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An EGFR targeted PET imaging probe for the detection of colonic adenocarcinomas in the setting of colitis.
- Source :
-
Theranostics [Theranostics] 2014 Jul 01; Vol. 4 (9), pp. 893-903. Date of Electronic Publication: 2014 Jul 01 (Print Publication: 2014). - Publication Year :
- 2014
-
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.
- Subjects :
- Adenocarcinoma complications
Animals
Antibodies, Monoclonal pharmacokinetics
Cell Line, Tumor
Cetuximab
Colitis, Ulcerative complications
Colorectal Neoplasms complications
Female
Humans
Mice
Mice, Inbred BALB C
Multimodal Imaging
Tomography, X-Ray Computed
Adenocarcinoma diagnostic imaging
Antibodies, Monoclonal, Humanized pharmacokinetics
Colitis, Ulcerative diagnostic imaging
Colorectal Neoplasms diagnostic imaging
ErbB Receptors antagonists & inhibitors
Immunoglobulin Fab Fragments
Organometallic Compounds pharmacokinetics
Positron-Emission Tomography
Radiopharmaceuticals chemical synthesis
Radiopharmaceuticals pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1838-7640
- Volume :
- 4
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Theranostics
- Publication Type :
- Academic Journal
- Accession number :
- 25057314
- Full Text :
- https://doi.org/10.7150/thno.9425