Targeted nanoparticles for imaging incipient pancreatic ductal adenocarcinoma.
BACKGROUND
Pancreatic 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.


RESULTS
Here, 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.


CONCLUSIONS
Our 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.
Kelly
Kimberly A
KA
Center for Molecular Imaging Research, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, United States of America. kkelly9@partners.org
Bardeesy
Nabeel
N
Anbazhagan
Rajesh
R
Gurumurthy
Sushma
S
Berger
Justin
J
Alencar
Herlen
H
Depinho
Ronald A
RA
Mahmood
Umar
U
Weissleder
Ralph
R
D000230:Adenocarcinoma / Q000175:diagnosis*; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000175:diagnosis*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D018613:Microscopy, Confocal; D053758:Nanoparticles; D010190:Pancreatic Neoplasms / Q000175:diagnosis*; D019151:Peptide Library; D010455:Peptides / Q000378:metabolism*; D051190:Plectin / Q000378:metabolism*
D019151:Peptide Library; D010455:Peptides; C495333:Plec protein, mouse; D051190:Plectin