Theranostics 2016; 6(12):2267-2277. doi:10.7150/thno.16744

Research Paper

A Pretargeted Approach for the Multimodal PET/NIRF Imaging of Colorectal Cancer

Pierre Adumeau1, Kathryn E. Carnazza2, Christian Brand2, Sean D. Carlin2, Thomas Reiner2,3, Brian J. Agnew4, Jason S. Lewis2,3,5, Brian M. Zeglis1,2,3,6✉

1. Department of Chemistry, Hunter College of the City University of New York, New York, NY, 10028;
2. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065;
3. Department of Radiology, Weill Cornell Medical College, New York, NY, 10065;
4. Licensing and Commercial Supply, Thermo Fisher Scientific, Eugene, OR, 97402;
5. Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY, 10065;
6. Ph.D. Program in Chemistry, the Graduate Center of the City University of New York, New York, NY, 10016.

Abstract

The complementary nature of positron emission tomography (PET) and near-infrared fluorescence (NIRF) imaging makes the development of strategies for the multimodal PET/NIRF imaging of cancer a very enticing prospect. Indeed, in the context of colorectal cancer, a single multimodal PET/NIRF imaging agent could be used to stage the disease, identify candidates for surgical intervention, and facilitate the image-guided resection of the disease. While antibodies have proven to be highly effective vectors for the delivery of radioisotopes and fluorophores to malignant tissues, the use of radioimmunoconjugates labeled with long-lived nuclides such as 89Zr poses two important clinical complications: high radiation doses to the patient and the need for significant lag time between imaging and surgery. In vivo pretargeting strategies that decouple the targeting vector from the radioactivity at the time of injection have the potential to circumvent these issues by facilitating the use of positron-emitting radioisotopes with far shorter half-lives. Here, we report the synthesis, characterization, and in vivo validation of a pretargeted strategy for the multimodal PET and NIRF imaging of colorectal carcinoma. This approach is based on the rapid and bioorthogonal ligation between a trans-cyclooctene- and fluorophore-bearing immunoconjugate of the huA33 antibody (huA33-Dye800-TCO) and a 64Cu-labeled tetrazine radioligand (64Cu-Tz-SarAr). In vivo imaging experiments in mice bearing A33 antigen-expressing SW1222 colorectal cancer xenografts clearly demonstrate that this approach enables the non-invasive visualization of tumors and the image-guided resection of malignant tissue, all at only a fraction of the radiation dose created by a directly labeled radioimmunoconjugate. Additional in vivo experiments in peritoneal and patient-derived xenograft models of colorectal carcinoma reinforce the efficacy of this methodology and underscore its potential as an innovative and useful clinical tool.

Keywords: PET, fluorescence imaging, multimodal imaging, colorectal carcinoma, pretargeting, bioorthogonal chemistry, site-specific bioconjugation.

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How to cite this article:
Adumeau P, Carnazza KE, Brand C, Carlin SD, Reiner T, Agnew BJ, Lewis JS, Zeglis BM. A Pretargeted Approach for the Multimodal PET/NIRF Imaging of Colorectal Cancer. Theranostics 2016; 6(12):2267-2277. doi:10.7150/thno.16744. Available from http://www.thno.org/v06p2267.htm