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[Cancer Research 64, 8009-8014, November 1, 2004]
© 2004 American Association for Cancer Research

Regular Articles

In vivo Near-Infrared Fluorescence Imaging of Integrin {alpha}vß3 in Brain Tumor Xenografts

Xiaoyuan Chen1,2, Peter S. Conti1 and Rex A. Moats3

1 PET Imaging Science Center, University of Southern California Keck School of Medicine, Los Angeles, California; 2 Molecular Imaging Program at Stanford, Stanford University, Stanford, California; and 3 Departments of Pediatrics, Radiology, and Pathology, Children’s Hospital Los Angeles, Los Angeles, California

Noninvasive visualization of cell adhesion molecule {alpha}vß3 integrin expression in vivo has been well studied by using the radionuclide imaging modalities in various preclinical tumor models. A literature survey indicated no previous use of cyanine dyes as contrast agents for in vivo optical detection of tumor integrin. Herein, we report the integrin receptor specificity of novel peptide-dye conjugate arginine-glycine-aspartic acid (RGD)-Cy5.5 as a contrast agent in vitro, in vivo, and ex vivo. The RGD-Cy5.5 exhibited intermediate affinity for {alpha}vß3 integrin (IC50 = 58.1 ± 5.6 nmol/L). The conjugate led to elevated cell-associated fluorescence on integrin-expressing tumor cells and endothelial cells and produced minimal cell fluorescence when coincubated with c(RGDyK). In vivo imaging with a prototype three-dimensional small-animal imaging system visualized subcutaneous U87MG glioblastoma xenograft with a broad range of concentrations of fluorescent probe administered via the tail vein. The intermediate dose (0.5 nmol) produces better tumor contrast than high dose (3 nmol) and low dose (0.1 nmol) during 30 minutes to 24 hours postinjection, because of partial self-inhibition of receptor-specific tumor uptake at high dose and the presence of significant amount of background fluorescence at low dose, respectively. The tumor contrast was also dependent on the mouse viewing angles. Tumor uptake of RGD-Cy5.5 was blocked by unlabeled c(RGDyK). This study suggests that the combination of the specificity of RGD peptide/integrin interaction with near-infrared fluorescence detection may be applied to noninvasive imaging of integrin expression and monitoring anti-integrin treatment efficacy providing near real-time measurements.




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Copyright © 2004 by the American Association for Cancer Research.