title: Irinophore C, a novel nanoformulation of irinotecan, alters tumor vascular function and enhances the distribution of 5-fluorouracil and doxorubicin.
abstract: OBJECTIVE
  To examine the antitumor effects of Irinophore C, a nanopharmaceutical formulation of irinotecan, on the tissue morphology and function of tumor vasculature in HT-29 human colorectal tumors.
  
  
  METHODS
  Fluorescence microscopy was used to map and quantify changes in tissue density, tumor vasculature, hypoxia, and the distribution of Hoechst 33342, a perfusion marker, and the anticancer drug, doxorubicin. Noninvasive magnetic resonance imaging was used to quantify Ktrans, the volume transfer constant of a solute between the blood vessels and extracellular tissue compartment of the tumor, as a measure of vascular function. Following treatment with Irinophore C, 19F magnetic resonance spectroscopy was used to monitor the delivery of 5-fluorouracil (5-FU) to the tumor tissue, whereas scintigraphy was used to quantify the presence of bound [14C]5-FU.
  
  
  RESULTS
  Irinophore C decreased cell density (P = 8.42 x 10(-5)), the overall number of endothelial cells in the entire section (P = 0.014), tumor hypoxia (P = 5.32 x 10(-9)), and K(trans) (P = 0.050). However, treatment increased the ratio of endothelial cells to cell density (P = 0.00024) and the accumulation of Hoechst 33342 (P = 0.022), doxorubicin (P = 0.243 x 10(-5)), and 5-FU (P = 0.0002) in the tumor. Vascular endothelial growth factor and interleukin-8, two proangiogenic factors, were down-regulated, whereas the antiangiogenic factor TIMP-1 was up-regulated in Irinophore C-treated tumors.
  
  
  CONCLUSIONS
  Irinophore C treatment improves the vascular function of the tumor, thereby reducing tumor hypoxia and increasing the delivery and accumulation of a second drug. Reducing hypoxia would enhance radiotherapy, whereas improving delivery of a second drug to the tumor should result in higher cell kill.
authors.affiliation: Medical Biophysics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jennifer H E
authors.initials: JH
authors.lastname: Baker
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lam
authors.forename: Alaistair H
authors.initials: AH
authors.lastname: Kyle
authors.forename: Jonathan
authors.initials: J
authors.lastname: Sy
authors.forename: Thomas
authors.initials: T
authors.lastname: Oliver
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Co
authors.forename: Wieslawa H
authors.initials: WH
authors.lastname: Dragowska
authors.forename: Euan
authors.initials: E
authors.lastname: Ramsay
authors.forename: Malathi
authors.initials: M
authors.lastname: Anantha
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Ruth
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Adam
authors.forename: Andrew
authors.initials: A
authors.lastname: Yung
authors.forename: Piotr
authors.initials: P
authors.lastname: Kozlowski
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Minchinton
authors.forename: Sylvia S W
authors.initials: SS
authors.lastname: Ng
authors.forename: Marcel B
authors.initials: MB
authors.lastname: Bally
authors.forename: Donald T T
authors.initials: DT
authors.lastname: Yapp
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015687:Cell Hypoxia / Q000187:drug effects; D004317:Doxorubicin / Q000493:pharmacokinetics*; D005472:Fluorouracil / Q000493:pharmacokinetics*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D000077146:Irinotecan; D008081:Liposomes; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D053769:Nanocapsules; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D053769:Nanocapsules; D000077146:Irinotecan; D004317:Doxorubicin; D005472:Fluorouracil; D002166:Camptothecin