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

Authors' Affiliations: ¹ Medical Biophysics, ² Advanced Therapeutics (BC Cancer Agency), ³ Department of Life Sciences (TRIUMF), ⁴ High Field MRI Centre, ⁵ Faculty of Pathology and Laboratory Sciences, and ⁶ Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada

Requests for reprints: Donald T.T. Yapp, Advanced Therapeutics (BC Cancer Agency), 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada. Phone: 604-675-8023; Fax: 604-675-8183; E-mail: dyapp{at}bccrc.ca.

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, 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.