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

Abstract

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 [ ), 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 factorTIMP-1was 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.The clinical management of metastatic disease originating from colon/colorectal cancer remains challenging. The liver is the most common site of distant metastases for colorectal cancer, with 70% of patients presenting with liver metastases followed by the lungs, bone, and brain (1, 2). At present, the only cure is complete surgical removal of the primary tumor if diagnosed early; however, up to 45% of these patients still relapse with metastatic disease. Standard of care for first-line therapy in patients is a combination of 5-fluorouracil (5-FU; plus leucovorin) with either irinotecan (FOLFIRI) or oxaliplatin (FOLFOX; ref.3). The treatments are associated with prolonged median survivals of 18 to 21 months. Capecitabine, an oral fluoropyrimidine carbamate, has also been used in combination with 5-FU, and clinical data suggest that this combination is comparable with the FOLFIRI and FOLFOX regimens (4, 5). In practice, however, combination therapy with capecitabine is limited because of severe toxicities such as hand-foot syndrome, diarrhea, nausea, vomiting, and bone marrow suppression (4, 5). More recently, monoclonal antibodies targeting the epidermal growth factor receptor, such as cetuximab and panitumumab, have been used in combination with standard chemotherapy with promising results (6). The safety and efficacy of bevacizumab, the monoclonal antibody that targets vascular endothelial growth factor (VEGF; ref. 7), in combination with FOLFIRI or FOLFOX, was also evaluated recently (8,9). Although both studies were carried out with small Cancer Therapy: Preclinical

Systems Pharmacological Analysis of Paclitaxel-Mediated Tumor Priming That Enhances Nanocarrier Deposition and Efficacy

“…These include approaches that use tumor-priming agents that alter tumor vascular perfusion/permeability, interstitial pressure, or stromal properties to enhance deposition and efficacy of subsequently administered agents. Effectors of tumor-priming include cytotoxic drugs (GriffonEtienne et al, 1999;Lu et al, 2007), physical modulation of the tumor stromal matrix with enzymes such as collagenase or hyaluronidase (Eikenes et al, 2004(Eikenes et al, , 2005Provenzano et al, 2012), inhibitors of select signaling pathways (Tong et al, 2004;Olive et al, 2009), hyperthermia (Kong et al, 2000;Xu et al, 2007;Choe et al, 2011;Sen et al, 2011), and drug delivery vehicles (Zhou et al, 2002;Arnold et al, 2005;Baker et al, 2008;Cho and Kwon, 2011).…”

Endothelial-Specific Notch Blockade Inhibits Vascular Function and Tumor Growth through an eNOS-Dependent Mechanism

“…The NO-reactive dye diaminorhodamine 4M-AM (DAR4M, 25 mmol/kg; SantaCruz) was injected intraperitoneally 1 hour before mice were killed as described (9). A custom robotic microscope was used to image immunofluorescent staining across entire tumor sections at 0.75 mm/pixel resolution, as previously described (19). Images were quantified using customized NIH-ImageJ software (19).…”

“…A custom robotic microscope was used to image immunofluorescent staining across entire tumor sections at 0.75 mm/pixel resolution, as previously described (19). Images were quantified using customized NIH-ImageJ software (19). The quantification of NO production in the microvasculature and larger vessels was performed with the activated eNOS (phospho-Ser1117)-specific antibody and the NO-specific probe DAR4M.…”

Penetration of paclitaxel and 5-fluorouracil in multicellular layers of human colorectal cancer cells

“…A nanoformulation of irinotecan, PTX-loaded microsparticle (TPM), and tumor-penetrating peptide (iRGD) have been reported to enhance distribution of various anticancer drugs, including small compounds, liposomal drugs, and monoclonal antibodies into tumor tissue in vivo (9,18,19). In the present study, we evaluated the penetration characteristics of PTX and 5-FU using MCL of human colorectal cancer cells (DLD-1 and HT-29) grown in Transwell inserts.…”