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.

Molecular imaging and deep learning analysis of uMUC1 expression in response to chemotherapy in an orthotopic model of ovarian cancer

“…Synthesis of the imaging probes. Iron-oxide based dextran-coated magnetic nanoparticles (MN) were synthesized as described previously 27 . Experimental probe (MN-EPPT) was synthesized by conjugating iron oxide nanoparticles to the EPPT peptide ( 27 .…”

“…Iron-oxide based dextran-coated magnetic nanoparticles (MN) were synthesized as described previously 27 . Experimental probe (MN-EPPT) was synthesized by conjugating iron oxide nanoparticles to the EPPT peptide (C-AHA-Y-C(ACM)-A-R-E-P-P-T-R-T-F-A-Y-W-G-K) 27 . Near infrared optical dye (Cy5.5) was conjugated to the nanoparticles for fluorescence microscopy and correlative near infrared optical imaging.…”

“…In addition, uMUC1 availability is directly related to tumor response to chemotherapy suggesting that it can serve as an intermediate biomarker for assessment of therapeutic response and prognosis 22,23 . In our previous studies we demonstrated the utility of in vivo MRI of uMUC1 antigen using targeted magnetic nanoparticles (MN) conjugated to uMUC1-specific peptide EPPT (MN-EPPT) for detection and monitoring of therapeutic response in breast, pancreatic and colon cancers 4,[24][25][26][27][28] . While we showed that MN-EPPT could be suitable for detection of uMUC1-expressing tumors and for monitoring changes in uMUC1 expression during chemotherapy, delineation of negatively contrasted tissues on MR images represents a challenge.…”

Targeting Glycans and Heavily Glycosylated Proteins for Tumor Imaging

“…In cancer, aberrant glycosylation is mainly characterized by increased N -glycan branching, augmented O -glycan density, incomplete glycan synthesis, and, in more advanced cancers, synthesis of neo-glycan determinants that carry large amounts of sialic acids or fucose residues [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61...…”

“…Several preclinical studies described MUC1 as a promising target for molecular imaging [ 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 55 ]. For instance, Chen et al evaluated MUC1-specific aptamers, conjugated to indocyanine green (ICG) as a fluorescence imaging tracer in breast, non-small cell lung, or hepatocellular carcinoma-bearing mice [ 52 ].…”