A32
Early detection of brain metastasis using novel MRI contrast agent targeting VCAM-1
Sebastien Serres, Martina McAteer, Lukxmi Balathasan, Thomas Weissensteiner, Shawn Carbonell, Daniel Anthony, Robin Choudhury, Ruth Muschel, Nicola Sibson
University of Oxford, UK
Background
Contrast-enhanced magnetic resonance imaging (MRI) is currently the most sensitive method for brain metastasis detection, but relies on blood-brain barrier (BBB) compromise and, consequently, is sensitive to late-stage metastases only. We have developed an MRI-detectable contrast agent targeted specifically at the endothelial adhesion molecule VCAM-1 (VCAM-MPIO) and have shown that this agent enables detection of endothelial activation early in brain pathology1. Based on our recent findings that brain metastases develop in close association with existing brain vessels2, we hypothesised that VCAM-1 is upregulated during metastasis development and that our VCAM-MPIO may enable early detection of brain metastases.
Method
Female balb/c mice were injected intracardially with 1x104 4T1 cells, a metastatic murine mammary carcinoma line. Ten days after 4T1 cell injection animals were anaesthetised and injected intravenously with either VCAM-MPIO or control IgG-MPIO (4 x 108; 4.5mg iron / kg body weight; n = 3 per group). After 1h animals underwent MRI at 7T and a T2*-weighted 3D gradient-echo dataset was acquired (acquisition ~1h; isotropic resolution m). Post-gadolinium Tm881-weighted images were acquired to assess BBB integrity.
Results
Immunohistochemically, upregulation of VCAM-1 was co-localised to brain metastases. In vivo MRI revealed focal areas of signal hypointensity throughout the brain, indicating VCAM-MPIO accumulation. Immunohistochemical analysis demonstrated co-localisation of the MRI hypointensities with metastases. Quantitatively, the volume of hypointensities in the VCAM-MPIO injected animals was 1.08mm3 greater than in IgG-MPIO-injected animals (i.e. Background). None of the animals showed BBB breakdown.
Conclusion
Upregulation of VCAM-1 during metastasis development enables earlier detection of metastases in the brain, using our novel VCAM-1-targeted contrast agent, than conventional clinical techniques. Early detection of brain metastases may significantly alter patient prognosis.
Acknowledgements
This work was funded by Cancer Research UK
References
[1] McAteer et al. (2007) Nature Medicine 13:1253-8.
[2] Carbonell et al. (2009) PLoS ONE (in press).
