title: Rapid Imaging of Tumor Cell Death In Vivo Using the C2A Domain of Synaptotagmin-I.
abstract: Cell death is an important target for imaging the early response of tumors to treatment. We describe here the validation of a phosphatidylserine-binding agent for detecting tumor cell death in vivo based on the C2A domain of synaptotagmin-I.Methods:The capability of near-infrared fluorophore-labeled and99mTc- and111In-labeled derivatives of C2Am for imaging tumor cell death, using planar near-infrared fluorescence imaging and SPECT, respectively, was evaluated in implanted and genetically engineered mouse models of lymphoma and in a human colorectal xenograft.Results:The fluorophore-labeled C2Am derivative showed predominantly renal clearance and high specificity and sensitivity for detecting low levels of tumor cell death (2%-5%). There was a significant correlation (R> 0.9,P< 0.05) between fluorescently labeled C2Am binding and histologic markers of cell death, including cleaved caspase-3, whereas there was no such correlation with a site-directed mutant of C2Am (iC2Am) that does not bind phosphatidylserine.99mTc-C2Am and111In-C2Am also showed favorable biodistribution profiles, with predominantly renal clearance and low nonspecific retention in the liver and spleen at 24 h after probe administration.99mTc-C2Am and111In-C2Am generated tumor-to-muscle ratios in drug-treated tumors of 4.3× and 2.2×, respectively, at 2 h and 7.3× and 4.1×, respectively, at 24 h after administration.Conclusion:Given the favorable biodistribution profile of99mTc- and111In-labeled C2Am, and their ability to produce rapid and cell death-specific image contrast, these agents have potential for clinical translation.
authors.affiliation: Cancer Research United Kingdom Cambridge Institute, Li Ka Shing Centre, Cambridge, United Kingdom; and andre.neves@cruk.cam.ac.uk.
authors.forename: André A
authors.initials: AA
authors.lastname: Neves
authors.affiliation: Cancer Research United Kingdom Cambridge Institute, Li Ka Shing Centre, Cambridge, United Kingdom; and.
authors.forename: Bangwen
authors.initials: B
authors.lastname: Xie
authors.affiliation: Cancer Research United Kingdom Cambridge Institute, Li Ka Shing Centre, Cambridge, United Kingdom; and.
authors.forename: Sarah
authors.initials: S
authors.lastname: Fawcett
authors.affiliation: Cancer Research United Kingdom Cambridge Institute, Li Ka Shing Centre, Cambridge, United Kingdom; and.
authors.forename: Israt S
authors.initials: IS
authors.lastname: Alam
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Witney
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Maaike M
authors.initials: MM
authors.lastname: de Backer
authors.affiliation: Cancer Research United Kingdom Cambridge Institute, Li Ka Shing Centre, Cambridge, United Kingdom; and.
authors.forename: Julia
authors.initials: J
authors.lastname: Summers
authors.affiliation: Cancer Research United Kingdom Cambridge Institute, Li Ka Shing Centre, Cambridge, United Kingdom; and.
authors.forename: William
authors.initials: W
authors.lastname: Hughes
authors.affiliation: Cancer Research United Kingdom Cambridge Institute, Li Ka Shing Centre, Cambridge, United Kingdom; and.
authors.forename: Sarah
authors.initials: S
authors.lastname: McGuire
authors.affiliation: Cancer Research United Kingdom Cambridge Institute, Li Ka Shing Centre, Cambridge, United Kingdom; and.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Soloviev
authors.affiliation: Cancer Research United Kingdom Cambridge Institute, Li Ka Shing Centre, Cambridge, United Kingdom; and.
authors.forename: Jodi
authors.initials: J
authors.lastname: Miller
authors.affiliation: Cancer Research United Kingdom Cambridge Institute, Li Ka Shing Centre, Cambridge, United Kingdom; and.
authors.forename: William J
authors.initials: WJ
authors.lastname: Howat
authors.affiliation: Cancer Research United Kingdom Cambridge Institute, Li Ka Shing Centre, Cambridge, United Kingdom; and.
authors.forename: De-En
authors.initials: DE
authors.lastname: Hu
authors.affiliation: Cancer Research United Kingdom Cambridge Institute, Li Ka Shing Centre, Cambridge, United Kingdom; and.
authors.forename: Tiago B
authors.initials: TB
authors.lastname: Rodrigues
authors.affiliation: Cancer Research United Kingdom Cambridge Institute, Li Ka Shing Centre, Cambridge, United Kingdom; and.
authors.forename: David Y
authors.initials: DY
authors.lastname: Lewis
authors.affiliation: Cancer Research United Kingdom Cambridge Institute, Li Ka Shing Centre, Cambridge, United Kingdom; and.|Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Brindle
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D057054:Molecular Imaging / Q000379:methods*; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology*; D049268:Positron-Emission Tomography / Q000379:methods*; D000072417:Protein Domains; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D050863:Synaptotagmin I / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D015415:Biomarkers; D019275:Radiopharmaceuticals; D050863:Synaptotagmin I
keywords: C2A; cell death; imaging; mouse; synaptotagmin; tumor