title: Investigation of a MMP-2 activity-dependent anchoring probe for nuclear imaging of cancer.
abstract: OBJECTIVE
  Since matrix metalloproteinase-2 (MMP-2) is an important marker of tumor malignancy, we developed an original drug design strategy, MMP-2 activity dependent anchoring probes (MDAP), for use in MMP-2 activity imaging, and evaluated the usefulness of this probe in in vitro and in vivo experiments.
  
  
  METHODS
  We designed and synthesized MDAP(1000), MDAP(3000), and MDAP(5000), which consist of 4 independent moieties: RI unit (111)In hydrophilic chelate), MMP-2 substrate unit (short peptide), anchoring unit (alkyl chain), and anchoring inhibition unit (polyethylene glycol (PEGn; where n represents the approximate molecular weight, n = 1000, 3000, and 5000). Probe cleavage was evaluated by chromatography after MMP-2 treatment. Cellular uptake of the probes was then measured. Radioactivity accumulation in tumor xenografts was evaluated after intravenous injection of the probes, and probe cleavage was evaluated in tumor homogenates.
  
  
  RESULTS
  MDAP(1000), MDAP(3000), and MDAP(5000) were cleaved by MMP-2 in a concentration-dependent manner. MDAP(3000) pretreated with MMP-2 showed higher accumulation in tumor cells, and was completely blocked by additional treatment with an MMP inhibitor. MDAP(3000) exhibited rapid blood clearance and a high tumor accumulation after intravenous injection in a rodent model. Furthermore, pharmacokinetic analysis revealed that MDAP(3000) exhibited a considerably slow washout rate from tumors to blood. A certain fraction of cleaved MDAP(3000) existed in tumor xenografts in vivo.
  
  
  CONCLUSIONS
  The results indicate the possible usefulness of our MDAP strategy for tumor imaging.
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Temma
authors.affiliation: Department of Molecular Imaging and Radiotherapy, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hanaoka
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Yonezawa
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Kondo
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan; Radioisotopes Research Laboratory, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Sano
authors.affiliation: Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Takeharu
authors.initials: T
authors.lastname: Sakamoto
authors.affiliation: Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Motoharu
authors.initials: M
authors.lastname: Seiki
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ono
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Saji
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000097:blood; D045744:Cell Line, Tumor; D003952:Diagnostic Imaging; D006801:Humans; D007275:Injections, Intravenous; D020778:Matrix Metalloproteinase 2 / Q000097:blood*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D009369:Neoplasms / Q000097:blood* / Q000235:genetics / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D061965:Matrix Metalloproteinase Inhibitors; D020778:Matrix Metalloproteinase 2