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.

  • Letter
  • Published:

Implantable magnetic relaxation sensors measure cumulative exposure to cardiac biomarkers

Abstract

Molecular biomarkers can be used as objective indicators of pathologic processes. Although their levels often change over time, their measurement is often constrained to a single time point. Cumulative biomarker exposure would provide a fundamentally different kind of measurement to what is available in the clinic. Magnetic resonance relaxometry can be used to noninvasively monitor changes in the relaxation properties of antibody-coated magnetic particles when they aggregate upon exposure to a biomarker of interest. We used implantable devices containing such sensors to continuously profile changes in three clinically relevant cardiac biomarkers at physiological levels for up to 72 h. Sensor response differed between experimental and control groups in a mouse model of myocardial infarction and correlated with infarct size. Our prototype for a biomarker monitoring device also detected doxorubicin-induced cardiotoxicity and can be adapted to detect other molecular biomarkers with a sensitivity as low as the pg/ml range.

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

Figure 1: Evidence of cardiac biomarker extravasation from serum to the subcutaneous space.
Figure 2: Use of functionalized MRSw particles, encapsulated within discrete sensors and calibrated in vitro, to measure cumulative exposure to analyte in vitro.
Figure 3: Sensor response differs markedly between MI and sham/control groups, and its magnitude correlates with the extent of infarction.
Figure 4: An implanted MRSw sensor device can detect the cardiotoxic effect of the chemotherapeutic drug doxorubicin in vivo.

Similar content being viewed by others

References

  1. Gutterman, D.D. Silent myocardial ischemia. Circ. J. 73, 785–797 (2009).

    Article  Google Scholar 

  2. Sheifer, S.E., Manolio, T.A. & Gersh, B.J. Unrecognized myocardial infarction. Ann. Intern. Med. 135, 801–811 (2001).

    Article  CAS  Google Scholar 

  3. Ammar, K.A., Kors, J.A., Yawn, B.P. & Rodeheffer, R.J. Defining unrecognized myocardial infarction: a call for standardized electrocardiographic diagnostic criteria. Am. Heart J. 148, 277–284 (2004).

    Article  Google Scholar 

  4. Shapiro, M.G., Atanasijevic, T., Faas, H., Westmeyer, G.G. & Jasanoff, A. Dynamic imaging with MRI contrast agents: quantitative considerations. Magn. Reson. Imaging 24, 449–462 (2006).

    Article  CAS  Google Scholar 

  5. Daniel, K.D. et al. Multi-reservoir device for detecting a soluble cancer biomarker. Lab Chip 7, 1288–1293 (2007).

    Article  CAS  Google Scholar 

  6. Kim, G.Y., Josephson, L., Langer, R. & Cima, M.J. Magnetic relaxation switch detection of human chorionic gonadotrophin. Bioconjug. Chem. 18, 2024–2028 (2007).

    Article  CAS  Google Scholar 

  7. Taktak, S., Sosnovik, D., Cima, M.J., Weissleder, R. & Josephson, L. Multiparameter magnetic relaxation switch assays. Anal. Chem. 79, 8863–8869 (2007).

    Article  CAS  Google Scholar 

  8. Tsourkas, A., Hofstetter, O., Hofstetter, H., Weissleder, R. & Josephson, L. Magnetic relaxation switch immunosensors detect enantiomeric impurities. Angew. Chem. Int. Edn Engl. 43, 2395–2399 (2004).

    Article  CAS  Google Scholar 

  9. Perez, J.M., Josephson, L., O'Loughlin, T., Hogemann, D. & Weissleder, R. Magnetic relaxation switches capable of sensing molecular interactions. Nat. Biotechnol. 20, 816–820 (2002).

    Article  CAS  Google Scholar 

  10. Perez, J.M., Josephson, L. & Weissleder, R. Use of magnetic nanoparticles as nanosensors to probe for molecular interactions. ChemBioChem 5, 261–264 (2004).

    Article  CAS  Google Scholar 

  11. Perez, J.M., O'Loughin, T., Simeone, F.J., Weissleder, R. & Josephson, L. DNA-based magnetic nanoparticle assembly acts as a magnetic relaxation nanoswitch allowing screening of DNA-cleaving agents. J. Am. Chem. Soc. 124, 2856–2857 (2002).

    Article  CAS  Google Scholar 

  12. Sun, E.Y., Weissleder, R. & Josephson, L. Continuous analyte sensing with magnetic nanoswitches. Small 2, 1144–1147 (2006).

    Article  CAS  Google Scholar 

  13. Wunderbaldinger, P., Josephson, L. & Weissleder, R. Crosslinked iron oxides (CLIO): a new platform for the development of targeted MR contrast agents. Acad. Radiol. 9 Suppl 2, S304–S306 (2002).

    Article  Google Scholar 

  14. Zhao, M., Josephson, L., Tang, Y. & Weissleder, R. Magnetic sensors for protease assays. Angew. Chem. Int. Edn Engl. 42, 1375–1378 (2003).

    Article  CAS  Google Scholar 

  15. Daniel, K.D. et al. Implantable diagnostic device for cancer monitoring. Biosens. Bioelectron. 24, 3252–3257 (2009).

    Article  CAS  Google Scholar 

  16. Jaffe, A.S., Babuin, L. & Apple, F.S. Biomarkers in acute cardiac disease: the present and the future. J. Am. Coll. Cardiol. 48, 1–11 (2006).

    Article  CAS  Google Scholar 

  17. Tarnavski, O. et al. Mouse cardiac surgery: comprehensive techniques for the generation of mouse models of human diseases and their application for genomic studies. Physiol. Genomics 16, 349–360 (2004).

    Article  CAS  Google Scholar 

  18. Thygesen, K., Alpert, J.S. & White, H.D. Universal definition of myocardial infarction. J. Am. Coll. Cardiol. 50, 2173–2195 (2007).

    Article  Google Scholar 

  19. Scherrer-Crosbie, M., Rodrigues, A.C.T., Hataishi, R. & Picard, M.H. Infarct size assessment in mice. Echocardiography 24, 90–96 (2007).

    Article  Google Scholar 

  20. Bello, D. et al. Infarct morphology identifies patients with substrate for sustained ventricular tachycardia. J. Am. Coll. Cardiol. 45, 1104–1108 (2005).

    Article  Google Scholar 

  21. Roes, S.D. et al. Comparison of myocardial infarct size assessed with contrast-enhanced magnetic resonance imaging and left ventricular function and volumes to predict mortality in patients with healed myocardial infarction. Am. J. Cardiol. 100, 930–936 (2007).

    Article  Google Scholar 

  22. Takemura, G. & Fujiwara, H. Doxorubicin-induced cardiomyopathy: from the cardiotoxic mechanisms to management. Prog. Cardiovasc. Dis. 49, 330–352 (2007).

    Article  CAS  Google Scholar 

  23. Robert, J. Long-term and short-term models for studying anthracycline cardiotoxicity and protectors. Cardiovasc. Toxicol. 7, 135–139 (2007).

    Article  CAS  Google Scholar 

  24. Wallace, K.B. et al. Serum troponins as biomarkers of drug-induced cardiac toxicity. Toxicol. Pathol. 32, 106–121 (2004).

    Article  CAS  Google Scholar 

  25. Josephson, L., Tung, C.H., Moore, A. & Weissleder, R. High-efficiency intracellular magnetic labeling with novel superparamagnetic-Tat peptide conjugates. Bioconjug. Chem. 10, 186–191 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by National Cancer Institute Centers of Cancer Nanotechnology Excellence no. 5 U54 CA119349-12 and CA151844 grants and National Science Foundation Division of Materials Research Award no. 0746264. Y.L. was supported by a National Defense Science and Engineering Graduate fellowship. T.P. was supported by an American Heart Association fellowship.

Author information

Authors and Affiliations

Authors

Contributions

Y.L. initiated the project, designed and performed experiments, analyzed data and wrote the manuscript. T.P. conceived experiments, designed and performed animal experiments, analyzed data and wrote the manuscript. C.C.V. contributed ideas, performed experiments, analyzed data and wrote the manuscript. P.L.H. contributed to the design experiments related to clinical relevance, doxorubicin toxicity and myocardial infarction model. M.J.C. was the principal investigator; he initiated the project, conceived experiments and obtained funding.

Corresponding author

Correspondence to Michael J Cima.

Ethics declarations

Competing interests

M.J.C. is a director at T2 Biosystems, a company developing in vitro diagnostic assays.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ling, Y., Pong, T., Vassiliou, C. et al. Implantable magnetic relaxation sensors measure cumulative exposure to cardiac biomarkers. Nat Biotechnol 29, 273–277 (2011). https://doi.org/10.1038/nbt.1780

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nbt.1780

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