title: Tumor targeting with radiolabeled alpha(v)beta(3) integrin binding peptides in a nude mouse model.
abstract: The alpha(v)beta(3) integrin is expressed on proliferating endothelial cells such as those present in growing tumors, as well as on tumor cells of various origin. Tumor-induced angiogenesis can be blocked in vivo by antagonizing the alpha(v)beta(3) integrin with small peptides containing the Arg-Gly-Asp (RGD) amino acid sequence. This tripeptidic sequence, naturally present in extracellular matrix proteins, is the primary binding site of the alpha(v)beta(3) integrin. Because of selective expression of alpha(v)beta(3) integrin in tumors, radiolabeled RGD peptides are attractive candidates for alpha(v)beta(3) integrin targeting in tumors. We studied the in vivo behavior of the radiolabeled dimeric RGD peptide E-[c(RGDfK)](2) in the NIH:OVCAR-3 s.c. ovarian carcinoma xenograft model in BALB/c nude mice. Conjugation of the 1,4,7,10-tetraazadodecane-N,N',N",N"'-tetraacetic acid (DOTA) and hydrazinonicotinamide (HYNIC) chelators enabled efficient radiolabeling with (111)In/(90)Y and (99m)Tc, respectively. The radiolabeled peptide was rapidly excreted renally. Uptake in nontarget organs such as liver and spleen was considerable. Tumor uptake peaked at 7.5% injected dose (ID)/g ((111)In-DOTA-E-[c(RGDfK)](2)) or 6.0%ID/g ((99m)Tc-HYNIC-E-[c(RGDfK)](2)) at 2 and 1 h postinjection, respectively. Integrin alpha(v)beta(3) receptor binding specificity was demonstrated by reduced tumor uptake after injection of the scrambled control peptide (111)In-DOTA-E-[c(RDKfD)](2) (0.28%ID/g at 2 h p.i.) and after coinjection of excess nonradioactive (115)In-DOTA-E-[c(RGDfK)](2) (0.22%ID/g at 2 h p.i.). A single injection of (90)Y-DOTA-E-[c(RGDfK)](2) at the maximum-tolerated dose (37 MBq) in mice with small s.c. tumors caused a significant growth delay as compared with mice treated with 37 MBq (90)Y-labeled scrambled peptide or untreated mice (median survival of 54 versus 33.5 versus 19 days, respectively). In conclusion, the radiolabeled RGD peptides (111)In-DOTA-E-[c(RGDfK)](2) and (99m)Tc-HYNIC-E-[c(RGDfK)](2) demonstrated high and specific tumor uptake in a human tumor xenograft. Injection of (90)Y-DOTA-E-[c(RGDfK)](2) induced a significant delay in tumor growth. Potentially, these peptides can be used for peptide receptor radionuclide imaging as well as therapy.
authors.affiliation: Department of Nuclear Medicine, University Medical Center Nijmegen, the Netherlands.
authors.forename: Marcel L
authors.initials: ML
authors.lastname: Janssen
authors.forename: Wim J
authors.initials: WJ
authors.lastname: Oyen
authors.forename: Ingrid
authors.initials: I
authors.lastname: Dijkgraaf
authors.forename: Leon F
authors.initials: LF
authors.lastname: Massuger
authors.forename: Cathelijne
authors.initials: C
authors.lastname: Frielink
authors.forename: D Scott
authors.initials: DS
authors.lastname: Edwards
authors.forename: Milind
authors.initials: M
authors.lastname: Rajopadhye
authors.forename: Henk
authors.initials: H
authors.lastname: Boonstra
authors.forename: Frans H
authors.initials: FH
authors.lastname: Corstens
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
mesh_terms: D000818:Animals; D005260:Female; D006801:Humans; D007205:Indium Radioisotopes / Q000627:therapeutic use*; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009842:Oligopeptides / Q000378:metabolism* / Q000493:pharmacokinetics; D010051:Ovarian Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000378:metabolism* / Q000493:pharmacokinetics; D013379:Substrate Specificity; D013667:Technetium / Q000627:therapeutic use*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D015021:Yttrium Radioisotopes / Q000627:therapeutic use*
chemical_list: D007205:Indium Radioisotopes; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D019275:Radiopharmaceuticals; D015021:Yttrium Radioisotopes; D013667:Technetium; C047981:arginyl-glycyl-aspartic acid