title: 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.affiliation: 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, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Kai
authors.initials: K
authors.lastname: Chen
authors.forename: Weibo
authors.initials: W
authors.lastname: Cai
authors.forename: Zibo
authors.initials: Z
authors.lastname: Li
authors.forename: Lina
authors.initials: L
authors.lastname: He
authors.forename: Amir
authors.initials: A
authors.lastname: Kashefi
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000494:pharmacology; D003301:Copper Radioisotopes / Q000493:pharmacokinetics; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000235:genetics; D051379:Mice; D009942:Organometallic Compounds / Q000493:pharmacokinetics / Q000494:pharmacology; D049268:Positron-Emission Tomography; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C530800:64Cu-DOTA-RGD4C-TNF; D000970:Antineoplastic Agents; D002614:Chelating Agents; D003301:Copper Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D039302:Integrin alphaVbeta3; D009942:Organometallic Compounds; C530799:RGD4C-TNF fusion protein; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid