title: Development of PEGylated peptide probes conjugated with (18)F-labeled BODIPY for PET/optical imaging of MT1-MMP activity.
abstract: Since the processing activity of the matrix metalloproteinase MT1-MMP regulates various cellular functions such as motility, invasion, growth, differentiation and apoptosis, precise in vivo evaluation of MT1-MMP activity in cancers can provide beneficial information for both basic and clinical studies. For this purpose, we designed a cleavable Positron Emission Tomography (PET)/optical imaging probe consisting of BODIPY650/665 and polyethylene glycol (PEG) conjugated to opposite ends of MT1-MMP substrate peptides. We used in vitro and in vivo fluorescence experiments to select suitable substrate peptide sequences and PEG sizes for the MT1-MMP probes and obtained an optimized structure referred to here as MBP-2k. Radiofluorinated MBP-2k ([(18)F]MBP-2k) was then successfully synthesized via an (18)F-(19)F isotopic exchange reaction in BODIPY650/665. After intravenous injection into mice with xenografted tumors, [(18)F]MBP-2k showed significantly higher accumulation in HT1080 tumors with high MT1-MMP activity than in A549 tumors that have low MT1-MMP activity. Moreover, PET images showed better contrast in HT1080 tumors. These results show that [(18)F]MBP-2k can be used as a hybrid PET/optical imaging agent and is a promising probe for non-invasive monitoring of MT1-MMP activity in cancers. This probe may also efficiently combine targeted tumor imaging with image-guided surgery that could be beneficial for patients in the future.
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Kondo
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan; Department of Investigative Radiology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Temma
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Deguchi
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Sano
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ono
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: hsaji@pharm.kyoto-u.ac.jp.
authors.forename: Hideo
authors.initials: H
authors.lastname: Saji
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001896:Boron Compounds / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D005354:Fibrosarcoma / Q000000981:diagnostic imaging* / Q000201:enzymology / Q000473:pathology; D005456:Fluorescent Dyes / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D005462:Fluorine Radioisotopes / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D064593:Heterografts; D006801:Humans; D007275:Injections, Intravenous; D008175:Lung Neoplasms / Q000000981:diagnostic imaging* / Q000201:enzymology / Q000473:pathology; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D061848:Optical Imaging / Q000379:methods*; D010455:Peptides / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000138:chemical synthesis; D049268:Positron-Emission Tomography / Q000379:methods*; D011237:Predictive Value of Tests; D019275:Radiopharmaceuticals / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D013379:Substrate Specificity; D014018:Tissue Distribution
chemical_list: C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; D014408:Biomarkers, Tumor; D001896:Boron Compounds; D005456:Fluorescent Dyes; D005462:Fluorine Radioisotopes; D010455:Peptides; D019275:Radiopharmaceuticals; D011092:Polyethylene Glycols; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14
keywords: MT1-MMP; Optical imaging; Peptide; Polyethylene glycol (PEG); Positron emission tomography (PET)