An EGFR Targeted PET Imaging Probe for the Detection of Colonic Adenocarcinomas in the Setting of Colitis

作者：Turker N Selcan; Heidari Pedram; Kucherlapati Raju; Kucherlapati Melanie; Mahmood Umar^*

来源：Theranostics, 2014, 4(9): 893-903.

DOI：10.7150/thno.9425

• Positron emission tomography (PET) imaging
• molecular imaging
• EGFR
• ulcerative colitis
• colorectal cancer
• mouse models

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 Ga-67 for cell based studies and Cu-64 for in vivo imaging. Competitive binding studies were performed on CT26 cells to assess affinity (K-D) and receptors per cell (B-max). In vivo imaging using the EGFR targeted PET probe and F-18 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 K-D was 6.6 +/- 0.7 nM and the B-max for CT26 cells was 3.3 +/- 0.1 x 10(6) receptors/cell. Target to background ratios (TBR) for CT26 tumors compared to colonic uptake demonstrated high values for both F-18-FDG (3.95 +/- 0.13) and the developed Cu-64-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 F-18 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.

• 出版日期2014