Development and preclinical validation of a cysteine knottin peptide targeting Integrin avß6 for near-infrared fluorescent-guided surgery in pancreatic cancer. Clinical cancer research : an official journal of the American Association for Cancer Research Tummers, W. S., Kimura, R. H., Abou-Elkacem, L., Vahrmeijer, A. L., Swijnenburg, R. J., Willmann, J. K., Gambhir, S. S. 2018

Abstract

Intraoperative near-infrared fluorescence (NIRF) imaging could help stratification for the proper primary treatment for patients with pancreatic ductal adenocarcinoma (PDAC), and achieve complete resection since it allows visualization of cancer in real time. Integrin avß6, a target specific for PDAC, is present in >90% of patients, and is able to differentiate between pancreatitis and PDAC. A clinically translatable avß6-targeting NIRF agent was developed, based on a previously developed cysteine knottin peptide for PET imaging, R01-MG, and validated in preclinical mouse models.The applicability of the agent was tested for cell and tissue binding characteristics using cell-based plate assays, subcutaneous and orthotopic pancreatic models, and a transgenic mouse model of PDAC development (Pdx1-Cre tg/+;KRas LSL G12D/+;Ink4a/Arf). IRDye800CW was conjugated to R01-MG in a 1:1 ratio. R01-MG-IRDye800, was compared to a control peptide and IRDye800 alone.In subcutaneous tumor models a significantly higher tumor-to-background ratio (TBR) was seen in BxPC-3 tumors (2.5±0.1) compared to MiaPaCa-2 (1.2±0.1) (p<0.001), and to the control peptide (1.6±0.4) (p<0.005). In an orthotopic tumor model tumor-specific uptake of R01-MG-IRDye800 was shown compared to IRDye800 alone (TBR 2.7 versus 0.86). The fluorescent signal in tumors of transgenic mice was significantly higher, TBR of 3.6±0.94, compared to the normal pancreas of wild type controls, TBR of 1.0±0.17 (p<0.001).R01-MG-IRDye800 shows specific targeting to avß6, and holds promise as a diagnostic and therapeutic tool to recognize PDAC for fluorescence-guided surgery. This agent can help improve the stratification of patients for a potentially curative, margin-negative resection.

View details for DOI 10.1158/1078-0432.CCR-17-2491

View details for PubMedID 29298796