Irinophore C, a Novel Nanoformulation of Irinotecan, Alters Tumor Vascular Function and Enhances the Distribution of 5-Fluorouracil and Doxorubicin

• Published in: Clinical cancer research Vol. 14; no. 22; pp. 7260 - 7271
• Main Authors: BAKER, Jennifer H. E, LAM, Jeffrey, ADAM, Michael J, YUNG, Andrew, KOZLOWSKI, Piotr, MINCHINTON, Andrew I, NG, Sylvia S. W, BALLY, Marcel B, YAPP, Donald T. T, KYLE, Alaistair H, SY, Jonathan, OLIVER, Thomas, CO, Steven J, DRAGOWSKA, Wieslawa H, RAMSAY, Euan, ANANTHA, Malathi, RUTH, Thomas J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.11.2008
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Camptothecin - pharmacokinetics; Camptothecin - therapeutic use; Cell Hypoxia - drug effects; Colorectal cancer; Doxorubicin - pharmacokinetics; Fluorouracil - pharmacokinetics; Humans; Image Processing, Computer-Assisted; Imaging; Immunohistochemistry; Liposomes; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Medical sciences; Mice; Nanocapsules; Neoplasms, Experimental - blood supply; Neoplasms, Experimental - drug therapy; Neovascularization, Pathologic - drug therapy; Pharmacology. Drug treatments; Tissue Distribution; Tumor Vasculature; Xenograft Model Antitumor Assays; Antineoplastic agent; Doxorubicin; Isomerases; Blood vessel; Topoisomerase I inhibitor; Fluorouracil; Camptothecin derivatives; DNA topoisomerase (ATP-hydrolysing); Enzyme; Fluoropyrimidine derivatives; Transferases; DNA topoisomerase; Enzyme inhibitor; Topoisomerase II inhibitor; Malignant tumor; Thymidylate synthase; Irinotecan; Antimetabolic; Methyltransferases; Distribution; Pyrimidine derivatives; Anthracyclins; Circulatory system; Pharmacokinetics; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-0736

Purpose: 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. Experimental Design: 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 K trans , 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, 19 F 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 [ 14 C]5-FU. Results: Irinophore C decreased cell density ( P = 8.42 × 10 −5 ), the overall number of endothelial cells in the entire section ( P = 0.014), tumor hypoxia ( P = 5.32 × 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 × 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.