Targeted Nanoparticles for Imaging Incipient Pancreatic Ductal Adenocarcinoma

Abstract

BackgroundPancreatic ductal adenocarcinoma (PDAC) carries an extremely poor prognosis, typically presenting with metastasis at the time of diagnosis and exhibiting profound resistance to existing therapies. The development of molecular markers and imaging probes for incipient PDAC would enable earlier detection and guide the development of interventive therapies. Here we sought to identify novel molecular markers and to test their potential as targeted imaging agents.Methods and FindingsHere, a phage display approach was used in a mouse model of PDAC to screen for peptides that specifically bind to cell surface antigens on PDAC cells. These screens yielded a motif that distinguishes PDAC cells from normal pancreatic duct cells in vitro, which, upon proteomics analysis, identified plectin-1 as a novel biomarker of PDAC. To assess their utility for in vivo imaging, the plectin-1 targeted peptides (PTP) were conjugated to magnetofluorescent nanoparticles. In conjunction with intravital confocal microscopy and MRI, these nanoparticles enabled detection of small PDAC and precursor lesions in engineered mouse models.ConclusionsOur approach exploited a well-defined model of PDAC, enabling rapid identification and validation of PTP. The developed specific imaging probe, along with the discovery of plectin-1 as a novel biomarker, may have clinical utility in the diagnosis and management of PDAC in humans.

Unexpected gain of function for the scaffolding protein plectin due to mislocalization in pancreatic cancer

“…Previous data indicated that plectin is a robust biomarker for pancreatic cancer and that it is overexpressed in PDAC specimens (7,15), with a hint of cell surface localization. However, in normal physiology, plectin is exclusively cytoplasmic (9).…”

“…Therefore, we sought to conclusively demonstrate cell surface localization and identify the path by which this protein localizes to the surface in PDAC. To confirm the cell surface localization of plectin, we performed a series of experiments including flow cytometry, immunogold TEM, and a plectin-binding assay that uses fluorescent-coupled plectintargeting peptide (PTP) (sequence: KTLLPTP) (7,15). Flow cytometric analysis using both plectin antibodies and PTP demonstrated specific cell surface binding to plectin in unfixed PDAC cells (Fig.…”

“…Recently, we used phage display and functional proteomics methods to identify biomarkers of pancreatic ductal adenocarcinoma (PDAC) (7). We were able to demonstrate overexpression and detect plectin on the surface of PDAC cells; however, in normal physiology, plectin is solely cytoplasmic (8).…”

Mixed-surface, lipid-tethered quantum dots for targeting cells and tissues

“…We expect this phenomenon to regulate other targeting approaches using either hydrophobic alpha-helix forming peptides [34] or specific targeting peptides. [35] Finally, QDs lacking specific targeting mechanisms such as antibody-antigen or ligandreceptor interactions are able to spatially localize to both subcellular and anatomical structures. …”

Superparamagnetic iron oxide nanoparticles for MR imaging of pancreatic cancer: Potential for early diagnosis through targeted strategies

“…62 To assess its utility for in vivo imaging, Kelly et al 63 conjugated plectin-1-targeted peptides (PTPs) to magnetofluorescent NPs. In conjunction with intravital confocal microscopy and MRI, these NPs enabled detection of small PDAC and precursor lesions in engineered mouse models.…”