonance imaging contrast agents. J. Am. Chem. Soc. 133, 12624–12631 (2011).

    CAS  Article  Google Scholar 

  34. 34.

    Estelrich, J., Sanchez-Martin, M. J. & Busquets, M. A. Nanoparticles in magnetic resonance imaging: from simple to dual contrast agents. Int. J. Nanomed. 10, 1727–1741 (2015).

    CAS  Google Scholar 

  35. 35.

    Dormann, J. L., Fiorani, D. & Tronc, E. On the models for interparticle interactions in nanoparticle assemblies: comparison with experimental results. J. Magn. Magn. Mater. 202, 251–267 (1999).

    CAS  Article  Google Scholar 

  36. 36.

    Kim, J. W. et al. Single-cell mechanogenetics using monovalent magnetoplasmonic nanoparticles. Nat. Protoc. 12, 1871–1889 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank S. J. Kim. for helpful discussions and support. This work was supported by grants from the Institute for Basic Science (IBS-R026-D1) and the Korea Healthcare Technology R&D Project, Ministry for Health & Welfare Affairs (HI08C2149).

Author information

Affiliations

Authors

Contributions

J.C. conceived and designed the project; T.-H.S., S.K., S.P., and J.-s.C. developed protocols for MRET sensor syntheses; P.K.K. contributed methods for MRI measurements; T.-H.S., S.K., J.-s.C., and J.C. wrote the manuscript.

Corresponding author

Correspondence to Jinwoo Cheon.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Related links

Key references using this protocol

Choi, J.-s. et al. Nat. Mater. 16, 537–542 (2017): https://doi.org/10.1038/nmat4846

Shin, T. H. et al. ACS Nano 8, 3393–3401 (2014): https://doi.org/10.1021/nn405977t

Choi, J.-s. et al. J. Am. Chem. Soc. 132, 11015–11017 (2010): https://doi.org/10.1021/ja104503g

Lee, J.-H. et al. Nat. Med. 13, 95–99 (2007): https://doi.org/10.1038/nm1467

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Shin, TH., Kang, S., Park, S. et al. A magnetic resonance tuning sensor for the MRI detection of biological targets. Nat Protoc 13, 2664–2684 (2018). https://doi.org/10.1038/s41596-018-0057-y

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing