Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer death in the United States and shows a rapid clinical course, with a median survival of 6 months and a 5-year survival rate of only 3%. As chemotherapy and radiotherapy have only modest benefits and surgery is only possible in 20% of patients, earliest detection that allows surgical resection offers the best hope for longer survival. The identification of novel molecular markers and the development of imaging probes for pre-neoplastic/early invasive lesions is thus a high priority. We used phage display to identify peptides that distinguish mouse and human PDAC cells from normal pancreatic duct cells in vitro. We subsequently conjugated 2 peptides with the highest affinities and specificities to magnetofluorescent nanoparticles (CLIO-VT680) and demonstrate that these agents can effectively detect emerging tumors and pre-neoplastic lesions in a relevant transgenic mouse model via intravital confocal microscopy (Olympus IV100) and optical/MR imaging (OV-100, Bruker Pharmascan). Correlative histology confirmed the specific tumoral localization of the PDAC targeted agents. Additionally, the peptide-binding partners identified from this approach represent a snapshot of the proteome in aberrant cells and also potential PDAC biomarkers. Using affinity chromatography, we identified the binding partners for several peptides and demonstrate their validity as biomarkers. These specific and sensitive probes may have clinical utility in the diagnosis and management of PDAC in humans.
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