title: An EGFR targeted PET imaging probe for the detection of colonic adenocarcinomas in the setting of colitis.
abstract: Colorectal cancer is a serious complication associated with inflammatory bowel disease, often indistinguishable by screening with conventional FDG PET probes. We have developed an alternative EGFR-targeted PET imaging probe that may be used to overcome this difficulty, and successfully assessed its utility for neoplastic lesion detection in preclinical models. Cetuximab F(ab')2 fragments were enzymatically generated, purified, and DOTA-conjugated. Radiolabeling was performed with (67)Ga for cell based studies and (64)Cu for in vivo imaging. Competitive binding studies were performed on CT26 cells to assess affinity (KD) and receptors per cell (Bmax). In vivo imaging using the EGFR targeted PET probe and (18)F FDG was performed on CT26 tumor bearing mice in both control and dextran sodium sulfate (DSS) induced colitis settings. Spontaneous adenomas in genetically engineered mouse (GEM) models of colon cancer were additionally imaged. The EGFR imaging agent was generated with high purity (> 98%), with a labeling efficiency of 60 ± 5% and ≥99% radiochemical purity. The KD was 6.6 ± 0.7 nM and the Bmax for CT26 cells was 3.3 ± 0.1 × 10(6) receptors/cell. Target to background ratios (TBR) for CT26 tumors compared to colonic uptake demonstrated high values for both (18)F-FDG (3.95 ± 0.13) and the developed (64)Cu-DOTA-cetuximab-F(ab')2 probe (4.42 ± 0.11) in control mice. The TBR for the EGFR targeted probe remained high (3.78 ± 0.06) in the setting of colitis, while for (18)F FDG, this was markedly reduced (1.54 ± 0.08). Assessment of the EGFR targeted probe in the GEM models demonstrated a correlation between radiotracer uptake in spontaneous colonic lesions and the EGFR staining level ex vivo. A clinically translatable PET imaging probe was successfully developed to assess EGFR. The imaging agent can detect colonic tumors with a high TBR for detection of in situ lesions in the setting of colitis, and opens the possibility for a new approach for screening high-risk patients.
authors: 1. Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA;
authors: N Selcan
authors: NS
authors: Turker
authors: 1. Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA;
authors: Pedram
authors: P
authors: Heidari
authors: 2. Department of Medicine/Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors: Raju
authors: R
authors: Kucherlapati
authors: 2. Department of Medicine/Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors: Melanie
authors: M
authors: Kucherlapati
authors: 1. Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA;
authors: Umar
authors: U
authors: Mahmood
mesh_terms: D000230:Adenocarcinoma / Q000150:complications / Q000000981:diagnostic imaging*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D000068818:Cetuximab; D003093:Colitis, Ulcerative / Q000150:complications / Q000000981:diagnostic imaging*; D015179:Colorectal Neoplasms / Q000150:complications / Q000000981:diagnostic imaging*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments; D051379:Mice; D008807:Mice, Inbred BALB C; D064847:Multimodal Imaging; D009942:Organometallic Compounds / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D014057:Tomography, X-Ray Computed
chemical_list: C532429:64Cu-DOTA-cetuximab; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007140:Immunoglobulin Fab Fragments; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D066246:ErbB Receptors; D000068818:Cetuximab
keywords: EGFR; Positron emission tomography (PET) imaging; colorectal cancer; molecular imaging; mouse models.; ulcerative colitis