Skip to main content

Thank you for visiting 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.

  • Technical Report
  • Published:

In vivo magnetic resonance imaging of acute brain inflammation using microparticles of iron oxide


Multiple sclerosis is a disease of the central nervous system that is associated with leukocyte recruitment and subsequent inflammation, demyelination and axonal loss. Endothelial vascular cell adhesion molecule-1 (VCAM-1) and its ligand, α4β1 integrin, are key mediators of leukocyte recruitment, and selective inhibitors that bind to the α4 subunit of α4β1 substantially reduce clinical relapse in multiple sclerosis. Urgently needed is a molecular imaging technique to accelerate diagnosis, to quantify disease activity and to guide specific therapy. Here we report in vivo detection of VCAM-1 in acute brain inflammation, by magnetic resonance imaging in a mouse model, at a time when pathology is otherwise undetectable. Antibody-conjugated microparticles carrying a large amount of iron oxide provide potent, quantifiable contrast effects that delineate the architecture of activated cerebral blood vessels. Their rapid clearance from blood results in minimal background contrast. This technology is adaptable to monitor the expression of endovascular molecules in vivo in various pathologies.

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

Access options

Buy this article

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

Figure 1: MPIO binding to cultured sEND-1 cells.
Figure 2: Flow cytometry.
Figure 3: In vivo T2*-weighted coronal images from 3D gradient echo data sets each with 90-μm isotropic resolution.
Figure 4: Three-dimensional volumetric maps of VCAM-MPIO binding and quantitative analyses of MPIO contrast effects.
Figure 5: Postmortem light micrographs of mouse brain.

Similar content being viewed by others


  1. Compston, A. & Coles, A. Multiple sclerosis. Lancet 359, 1221–1231 (2002).

    Article  Google Scholar 

  2. McDonald, W.I. et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Ann. Neurol. 50, 121–127 (2001).

    Article  CAS  Google Scholar 

  3. Polman, C.H. et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the 'McDonald Criteria'. Ann. Neurol. 58, 840–846 (2005).

    Article  Google Scholar 

  4. Goldberg-Zimring, D., Mewes, A.U.J., Maddah, M. & Warfield, S.K. Diffusion tensor magnetic resonance imaging in multiple sclerosis. J. Neuroimaging 15, 68S–81S (2005).

    Article  Google Scholar 

  5. Ropele, S. et al. A comparison of magnetization transfer ratio, magnetization transfer rate, and the native relaxation time of water protons related to relapsing-remitting multiple sclerosis. AJNR Am. J. Neuroradiol. 21, 1885–1891 (2000).

    CAS  PubMed  Google Scholar 

  6. Bitsch, A. et al. Inflammatory CNS demyelination: histopathologic correlation with in vivo quantitative proton MR spectroscopy. AJNR Am. J. Neuroradiol. 20, 1619–1627 (1999).

    CAS  PubMed  Google Scholar 

  7. Guttmann, C.R., Meier, D.S. & Holland, C.M. Can MRI reveal phenotypes of multiple sclerosis? Magn. Reson. Imaging 24, 475–481 (2006).

    Article  Google Scholar 

  8. Elices, M.J. et al. VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4/fibronectin binding site. Cell 60, 577–584 (1990).

    Article  CAS  Google Scholar 

  9. Carlos, T.M. et al. Vascular cell adhesion molecule-1 mediates lymphocyte adherence to cytokine-activated cultured human endothelial cells. Blood 76, 965–970 (1990).

    CAS  PubMed  Google Scholar 

  10. Yednock, T.A. et al. Prevention of experimental autoimmune encephalomyelitis by antibodies against α4β1 integrin. Nature 356, 63–66 (1992).

    Article  CAS  Google Scholar 

  11. Polman, C.H. et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 354, 899–910 (2006).

    Article  CAS  Google Scholar 

  12. Shapiro, E.M. et al. MRI detection of single particles for cellular imaging. Proc. Natl. Acad. Sci. USA 101, 10901–10906 (2004).

    Article  CAS  Google Scholar 

  13. Briley-Saebo, K. et al. Hepatic cellular distribution and degradation of iron oxide nanoparticles following single intravenous injection in rats: implications for magnetic resonance imaging. Cell Tissue Res. 316, 315–323 (2004).

    Article  CAS  Google Scholar 

  14. Cybulsky, M.I. et al. A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J. Clin. Invest. 107, 1255–1262 (2001).

    Article  CAS  Google Scholar 

  15. Nakashima, Y., Raines, E.W., Plump, A.S., Breslow, J.L. & Ross, R. Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in the ApoE-deficient mouse. Arterioscler. Thromb. Vasc. Biol. 18, 842–851 (1998).

    Article  CAS  Google Scholar 

  16. Orosz, C.G. et al. Role of the endothelial adhesion molecule VCAM in murine cardiac allograft rejection. Immunol. Lett. 32, 7–12 (1992).

    Article  CAS  Google Scholar 

  17. Maurer, C.A. et al. Over-expression of ICAM-1, VCAM-1 and ELAM-1 might influence tumor progression in colorectal cancer. Int. J. Cancer 79, 76–81 (1998).

    Article  CAS  Google Scholar 

  18. Dedrick, R.L., Bodary, S. & Garovoy, M.R. Adhesion molecules as therapeutic targets for autoimmune diseases and transplant rejection. Expert Opin. Biol. Ther. 3, 85–95 (2003).

    Article  CAS  Google Scholar 

  19. Gosk, S., Gottstein, C. & Bendas, G. Targeting of immunoliposomes to endothelial cells expressing VCAM: a future strategy in cancer therapy. Int. J. Clin. Pharmacol. Ther. 43, 581–582 (2005).

    Article  CAS  Google Scholar 

  20. Villanueva, F.S. et al. Microbubbles targeted to intercellular adhesion molecule-1 bind to activated coronary artery endothelial cells. Circulation 98, 1–5 (1998).

    Article  CAS  Google Scholar 

  21. Reinhardt, M. et al. Ultrasound derived imaging and quantification of cell adhesion molecules in experimental autoimmune encephalomyelitis (EAE) by Sensitive Particle Acoustic Quantification (SPAQ). Neuroimage 27, 267–278 (2005).

    Article  CAS  Google Scholar 

  22. Aime, S. et al. Insights into the use of paramagnetic Gd(III) complexes in MR-molecular imaging investigations. J. Magn. Reson. Imaging 16, 394–406 (2002).

    Article  Google Scholar 

  23. Sipkins, D.A. et al. ICAM-1 expression in autoimmune encephalitis visualized using magnetic resonance imaging. J. Neuroimmunol. 104, 1–9 (2000).

    Article  CAS  Google Scholar 

  24. Sibson, N.R. et al. MRI detection of early endothelial activation in brain inflammation. Magn. Reson. Med. 51, 248–252 (2004).

    Article  CAS  Google Scholar 

  25. Nahrendorf, M. et al. Noninvasive vascular cell adhesion molecule-1 imaging identifies inflammatory activation of cells in atherosclerosis. Circulation 114, 1504–1511 (2006).

    Article  CAS  Google Scholar 

  26. Sakhalkar, H.S. et al. Leukocyte-inspired biodegradable particles that selectively and avidly adhere to inflamed endothelium in vitro and in vivo. Proc. Natl. Acad. Sci. USA 100, 15895–15900 (2003).

    Article  CAS  Google Scholar 

  27. Chen, H.H. et al. MR imaging of biodegradable polymeric microparticles: a potential method of monitoring local drug delivery. Magn. Reson. Med. 53, 614–620 (2005).

    Article  CAS  Google Scholar 

  28. Will, O. et al. Diagnostic precision of nanoparticle-enhanced MRI for lymph-node metastases: a meta-analysis. Lancet Oncol. 7, 52–60 (2006).

    Article  Google Scholar 

Download references


We thank W. N. Haining for expertise in FACS analysis; T. Bannister for image analysis; D.R. Greaves for critical appraisal of the manuscript; and P. Townsend for overall laboratory management. This work was funded by the Wellcome Trust (R.P.C.) and the Medical Research Council (N.R.S. and D.C.A.).

Author information

Authors and Affiliations



R.P.C. and M.A.M. designed the contrast agent. M.A.M. manufactured the contrast agent and, in conjunction with N.W., K.M.C., C.v.z.M. and J.E.S., undertook the in vitro experiments. N.R.S., D.C.A., R.P.C. and M.A.M. designed the in vivo experiments. N.R.S., A.S.L. and D.C.A. conducted the MRI component, and C.v.z.M. and D.C.A. undertook histological analysis. R.P.C. supervised image analysis and analyzed the data. M.A.M., N.R.S. and R.P.C. contributed to the writing of the manuscript, and all authors discussed and refined the manuscript.

Note: Supplementary information is available on the Nature Medicine website.

Corresponding author

Correspondence to Robin P Choudhury.

Ethics declarations

Competing interests

D.C.A. and N.R.S. have filed a patent application related to the use of biodegradable microparticles of iron oxide (MPIOs). R.P.C. is a named contributor on the patent.

Supplementary information

Supplementary Text and Figures

Supplementary Methods (PDF 87 kb)

Supplementary Video 1

Serial in vivo T2*-weighted coronal images of mouse brain taken from a 3D gradient echo data set with 90 μmm isotropic resolution. This mouse received intrastriatal injection of 1 ng IL-1β in 1 μl saline 3 h prior to intravenous injection of VCAM+P-selectin-MPIO (4.5 mg iron per kg body weight). Intense low signal areas (i.e. black) on the left side of the brain reflect the specific retention of MPIO on acutely activated vascular endothelium with virtually absent contrast effect in the contra-lateral control hemisphere. (MOV 1521 kb)

Supplementary Video 2

Serial in vivo T2*-weighted coronal images of mouse brain taken from a 3D gradient echo data set with 90 μm isotropic resolution. This mouse also received intrastriatal injection of 1 ng IL-1β in 1 μl saline but pre-treatment with VCAM-1 antibody prior to VCAM-MPIO abolished MPIO retention in the injected hemisphere. (MOV 1296 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

McAteer, M., Sibson, N., von zur Muhlen, C. et al. In vivo magnetic resonance imaging of acute brain inflammation using microparticles of iron oxide. Nat Med 13, 1253–1258 (2007).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


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