title: Alpha v beta 3 integrin-targeting of intraperitoneally growing tumors with a radiolabeled RGD peptide.
abstract: Ovarian cancer is the fourth most common cause of cancer deaths among females in the western world after cancer of the breast, colon and lung. The inability to control the disease within the peritoneal cavity is the major cause of treatment failure in patients with ovarian cancer. The majority of ovarian carcinomas express the alpha(v)beta(3) integrin. Here we studied the tumor targeting potential of an (111)In-labeled cyclic RGD peptide in athymic BALB/c mice with intraperitoneally (i.p.) growing NIH:OVCAR-3 human ovarian carcinoma tumors. The cyclic RGD peptide, c(RGDfK)E, was synthesized, conjugated with DOTA and radiolabeled with (111)In. The targeting potential of (111)In-DOTA-E-c(RGDfK) was studied in athymic mice with i.p. growing NIH:OVCAR-3 xenografts and the optimal dose of this compound was determined (0.01 microg up to 10 microg). The biodistribution at optimal peptide dose was determined at various time points (0.5 up to 72 hr). Furthermore, the therapeutic potential of (177)Lu-DOTA-E-c(RGDfK) was studied in this model. Two hours after i.p. administration, (111)In-DOTA-E-c(RGDfK) showed high and specific uptake in the i.p. growing tumors. Optimal uptake in the i.p. growing tumors was observed at a 0.03-0.1 microg dose range. Tumor uptake of (111)In-DOTA-E-c(RGDfK) peaked 4 hr p.i. [(38.8 +/- 2.7)% ID/g], gradually decreasing at later time points [(24.0 +/- 4.1)% ID/g at 48 hr p.i.]. Intraperitoneal growth of OVCAR-3 could be significantly delayed by injecting 37 MBq (177)Lu-labeled peptide i.p. Radiolabeled DOTA-E-c(RGDfK) is suitable for targeting of i.p. growing tumors and potentially can be used for peptide receptor radionuclide therapy of these tumors.
authors.affiliation: Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. I.Dijkgraaf@nucmed.umcn.nl
authors.forename: Ingrid
authors.initials: I
authors.lastname: Dijkgraaf
authors.forename: John A W
authors.initials: JA
authors.lastname: Kruijtzer
authors.forename: Cathelijne
authors.initials: C
authors.lastname: Frielink
authors.forename: Frans H M
authors.initials: FH
authors.lastname: Corstens
authors.forename: Wim J G
authors.initials: WJ
authors.lastname: Oyen
authors.forename: Rob M J
authors.initials: RM
authors.lastname: Liskamp
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D006801:Humans; D007205:Indium Radioisotopes; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009842:Oligopeptides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D010534:Peritoneal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D019275:Radiopharmaceuticals / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D016019:Survival Analysis; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D019275:Radiopharmaceuticals; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; C047981:arginyl-glycyl-aspartic acid