Molecular MR imaging of melanoma angiogenesis with α _νβ₃-targeted paramagnetic nanoparticles

Neovascularization is a critical component in the progression of malignant melanoma. The objective of this study was to determine whether α_νβ₃-targeted paramagnetic nanoparticles can detect and characterize sparse α_νβ integrin expression on neovasculature induced by nascent melanoma xenografts (∼30 mm ₃) at 1.5T. Athymic nude mice bearing human melanoma tumors were intravenously injected with α_νβ₃-integrin- targeted paramagnetic nanoparticles, nontargeted paramagnetic nanoparticles, or α_νβ₃-targeted nonparamagnetic nanoparticles 2 hr before they were injected with α_νβ₃- integrin-targeted paramagnetic nanoparticles (i.e., in vivo competitive blockade) and imaged with MRI. Contrast enhancement of neovascularity in animals that received α_νβ₃-targeted paramagnetic nanoparticles increased 173% by 120 min. Signal contrast with nontargeted paramagnetic nanoparticles was approximately 50% less than that in the targeted group (P < 0.05). Molecular MRI results were corroborated by histology. In a competitive cell adhesion assay, incubation of α_νβ ₃-expressing cells with targeted nanoparticles significantly inhibited binding to a vitronectin-coated surface, confirming the bioactivity of the targeted nanoparticles. The present study lowers the limit previously reported for detecting sparse biomarkers with molecular MRI in vivo. This technique may be employed to noninvasively detect very small regions of angiogenesis associated with nascent melanoma tumors, and to phenotype and stage early melanoma in a clinical setting.