title: Tumor Targeting and Pharmacokinetics of a Near-Infrared Fluorescent-Labeled δ-Opioid Receptor Antagonist Agent, Dmt-Tic-Cy5.
abstract: Fluorescence molecular imaging can be employed for the development of novel cancer targeting agents. Herein, we investigated the pharmacokinetics (PK) and cellular uptake of Dmt-Tic-Cy5, a delta-opioid receptor (δOR) antagonist-fluorescent dye conjugate, as a tumor-targeting molecular imaging agent. δOR expression is observed normally in the CNS, and pathologically in some tumors, including lung liver and breast cancers. In vitro, in vivo, and ex vivo experiments were conducted to image and quantify the fluorescence signal associated with Dmt-Tic-Cy5 over time using in vitro and intravital fluorescence microscopy and small animal fluorescence imaging of tumor-bearing mice. We observed specific retention of Dmt-Tic-Cy5 in tumors with maximum uptake in δOR-expressing positive tumors at 3 h and observable persistence for >96 h; clearance from δOR nonexpressing negative tumors by 6 h; and systemic clearance from normal organs by 24 h. Live-cell and intravital fluorescence microscopy demonstrated that Dmt-Tic-Cy5 had sustained cell-surface binding lasting at least 24 h with gradual internalization over the initial 6 h following administration. Dmt-Tic-Cy5 is a δOR-targeted agent that exhibits long-lasting and specific signal in δOR-expressing tumors, is rapidly cleared from systemic circulation, and is not retained in non-δOR-expressing tissues. Hence, Dmt-Tic-Cy5 has potential as a fluorescent tumor imaging agent.
authors.forename: Amanda Shanks
authors.initials: AS
authors.lastname: Huynh
authors.forename: Veronica
authors.initials: V
authors.lastname: Estrella
authors.forename: Valerie E
authors.initials: VE
authors.lastname: Stark
authors.forename: Allison S
authors.initials: AS
authors.lastname: Cohen
authors.forename: Tingan
authors.initials: T
authors.lastname: Chen
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Casagni
authors.affiliation: Department of Chemistry, The University of Arizona , 1306 East University Boulevard, Tucson, Arizona 85719, United States.
authors.forename: Jatinder S
authors.initials: JS
authors.lastname: Josan
authors.forename: Mark C
authors.initials: MC
authors.lastname: Lloyd
authors.forename: Joseph
authors.initials: J
authors.lastname: Johnson
authors.forename: Jongphil
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Chemistry, The University of Arizona , 1306 East University Boulevard, Tucson, Arizona 85719, United States.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
authors.affiliation: The BIO5 Research Institute, University of Arizona , 1657 East Helen Street, Tucson, Arizona 85721, United States.
authors.forename: Josef
authors.initials: J
authors.lastname: Vagner
authors.forename: David L
authors.initials: DL
authors.lastname: Morse
mesh_terms: D000818:Animals; D017209:Apoptosis; D002232:Carbocyanines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004151:Dipeptides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D005456:Fluorescent Dyes / Q000737:chemistry*; D006801:Humans; D007124:Immunoenzyme Techniques; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017465:Receptors, Opioid, delta / Q000737:chemistry*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019265:Spectroscopy, Near-Infrared; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C446951:2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; D002232:Carbocyanines; D004151:Dipeptides; D005456:Fluorescent Dyes; D009292:Narcotic Antagonists; D012333:RNA, Messenger; D017465:Receptors, Opioid, delta; D044005:Tetrahydroisoquinolines; C085321:cyanine dye 5
keywords: biodistribution; cancer; cancer imaging; delta opioid receptor antagonist; dorsal window chamber; fluorescence imaging agent; intravital microscopy; live cell imaging; pharmacokinetics; tumor targeting; uptake