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.
Highlights
The aggressive tumor biology of pancreatic ductal adenocarcinoma (PDAC) together with the asymptomatic early phase of the disease leaves only 10 to 20% of patients as candidates for resection
Using preclinical fluorescence imaging systems, Optix MX2 and IVIS Spectrum, as well as the Quest Spectrum clinical device for fluorescence-guided surgery (FGS), we show that fluorescently labeled Cetuximab allows the visualization of primary tumors and the metastatic spread in two EGFRexpressing PDAC mouse models, AsPC-1 and MIA PaCa-2, showing promise for future clinical translation in FGS
Pancreatic tumor cells express different levels of epidermal growth factor receptor (EGFR) in vitro EGFR expression was assessed by Western Blotting in five human PDAC cell lines: AsPC-1, PANC-1, BxPC-3, MIA PaCa2 and Capan-1, along with lysates of positive and negative controls, MDA-methylene blue (MB)-468 (1) and MCF7 (2) breast cancer cells, respectively
Summary
The aggressive tumor biology of pancreatic ductal adenocarcinoma (PDAC) together with the asymptomatic early phase of the disease leaves only 10 to 20% of patients as candidates for resection Within this patient group the so called R1resection, defined as microscopically positive tumor margins undesirably remaining after surgery, results in a high risk of tumor recurrence of up to 80%.1–3. This is partially due to the difficulty in the intraoperative assessment of tumor margins, which currently relies only on images taken before the operation, on visual inspection by the surgeons during the resection and on accompanying histological analysis.[4] Fluorescence-guided surgery (FGS), a recent technique introduced in the clinic, in combination with cancer specific fluorescence labels, may improve the precise identification of the local extent of the tumor and the presence of metastasis invisible to the naked eye. This problem has persuaded investigators to develop new NIR optical probes with comparable structural and spectral properties as IRDye 800CW or ZW800-1,19 both currently in the process of clinical translation
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