title: Predictive imaging of chemotherapeutic response in a transgenic mouse model of pancreatic cancer.
abstract: The underglycosylated mucin 1 tumor antigen (uMUC1) is a biomarker that forecasts the progression of adenocarcinomas. In this study, we evaluated the utility of a dual-modality molecular imaging approach based on targeting uMUC1 for monitoring chemotherapeutic response in a transgenic murine model of pancreatic cancer (KCM triple transgenic mice). An uMUC1-specific contrast agent (MN-EPPT) was synthesized for use with magnetic resonance imaging (MRI) and fluorescence optical imaging. It consisted of dextran-coated iron oxide nanoparticles conjugated to the near infrared fluorescent dye Cy5.5 and to a uMUC1-specific peptide (EPPT). KCM triple transgenic mice were given gemcitabine as chemotherapy while control animals received saline injections following the same schedule. Changes in uMUC1 levels following chemotherapy were monitored using T2-weighted MRI and optical imaging before and 24 hr after injection of the MN-EPPT. uMUC1 expression in tumors from both groups was evaluated by histology and qRT-PCR. We observed that the average delta-T2 in the gemcitabine-treated group was significantly reduced compared to the control group indicating lower accumulation of MN-EPPT, and correspondingly, a lower level of uMUC1 expression. In vivo optical imaging confirmed the MRI findings. Fluorescence microscopy of pancreatic tumor sections showed a lower level of uMUC1 expression in the gemcitabine-treated group compared to the control, which was confirmed by qRT-PCR. Our data proved that changes in uMUC1 expression after gemcitabine chemotherapy could be evaluated using MN-EPPT-enhanced in vivo MR and optical imaging. These results suggest that the uMUC1-targeted imaging approach could provide a useful tool for the predictive assessment of therapeutic response.
authors.affiliation: Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA.
authors.forename: Byunghee
authors.initials: B
authors.lastname: Yoo
authors.affiliation: Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Sherman
authors.affiliation: Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte and School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Pinku
authors.initials: P
authors.lastname: Mukherjee
authors.affiliation: Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA.
authors.forename: Alana
authors.initials: A
authors.lastname: Ross
authors.affiliation: Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Pantazopoulos
authors.affiliation: Molecular Medicine Core, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Petkova
authors.affiliation: MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA.
authors.forename: Christian
authors.initials: C
authors.lastname: Farrar
authors.affiliation: Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA.
authors.forename: Zdravka
authors.initials: Z
authors.lastname: Medarova
authors.affiliation: Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA.
authors.forename: Anna
authors.initials: A
authors.lastname: Moore
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003287:Contrast Media; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D057054:Molecular Imaging / Q000379:methods; D018396:Mucin-1 / Q000378:metabolism; D061848:Optical Imaging / Q000379:methods; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015203:Reproducibility of Results; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D003287:Contrast Media; D018396:Mucin-1
keywords: in vivo imaging; nanoparticles; pancreatic cancer; underglycosylated mucin 1 tumor antigen (uMUC1)