Letter | Published:

Implantable magnetic relaxation sensors measure cumulative exposure to cardiac biomarkers

Nature Biotechnology volume 29, pages 273277 (2011) | Download Citation

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

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

  2. 2.

    , & Unrecognized myocardial infarction. Ann. Intern. Med. 135, 801–811 (2001).

  3. 3.

    , , & Defining unrecognized myocardial infarction: a call for standardized electrocardiographic diagnostic criteria. Am. Heart J. 148, 277–284 (2004).

  4. 4.

    , , , & Dynamic imaging with MRI contrast agents: quantitative considerations. Magn. Reson. Imaging 24, 449–462 (2006).

  5. 5.

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

  6. 6.

    , , & Magnetic relaxation switch detection of human chorionic gonadotrophin. Bioconjug. Chem. 18, 2024–2028 (2007).

  7. 7.

    , , , & Multiparameter magnetic relaxation switch assays. Anal. Chem. 79, 8863–8869 (2007).

  8. 8.

    , , , & Magnetic relaxation switch immunosensors detect enantiomeric impurities. Angew. Chem. Int. Edn Engl. 43, 2395–2399 (2004).

  9. 9.

    , , , & Magnetic relaxation switches capable of sensing molecular interactions. Nat. Biotechnol. 20, 816–820 (2002).

  10. 10.

    , & Use of magnetic nanoparticles as nanosensors to probe for molecular interactions. ChemBioChem 5, 261–264 (2004).

  11. 11.

    , , , & 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).

  12. 12.

    , & Continuous analyte sensing with magnetic nanoswitches. Small 2, 1144–1147 (2006).

  13. 13.

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

  14. 14.

    , , & Magnetic sensors for protease assays. Angew. Chem. Int. Edn Engl. 42, 1375–1378 (2003).

  15. 15.

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

  16. 16.

    , & Biomarkers in acute cardiac disease: the present and the future. J. Am. Coll. Cardiol. 48, 1–11 (2006).

  17. 17.

    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).

  18. 18.

    , & Universal definition of myocardial infarction. J. Am. Coll. Cardiol. 50, 2173–2195 (2007).

  19. 19.

    , , & Infarct size assessment in mice. Echocardiography 24, 90–96 (2007).

  20. 20.

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

  21. 21.

    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).

  22. 22.

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

  23. 23.

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

  24. 24.

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

  25. 25.

    , , & High-efficiency intracellular magnetic labeling with novel superparamagnetic-Tat peptide conjugates. Bioconjug. Chem. 10, 186–191 (1999).

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

Author notes

    • Yibo Ling
    • , Terrence Pong
    •  & Christophoros C Vassiliou

    These authors contributed equally to this work.

Affiliations

  1. Harvard-MIT Division of Health Sciences & Technology, Cambridge, Massachusetts, USA.

    • Yibo Ling
    •  & Terrence Pong
  2. Department of Electrical Engineering & Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Yibo Ling
    •  & Christophoros C Vassiliou
  3. The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Yibo Ling
    • , Christophoros C Vassiliou
    •  & Michael J Cima
  4. Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Terrence Pong
    •  & Paul L Huang
  5. School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA.

    • Terrence Pong
  6. Cardiology Division, Harvard Medical School, Boston, Massachusetts, USA.

    • Paul L Huang
  7. Department of Materials Science & Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Michael J Cima

Authors

  1. Search for Yibo Ling in:

  2. Search for Terrence Pong in:

  3. Search for Christophoros C Vassiliou in:

  4. Search for Paul L Huang in:

  5. Search for Michael J Cima in:

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.

Competing interests

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

Corresponding author

Correspondence to Michael J Cima.

About this article

Publication history

Received

Accepted

Published

DOI

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