Development and preclinical validation of an Integrin αvβ6-targeting imaging agent for near-infrared fluorescent-guided surgery in pancreatic cancer

Abstract

Background: Margin positive resections or early recurrence due to occult metastases after surgery of pancreatic ductal adenocarcinoma (PDAC) are common. Intraoperative near-infrared fluorescent (NIRF) imaging allows cancer visualization to improve surgical accuracy, however targeted agents are lacking. Integrin αvβ6 is a target specific for PDAC, able to detect positive lymph nodes and differentiate between pancreatitis and PDAC. We developed R01-MG-IRDye800, a clinically translatable αvβ6-targeting NIRF agent, based on a cysteine knot peptide, to visualize PDAC. Methods: The applicability of the tracer was tested for cell and tissue binding using cell-based plate assays, and subcutaneous (BxPC-3, αvβ6 positive), orthotopic pancreatic (AsPC-1, αvβ6 positive), and spontaneous transgenic PDAC-mouse models. The agent was compared to a scrambled control peptide. NIRF signals were visualized using PEARL imaging system. Results: R01-MG-IRDye800 accumulated selectively in PDAC with highest tumor-to-background ratios of 7.6, which proved suitable for intraoperative detection and delineation of PDAC and small tumor nodules in mice, between 6 and 24 hr postinjection. The agent outperformed the control peptide. Ex vivo fluorescence and pathologic examination confirmed tumor specificity and distribution. Conclusion: Our Results indicate that R01-MG-IRDye800 shows promise to recognize PDAC for fluorescent-guided surgery. This tracer can help improve the stratification of patients for potentially curative, margin-negative resection.