Irinophore C, a novel nanoformulation of irinotecan, alters tumor vascular function and enhances the distribution of 5-fluorouracil and doxorubicin.
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.
Baker
Jennifer H E
JH
Medical Biophysics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
Lam
Jeffrey
J
Kyle
Alaistair H
AH
Sy
Jonathan
J
Oliver
Thomas
T
Co
Steven J
SJ
Dragowska
Wieslawa H
WH
Ramsay
Euan
E
Anantha
Malathi
M
Ruth
Thomas J
TJ
Adam
Michael J
MJ
Yung
Andrew
A
Kozlowski
Piotr
P
Minchinton
Andrew I
AI
Ng
Sylvia S W
SS
Bally
Marcel B
MB
Yapp
Donald T T
DT
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
D000970:Antineoplastic Agents; D008081:Liposomes; D053769:Nanocapsules; D000077146:Irinotecan; D004317:Doxorubicin; D005472:Fluorouracil; D002166:Camptothecin