title: Molecular MRI enables early and sensitive detection of brain metastases.
abstract: Metastasis to the brain is a leading cause of cancer mortality. The current diagnostic method of gadolinium-enhanced MRI is sensitive only to larger tumors, when therapeutic options are limited. Earlier detection of brain metastases is critical for improved treatment. We have developed a targeted MRI contrast agent based on microparticles of iron oxide that enables imaging of endothelial vascular cell adhesion molecule-1 (VCAM-1). Our objectives here were to determine whether VCAM-1 is up-regulated on vessels associated with brain metastases, and if so, whether VCAM-1-targeted MRI enables early detection of these tumors. Early up-regulation of cerebrovascular VCAM-1 expression was evident on tumor-associated vessels in two separate murine models of brain metastasis. Metastases were detectable in vivo using VCAM-1-targeted MRI 5 d after induction (<1,000 cells). At clinical imaging resolutions, this finding is likely to translate to detection at tumor volumes two to three orders of magnitude smaller (0.3-3 × 10(5) cells) than those volumes detectable clinically (10(7)-10(8) cells). VCAM-1 expression detected by MRI increased significantly (P < 0.0001) with tumor progression, and tumors showed no gadolinium enhancement. Importantly, expression of VCAM-1 was shown in human brain tissue containing both established metastases and micrometastases. Translation of this approach to the clinic could increase therapeutic options and change clinical management in a substantial number of cancer patients.
authors.affiliation: CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford OX3 7LJ,  United Kingdom.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Serres
authors.forename: Manuel Sarmiento
authors.initials: MS
authors.lastname: Soto
authors.forename: Alastair
authors.initials: A
authors.lastname: Hamilton
authors.forename: Martina A
authors.initials: MA
authors.lastname: McAteer
authors.forename: W Shawn
authors.initials: WS
authors.lastname: Carbonell
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Robson
authors.forename: Olaf
authors.initials: O
authors.lastname: Ansorge
authors.forename: Alexandre
authors.initials: A
authors.lastname: Khrapitchev
authors.forename: Claire
authors.initials: C
authors.lastname: Bristow
authors.forename: Lukxmi
authors.initials: L
authors.lastname: Balathasan
authors.forename: Thomas
authors.initials: T
authors.lastname: Weissensteiner
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Anthony
authors.forename: Robin P
authors.initials: RP
authors.lastname: Choudhury
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Muschel
authors.forename: Nicola R
authors.initials: NR
authors.lastname: Sibson
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000175:diagnosis / Q000378:metabolism / Q000556:secondary*; D018450:Disease Progression; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D012680:Sensitivity and Specificity; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D019010:Vascular Cell Adhesion Molecule-1