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

Abstract

This study used integrin alpha v beta3 as a target for tumor-specific delivery of tumor necrosis factor-alpha (TNF). The fusion protein RGD4C-TNF bound specifically to alpha v beta3 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 alpha v beta3 level (U87MG > MDA-MB-435 > C6). Tumor accumulation of 64Cu-DOTA-RGD4C-TNF could be effectively blocked by c(RGDyK) peptide in alpha v beta3-positive tumor models, suggesting alpha v beta3 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.

• Authors: Hui Wang, Kai Chen, Weibo Cai, Zibo Li, Lina He, Amir Kashefi, Xiaoyuan Chen
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 5 Pg. 1044-53 (May 2008) ISSN: 1535-7163 [Print] United States
• PMID: 18483294 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 64Cu-DOTA-RGD4C-TNF
• Antineoplastic Agents
• Chelating Agents
• Copper Radioisotopes
• Heterocyclic Compounds, 1-Ring
• Integrin alphaVbeta3
• Organometallic Compounds
• RGD4C-TNF fusion protein
• Recombinant Fusion Proteins
• Tumor Necrosis Factor-alpha
• 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Chelating Agents (pharmacology)
• Copper Radioisotopes (pharmacokinetics)
• Female
• Heterocyclic Compounds, 1-Ring (pharmacokinetics, pharmacology)
• Humans
• Integrin alphaVbeta3 (antagonists & inhibitors, genetics)
• Mice
• Organometallic Compounds (pharmacokinetics, pharmacology)
• Positron-Emission Tomography
• Recombinant Fusion Proteins (pharmacokinetics, pharmacology)
• Sensitivity and Specificity
• Tissue Distribution
• Tumor Necrosis Factor-alpha (pharmacokinetics, pharmacology)