Abstract
Fluorescent-antibody targeting of metastatic cancer has been demonstrated by our laboratory to enable tumor visualization and effective fluorescence-guided surgery. The goal of the present study was to determine whether insulin-like growth factor-1 receptor (IGF-1R) antibodies, conjugated with bright fluorophores, could enable visualization of metastatic colon cancer in orthotopic nude mouse models. IGF-1R antibody (clone 24ā31) was conjugated with 550 nm, 650 nm or PEGylated 650 nm fluorophores. Subcutaneous, orthotopic, and liver metastasis models of colon cancer in nude mice were targeted with the fluorescent IGF-1R antibodies. Western blotting confirmed the expression of IGF-1R in HT-29 and HCT 116 human colon cancer cell lines, both expressing green fluorescent protein (GFP). Labeling with fluorophore-conjugated IGF-1R antibody demonstrated fluorescent foci on the membrane of colon cancer cells. Subcutaneously- and orthotopically-transplanted HT-29-GFP and HCT 116-GFP tumors brightly fluoresced at the longer wavelengths after intravenous administration of fluorescent IGF-1R antibodies. Orthotopically-transplanted HCT 116-GFP tumors were brightly labeled by fluorescent IGF-1R antibodies such that they could be imaged non-invasively at the longer wavelengths. In an experimental liver metastasis model, IGF-1R antibodies conjugated with PEGylated 650 nm fluorophores selectively highlighted the liver metastases, which could then be non-invasively imaged. The IGF-1R fluorescent-antibody labeled liver metastases were very bright compared to the normal liver and the fluorescent-antibody label co-located with green fluorescent protein (GFP) expression of the colon cancer cells. The present study thus demonstrates that fluorophore-conjugated IGF-1R antibodies selectively visualize metastatic colon cancer and have clinical potential for improved diagnosis and fluorescence-guided surgery.
Highlights
Colorectal cancer is the second leading cause of cancer-related deaths in Western countries [1]
We have previously shown that targeting orthotopic metastatic colon cancer, including patient-derived orthotopic xenografts (PDOX) models, with fluorescent anti-carcinoembyronic antigen (CEA) antibodies enabled improved tumor visualization and effective fluorescence-guided surgery (FGS) [6]
After incubation with the fluorescent conjugated insulin-like growth factor-1 receptor (IGF-1R) antibody, without permeation, multiple fluorescent foci were visualized on the HT-29 and HCT 116 cells in monolayer culture, as observed under fluorescence microscopy (Fig 1B)
Summary
Colorectal cancer is the second leading cause of cancer-related deaths in Western countries [1]. Development of colonoscopy enables early detection and removal of precancerous adenomatous polyps [2,3]. Complete surgical resection can cure well selected patients with liver metastasis [4,5]. Improved imaging of metastatic colon cancer should increase survival by making colonoscopy and surgery more effective. We have previously shown that targeting orthotopic metastatic colon cancer, including patient-derived orthotopic xenografts (PDOX) models, with fluorescent anti-carcinoembyronic antigen (CEA) antibodies enabled improved tumor visualization and effective fluorescence-guided surgery (FGS) [6]. Targeting of the epidermal growth factor receptor with fluorescent antibodies improved colonoscopy [7]
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