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

Abstract

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.

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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.

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Acknowledgements

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.).

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Authors and Affiliations

Authors

Contributions

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.

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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)

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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). https://doi.org/10.1038/nm1631

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