title: Near-infrared fluorescence imaging of both colorectal cancer and ureters using a low-dose integrin targeted probe.
abstract: BACKGROUND
  Irradical tumor resections and iatrogenic ureteral injury remain a significant problem during lower abdominal surgery. The aim of the current study was to intraoperatively identify both colorectal tumors and ureters in subcutaneous and orthotopic animal models using cRGD-ZW800-1 and near-infrared (NIR) fluorescence.
  
  
  METHODS
  The zwitterionic fluorophore ZW800-1 was conjugated to the tumor specific peptide cRGD (targeting integrins) and to the a-specific peptide cRAD. One nmol cRGD-ZW800-1, cRAD-ZW800-1, or ZW800-1 alone was injected in mice bearing subcutaneous HT-29 human colorectal tumors. Subsequently, cRGD-ZW800-1 was injected at dosages of 0.25 and 1 nmol in mice bearing orthotopic HT-29 tumors transfected with luciferase2. In vivo biodistribution and ureteral visualization were investigated in rats. Fluorescence was measured intraoperatively at several time points after probe administration using the FLARE imaging system.
  
  
  RESULTS
  Both subcutaneous and orthotopic tumors could be clearly identified using cRGD-ZW800-1. A significantly higher signal-to-background ratio was observed in mice injected with cRGD-ZW800-1 (2.42 ± 0.77) compared with mice injected with cRAD-ZW800-1 or ZW800-1 alone (1.21 ± 0.19 and 1.34 ± 0.19, respectively) when measured at 24 h after probe administration. The clearance of cRGD-ZW800-1 permitted visualization of the ureters and also generated minimal background fluorescence in the gastrointestinal tract.
  
  
  CONCLUSIONS
  This study appears to be the first to demonstrate both clear tumor demarcation and ureteral visualization after a single intravenous injection of a targeted NIR fluorophore. As a low dose of cRGD-ZW800-1 provided clear tumor identification, clinical translation of these results should be possible.
authors: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors: Floris P R
authors: FP
authors: Verbeek
authors: Joost R
authors: JR
authors: van der Vorst
authors: Quirijn R J G
authors: QR
authors: Tummers
authors: Martin C
authors: MC
authors: Boonstra
authors: Karien E
authors: KE
authors: de Rooij
authors: Clemens W G M
authors: CW
authors: Löwik
authors: A Rob P M
authors: AR
authors: Valentijn
authors: Cornelis J H
authors: CJ
authors: van de Velde
authors: Hak Soo
authors: HS
authors: Choi
authors: John V
authors: JV
authors: Frangioni
authors: Alexander L
authors: AL
authors: Vahrmeijer
mesh_terms: D000818:Animals; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000601:surgery; D005260:Female; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000493:pharmacokinetics; D019073:HT29 Cells; D006801:Humans; D016023:Integrins; D007432:Intraoperative Period; D051379:Mice; D009368:Neoplasm Transplantation; D061848:Optical Imaging / Q000379:methods*; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000493:pharmacokinetics; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics; D013451:Sulfonic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics; D014513:Ureter
chemical_list: D005456:Fluorescent Dyes; D016023:Integrins; D010456:Peptides, Cyclic; D000644:Quaternary Ammonium Compounds; D013451:Sulfonic Acids; C562069:ZW800-1 compound; C507169:cyclic arginine-glycine-aspartic acid peptide