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Research Articles: Therapeutics, Targets, and Development

Integrin-targeted imaging and therapy with RGD4C-TNF fusion protein

Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, California

Requests for reprints: Xiaoyuan Chen, Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University School of Medicine, 1201 Welch Road, P095, Stanford, CA 94305-5484. Phone: 650-725-0950; Fax: 650-736-7925. E-mail: shawchen{at}stanford.edu

Abstract

This study used integrin _vβ₃ as a target for tumor-specific delivery of tumor necrosis factor- (TNF). The fusion protein RGD4C-TNF bound specifically to _vβ₃ as evidenced by cell receptor binding assay and noninvasive micro-positron emission tomography imaging. ⁶⁴Cu-DOTA-RGD4C-TNF had significantly higher activity accumulation in integrin-positive tumors (U87MG and MDA-MB-435) but not in integrin-negative tumors (C6) compared with ⁶⁴Cu-DOTA-TNF. The magnitude of tumor uptake of ⁶⁴Cu-DOTA-RGD4C-TNF correlated well with the _vβ₃ level (U87MG > MDA-MB-435 > C6). Tumor accumulation of ⁶⁴Cu-DOTA-RGD4C-TNF could be effectively blocked by c(RGDyK) peptide in _vβ₃-positive tumor models, suggesting _vβ₃ specificity of RGD4C-TNF fusion protein in vivo. Furthermore, although the fusion of RGD4C moiety to TNF had little effect on the bioactivity and cytotoxicity of RGD4C-TNF compared with TNF in cell culture, RGD4C-TNF was significantly more potent than TNF in inhibiting orthotopic MDA-MB-435 tumor growth. Ex vivo tissue staining confirmed specific cytotoxicity of RGD4C-TNF against integrin-positive tumor cells and tumor vasculature. [Mol Cancer Ther 2008;7(5):1044–53]

Grant support: National Cancer Institute grants R21 CA102123, R21 CA121842, P50 CA114747, R24 CA93862, and U54 CA119367 and Department of Defense grants W81XWH-04-1-0697, W81XWH-06-1-0665, W81XWH-06-1-0042, and W81XWH-07-1-0374.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 9/17/07; revised 1/18/08; accepted 2/ 4/08.