title: Selective visualization of cyclooxygenase-2 in inflammation and cancer by targeted fluorescent imaging agents.
abstract: Effective diagnosis of inflammation and cancer by molecular imaging is challenging because of interference from nonselective accumulation of the contrast agents in normal tissues. Here, we report a series of novel fluorescence imaging agents that efficiently target cyclooxygenase-2 (COX-2), which is normally absent from cells, but is found at high levels in inflammatory lesions and in many premalignant and malignant tumors. After either i.p. or i.v. injection, these reagents become highly enriched in inflamed or tumor tissue compared with normal tissue and this accumulation provides sufficient signal for in vivo fluorescence imaging. Further, we show that only the intact parent compound is found in the region of interest. COX-2-specific delivery was unambiguously confirmed using animals bearing targeted deletions of COX-2 and by blocking the COX-2 active site with high-affinity inhibitors in both in vitro and in vivo models. Because of their high specificity, contrast, and detectability, these fluorocoxibs are ideal candidates for detection of inflammatory lesions or early-stage COX-2-expressing human cancers, such as those in the esophagus, oropharynx, and colon.
authors.affiliation: AB Hancock, Jr Memorial Laboratory for Cancer Research, Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.
authors.forename: Md Jashim
authors.initials: MJ
authors.lastname: Uddin
authors.forename: Brenda C
authors.initials: BC
authors.lastname: Crews
authors.forename: Anna L
authors.initials: AL
authors.lastname: Blobaum
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Kingsley
authors.forename: D Lee
authors.initials: DL
authors.lastname: Gorden
authors.forename: J Oliver
authors.initials: JO
authors.lastname: McIntyre
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Matrisian
authors.forename: Kotha
authors.initials: K
authors.lastname: Subbaramaiah
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dannenberg
authors.forename: David W
authors.initials: DW
authors.lastname: Piston
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Marnett
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology; D002351:Carrageenan; D015179:Colorectal Neoplasms / Q000201:enzymology; D051546:Cyclooxygenase 2 / Q000032:analysis*; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005260:Female; D005456:Fluorescent Dyes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045325:HCT116 Cells; D006258:Head and Neck Neoplasms / Q000201:enzymology; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology; D008264:Macrophages / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D018613:Microscopy, Confocal / Q000379:methods; D057054:Molecular Imaging / Q000379:methods*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D005456:Fluorescent Dyes; D002351:Carrageenan; D051546:Cyclooxygenase 2