title: alpha(v)beta(3) Integrin-targeting radionuclide therapy and imaging with monomeric RGD peptide.
abstract: The alpha(v)beta(3) integrin plays a pivotal role in angiogenesis and tumor metastasis. Angiogenic blood vessels overexpress alpha(v)beta(3) integrin, as in tumor neovascularization, and alpha(v)beta(3) integrin expression in other microvascular beds and organs is limited. Therefore, alpha(v)beta(3) integrin is a suitable receptor for tumor-targeting imaging and therapy. Recently, tetrameric and dimeric RGD peptides have been developed to enhance specificity to alpha(v)beta(3) integrin. In comparison to the corresponding monomeric peptide, however, these peptides show high levels of accumulation in kidney and liver. The purpose of this study is to evaluate tumor-targeting properties and the therapeutic potential of 111In- and 90Y-labeled monomeric RGD peptides in BALB/c nude mice with SKOV-3 human ovarian carcinoma tumors. DOTA-c(RGDfK) was labeled with 111In or 90Y and purified by HPLC. A biodistribution study and scintigraphic images revealed the specific uptake to alpha(v)beta(3) integrin and the rapid clearance from normal tissues. These peptides were renally excreted. At 10 min after injection of tracers, 111In-DOTA-c(RGDfK) and 90Y-DOTA-c(RGDfK) showed high uptake in tumors (7.3 +/- 0.6% ID/g and 4.6 +/- 0.8% ID/g, respectively) and gradually decreased over time (2.3 +/- 0.4% ID/g and 1.5 +/- 0.5% ID/g at 24 hr, respectively). High tumor-to-blood and -muscle ratios were obtained from these peptides. In radionuclide therapeutic study, multiple-dose administration of 90Y-DOTA-c(RGDfK) (3 x 11.1 MBq) suppressed tumor growth in comparison to the control group and a single-dose administration (11.1 MBq). Monomeric RGD peptides, 111In-DOTA-c(RGDfK) and (90)Y-DOTA-c(RGDfK), could be promising tracers for alpha(v)beta(3) integrin-targeting imaging and radiotherapy.
authors.affiliation: Division of Health Sciences, Graduate School of Medicine, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa, Japan. myoshi@mhs.mp.kanazawa-u.ac.jp
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Yoshimoto
authors.forename: Kazuma
authors.initials: K
authors.lastname: Ogawa
authors.forename: Kohshin
authors.initials: K
authors.lastname: Washiyama
authors.forename: Naoto
authors.initials: N
authors.lastname: Shikano
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Mori
authors.forename: Ryohei
authors.initials: R
authors.lastname: Amano
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kawai
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006573:Heterocyclic Compounds, 1-Ring / Q000494:pharmacology*; D006801:Humans; D007205:Indium Radioisotopes; D039302:Integrin alphaVbeta3 / Q000187:drug effects* / Q000378:metabolism; D007553:Isotope Labeling; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009842:Oligopeptides / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000532:radiotherapy*; D011487:Protein Conformation; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays; D015021:Yttrium Radioisotopes
chemical_list: D000970:Antineoplastic Agents; D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D019275:Radiopharmaceuticals; D015021:Yttrium Radioisotopes; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; C047981:arginyl-glycyl-aspartic acid