title: A Pretargeted Approach for the Multimodal PET/NIRF Imaging of Colorectal Cancer.
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 as89Zr poses two important clinical complications: high radiation doses to the patient and the need for significant lag time between imaging and surgery.In vivopretargeting 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, andin vivovalidation 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 atrans-cyclooctene- and fluorophore-bearing immunoconjugate of the huA33 antibody (huA33-Dye800-TCO) and a64Cu-labeled tetrazine radioligand (64Cu-Tz-SarAr).In vivoimaging experiments in mice bearing A33 antigen-expressing SW1222 colorectal cancer xenografts clearly demonstrate that this approach enables the non-invasive visualization of tumorsandthe image-guided resection of malignant tissue, all at only a fraction of the radiation dose created by a directly labeled radioimmunoconjugate. Additionalin vivoexperiments 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.
authors.affiliation: Department of Chemistry, Hunter College of the City University of New York, New York, NY, 10028.
authors.forename: Pierre
authors.initials: P
authors.lastname: Adumeau
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carnazza
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065.
authors.forename: Christian
authors.initials: C
authors.lastname: Brand
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065.
authors.forename: Sean D
authors.initials: SD
authors.lastname: Carlin
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065;; Department of Radiology, Weill Cornell Medical College, New York, NY, 10065.
authors.forename: Thomas
authors.initials: T
authors.lastname: Reiner
authors.affiliation: Licensing and Commercial Supply, Thermo Fisher Scientific, Eugene, OR, 97402.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Agnew
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065;; Department of Radiology, Weill Cornell Medical College, New York, NY, 10065;; Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY, 10065.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
authors.affiliation: Department of Chemistry, Hunter College of the City University of New York, New York, NY, 10028;; Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065;; Department of Radiology, Weill Cornell Medical College, New York, NY, 10065;; Ph.D. Program in Chemistry, the Graduate Center of the City University of New York, New York, NY, 10016.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Zeglis
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000008:administration & dosage* / Q000737:chemistry; D002277:Carcinoma / Q000000981:diagnostic imaging*; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging*; D003301:Copper Radioisotopes / Q000008:administration & dosage* / Q000737:chemistry; D004195:Disease Models, Animal; D005456:Fluorescent Dyes / Q000008:administration & dosage* / Q000737:chemistry; D064593:Heterografts; D051379:Mice; D061848:Optical Imaging / Q000379:methods*; D049268:Positron-Emission Tomography / Q000379:methods*
chemical_list: D000912:Antibodies, Neoplasm; D003301:Copper Radioisotopes; D005456:Fluorescent Dyes
keywords: PET; bioorthogonal chemistry; colorectal carcinoma; fluorescence imaging; multimodal imaging; pretargeting; site-specific bioconjugation.