title: Fluorocoxib A loaded nanoparticles enable targeted visualization of cyclooxygenase-2 in inflammation and cancer.
abstract: Cyclooxygenase-2 (COX-2) is expressed in virtually all solid tumors and its overexpression is a hallmark of inflammation. Thus, it is a potentially powerful biomarker for the early clinical detection of inflammatory disease and human cancers. We report a reactive oxygen species (ROS) responsive micellar nanoparticle, PPS-b-POEGA, that solubilizes the first fluorescent COX-2-selective inhibitor fluorocoxib A (FA) for COX-2 visualization in vivo. Pharmacokinetics and biodistribution of FA-PPS-b-POEGA nanoparticles (FA-NPs) were assessed after a fully-aqueous intravenous (i.v.) administration in wild-type mice and revealed 4-8 h post-injection as an optimal fluorescent imaging window. Carrageenan-induced inflammation in the rat and mouse footpads and 1483 HNSCC tumor xenografts were successfully visualized by FA-NPs with fluorescence up to 10-fold higher than that of normal tissues. The targeted binding of the FA cargo was blocked by pretreatment with the COX-2 inhibitor indomethacin, confirming COX-2-specific binding and local retention of FA at pathological sites. Our collective data indicate that FA-NPs are the first i.v.-ready FA formulation, provide high signal-to-noise in inflamed, premalignant, and malignant tissues, and will uniquely enable clinical translation of the poorly water-soluble FA compound.
authors.affiliation: A. B. Hancock, Jr. Memorial Laboratory for Cancer Research, Department of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Md Jashim
authors.initials: MJ
authors.lastname: Uddin
authors.affiliation: Department of Biomedical Engineering, Vanderbilt Institute for Nanoscale Science and Engineering, Vanderbilt University School of Engineering, Nashville, TN 37232, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Werfel
authors.affiliation: A. B. Hancock, Jr. Memorial Laboratory for Cancer Research, Department of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Brenda C
authors.initials: BC
authors.lastname: Crews
authors.affiliation: Department of Biomedical Engineering, Vanderbilt Institute for Nanoscale Science and Engineering, Vanderbilt University School of Engineering, Nashville, TN 37232, USA.
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Gupta
authors.affiliation: Department of Biomedical Engineering, Vanderbilt Institute for Nanoscale Science and Engineering, Vanderbilt University School of Engineering, Nashville, TN 37232, USA.
authors.forename: Taylor E
authors.initials: TE
authors.lastname: Kavanaugh
authors.affiliation: A. B. Hancock, Jr. Memorial Laboratory for Cancer Research, Department of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Kingsley
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Kelli
authors.initials: K
authors.lastname: Boyd
authors.affiliation: A. B. Hancock, Jr. Memorial Laboratory for Cancer Research, Department of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: larry.marnett@vanderbilt.edu.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Marnett
authors.affiliation: Department of Biomedical Engineering, Vanderbilt Institute for Nanoscale Science and Engineering, Vanderbilt University School of Engineering, Nashville, TN 37232, USA. Electronic address: craig.duvall@vanderbilt.edu.
authors.forename: Craig L
authors.initials: CL
authors.lastname: Duvall
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D000067493:Dynamic Light Scattering; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D007249:Inflammation / Q000201:enzymology*; D007274:Injections, Intraperitoneal; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D057054:Molecular Imaging; D053758:Nanoparticles / Q000737:chemistry* / Q000633:toxicity / Q000648:ultrastructure; D009369:Neoplasms / Q000201:enzymology*; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry; D012235:Rhodamines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D007211:Indoles; D011108:Polymers; D012235:Rhodamines; C579286:fluorocoxib A; D051546:Cyclooxygenase 2
keywords: COX-2; Cancer; Inflammation; Molecular imaging; Nanoparticles; Reactive oxygen species