title: Preclinical evaluation of near-infrared (NIR) fluorescently labeled cetuximab as a potential tool for fluorescence-guided surgery.
abstract: The high rate of recurrence in patients with pancreatic ductal adenocarcinoma (PDAC) could be reduced by supporting the surgeons in discriminating healthy from diseased tissues with intraoperative fluorescence-guidance. Here, we studied the suitability of Cetuximab, a therapeutic monoclonal antibody targeting the human epidermal growth factor receptor (EGFR), near-infrared (NIR) fluorescently labeled as a new tool for fluorescence-guided surgery. Distribution and binding of systemically injected Cetuximab Alexa Fluor 647 conjugate (Cetux-Alexa-647) and the co-injected control human IgG Alexa Fluor 750 conjugate (hIgG-Alexa-750) was studied over 48 h by NIR fluorescence imaging in mice bearing human orthotopic AsPC-1 and MIA PaCa-2 PDAC tumors. Cetux-Alexa-647, but not the control hIgG-Alexa-750 fluorescence, was specifically detected in vivo in both primary pancreatic tumors with maximum fluorescence intensities at 24 h, and in metastases of AsPC-1 tumors as small as 1 mm. Lifetime analysis and NIR fluorescence microscopy of tumor sections confirmed the binding specificity of Cetux-Alexa-647 to PDAC cells. Comparable results were obtained with Cetuximab conjugated to Alexa Fluor 750 dye (Cetux-Alexa-750). Fluorescence-guided dissection, performed 24 h after injection of Cetuximab conjugated to IRDye 800CW (Cetux-800CW), enabled a real-time delineation of AsPC-1 tumor margins, and small metastases. Odyssey scans revealed that only the vital part of the tumor, but not the necrotic part was stained with Cetux-800CW. NIR fluorescently labeled Cetuximab may be a promising tool that can be applied for fluorescence-guided surgery to visualize tumor margins and metastatic sites in order to allow a precise surgical resection.
authors.affiliation: Department of Molecular Biology of Neuronal Signals, Max-Planck-Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Mara
authors.initials: M
authors.lastname: Saccomano
authors.affiliation: Institute of Interventional and Diagnostic Radiology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Dullin
authors.affiliation: Department of Molecular Biology of Neuronal Signals, Max-Planck-Institute of Experimental Medicine, Göttingen, Germany.|Institute of Interventional and Diagnostic Radiology, University Medical Center Göttingen, Göttingen, Germany.|Department of Haematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Alves
authors.affiliation: Department of Molecular Biology of Neuronal Signals, Max-Planck-Institute of Experimental Medicine, Göttingen, Germany. napp@em.mpg.de.|Institute of Interventional and Diagnostic Radiology, University Medical Center Göttingen, Göttingen, Germany. napp@em.mpg.de.|Department of Haematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany. napp@em.mpg.de.
authors.forename: Joanna
authors.initials: J
authors.lastname: Napp
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000000981:diagnostic imaging*; D002232:Carbocyanines / Q000032:analysis; D021441:Carcinoma, Pancreatic Ductal / Q000000981:diagnostic imaging* / Q000201:enzymology; D000068818:Cetuximab / Q000032:analysis* / Q000378:metabolism; D066246:ErbB Receptors / Q000096:biosynthesis / Q000378:metabolism; D005260:Female; D005456:Fluorescent Dyes / Q000032:analysis; D064593:Heterografts; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence / Q000379:methods*; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging* / Q000201:enzymology; D019265:Spectroscopy, Near-Infrared / Q000379:methods*; D013388:Succinimides / Q000032:analysis
chemical_list: C569686:Alexa Fluor 647; C502599:Alexa Fluor 750; D002232:Carbocyanines; D005456:Fluorescent Dyes; D013388:Succinimides; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab
keywords: Cetuximab; IRDye 800CW; clinical translation; fluorescence-guided surgery (FGS); near-infrared fluorescence; orthotopic pancreatic tumor mouse models; pancreatic ductal adenocarcinoma (PDAC)