title: Molecular MR imaging of melanoma angiogenesis with alphanubeta3-targeted paramagnetic nanoparticles.
abstract: Neovascularization is a critical component in the progression of malignant melanoma. The objective of this study was to determine whether alpha(nu)beta(3)-targeted paramagnetic nanoparticles can detect and characterize sparse alpha(nu)beta integrin expression on neovasculature induced by nascent melanoma xenografts ( approximately 30 mm(3)) at 1.5T. Athymic nude mice bearing human melanoma tumors were intravenously injected with alpha(v)beta(3)-integrin-targeted paramagnetic nanoparticles, nontargeted paramagnetic nanoparticles, or alpha(v)beta(3)-targeted-nonparamagnetic nanoparticles 2 hr before they were injected with alpha(v)beta(3)-integrin-targeted paramagnetic nanoparticles (i.e., in vivo competitive blockade) and imaged with MRI. Contrast enhancement of neovascularity in animals that received alpha(nu)beta(3)-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 alpha(nu)beta(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.
authors.affiliation: Department of Biomedical Engineering, Washington University, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Anne H
authors.initials: AH
authors.lastname: Schmieder
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Winter
authors.forename: Shelton D
authors.initials: SD
authors.lastname: Caruthers
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Harris
authors.forename: Todd A
authors.initials: TA
authors.lastname: Williams
authors.forename: John S
authors.initials: JS
authors.lastname: Allen
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Lacy
authors.forename: Huiying
authors.initials: H
authors.lastname: Zhang
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Scott
authors.forename: Grace
authors.initials: G
authors.lastname: Hu
authors.forename: J David
authors.initials: JD
authors.lastname: Robertson
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Wickline
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Lanza
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D039302:Integrin alphaVbeta3 / Q000096:biosynthesis / Q000378:metabolism*; D018810:Magnetic Resonance Angiography; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D036103:Nanotechnology; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology*; D010316:Particle Size
chemical_list: D039302:Integrin alphaVbeta3