A Pretargeted Strategy for the Multimodal PET and Optical Imaging of Colorectal Cancer
2016
387 Objectives Our over-arching objective was the synthesis and in vivo validation of a next generation pretargeted PET/NIRF imaging tool based on the bioorthogonal inverse electron demand Diels-Alder reaction.[1] This strategy facilitates both the non-invasive in vivo imaging of tumors via PET as well as intraoperative NIRF imaging for the resection of tumors and the delineation of tumor margins.[2,3] Importantly, the use of a pretargeted approach (Figure A) confers two critical benefits over directly radiolabeled PET/OI immunoconjugates: (i) drastic reductions in the radiation dose to healthy organs and (ii) the ability to perform surgeries in the absence of radioactivity after only a short interval following PET imaging. Methods Using an enzyme-mediated methodology, a NIR fluorophore (Dye800) was site-specifically conjugated to the heavy chain glycans of the colorectal cancer-targeting huA33 antibody.[4] Transcyclooctene (TCO) was subsequently grafted to the antibody via conjugation to lysines to afford the conjugate Dye800-huA33-TCO (Figure B). The in vivo performance of this system was investigated in mice bearing subcutaneous SW1222 colorectal cancer xenografts. The mice were first injected with the Dye800-huA33-TCO immunoconjugate and then, after a 48 h interval, with a 64Cu-labeled tetrazine radioligand (64Cu-Tz-SarAr) and followed by small animal PET and NIRF imaging. Results The in vivo imaging experiments revealed that this strategy was able to quickly and clearly delineate the A33 antigen-expressing tumors via PET with excellent tumor-to-background contrast (tumor:muscle = 16 at 4 h and more than 40 at 24 h, Figure C). Furthermore, simulated tumor resections using a NIRF camera confirmed that the fluorophore-tagged antibody could be a very powerful tool for the delineation of the tumor margins during surgery (Figure D). Finally, dosimetry calculations revealed that this approach produces only a fraction of the radiation dose to healthy tissue created by traditional radioimmunoconjugates. Conclusions This pretargeted multimodal imaging strategy has proven extremely effective for both the non-invasive PET imaging and intraoperative NIRF imaging of colorectal cancer xenografts and offers significant dosimetric and logistical advantages over traditional, directly radiolabeled multimodal immunoconjugates.
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
0
References
0
Citations
NaN
KQI