title: Synthesis and evaluation of near-infrared fluorescent sulfonamide derivatives for imaging of hypoxia-induced carbonic anhydrase IX expression in tumors.
abstract: A series of human carbonic anhydrase (hCA) IX inhibitors conjugated to various near-infrared fluorescent dyes was synthesized with the aim of imaging hypoxia-induced hCA IX expression in tumor cells in vitro, ex vivo and in vivo. The resulting compounds were profiled for inhibition of transmembrane hCA IX showing a range of potencies from 7.5 to 116 nM and up to 50-fold selectivity over the cytosolic form hCA II. Some of the compounds also showed inhibition selectivity for other transmembrane forms hCA XII and XIV as well. Compounds incubated in vitro with HeLa cells cultured under normoxic and hypoxic conditions detected upregulation of hCA IX under hypoxia by fluorescence microscopy. A pilot in vivo study in HT-29 tumor bearing mice showed significant accumulation of a fluorescent acetazolamide derivative in tumor tissue with little accumulation in other tissues. Approximately 10% of injected dose was non-invasively quantified in tumors by fluorescence molecular tomography (FMT), demonstrating the promise of these new compounds for quantitative imaging of hCA IX upregulation in live animals.
authors.affiliation: PerkinElmer, 549 Albany St., Boston, MA 02118, United States. kevin.groves@perkinelmer.com
authors.forename: Kevin
authors.initials: K
authors.lastname: Groves
authors.forename: Bagna
authors.initials: B
authors.lastname: Bao
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Emma
authors.initials: E
authors.lastname: Handy
authors.forename: Paul
authors.initials: P
authors.lastname: Kennedy
authors.forename: Garry
authors.initials: G
authors.lastname: Cuneo
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Wael
authors.initials: W
authors.lastname: Yared
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Peterson
authors.forename: Milind
authors.initials: M
authors.lastname: Rajopadhye
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005456:Fluorescent Dyes / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells; D006801:Humans; D000860:Hypoxia; D007700:Kinetics; D051379:Mice; D008856:Microscopy, Fluorescence / Q000379:methods; D008956:Models, Chemical; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D013449:Sulfonamides / Q000494:pharmacology*; D014057:Tomography, X-Ray Computed / Q000379:methods; D015854:Up-Regulation
chemical_list: D000951:Antigens, Neoplasm; D005456:Fluorescent Dyes; D013449:Sulfonamides; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases