VCAM-1-targeted MRI Enables Detection of Brain Micrometastases from Different Primary Tumors.

ABSTRACT

PURPOSE: A major issue for the effective treatment of brain metastasis is the late stage of diagnosis with existing clinical tools. The aim of this study was to evaluate the potential of vascular cell adhesion molecule 1 (VCAM-1)-targeted MRI for early detection of brain micrometastases in mouse models across multiple primary tumor types.Experimental Design: Xenograft models of brain micrometastasis for human breast carcinoma (MDA231Br-GFP), lung adenocarcinoma (SEBTA-001), and melanoma (H1_DL2) were established via intracardiac injection in mice. Animals (n = 5-6/group) were injected intravenously with VCAM-1-targeted microparticles of iron oxide (VCAM-MPIO) and, subsequently, underwent T 2*-weighted MRI. Control groups of naïve mice injected with VCAM-MPIO and tumor-bearing mice injected with nontargeting IgG-MPIO were included. RESULTS: All models showed disseminated micrometastases in the brain, together with endothelial VCAM-1 upregulation across the time course. T 2*-weighted MRI of all tumor-bearing mice injected with VCAM-MPIO showed significantly more signal hypointensities (P < 0.001; two-sided) than control cohorts, despite a lack of blood-brain barrier (BBB) impairment. Specific MPIO binding to VCAM-1-positive tumor-associated vessels was confirmed histologically. VCAM-1 expression was demonstrated in human brain metastasis samples, across all three primary tumor types. CONCLUSIONS: VCAM-1-targeted MRI enables the detection of brain micrometastases from the three primary tumor types known to cause the majority of clinical cases. These findings represent an important step forward in the development of a broadly applicable and clinically relevant imaging technique for early diagnosis of brain metastasis, with significant implications for improved patient survival.