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dc.contributor.authorBulat, Flaviu
dc.contributor.authorHesse, Friederike
dc.contributor.authorHu, De-En
dc.contributor.authorRos, Susana
dc.contributor.authorWillminton-Holmes, Connor
dc.contributor.authorXie, Bangwen
dc.contributor.authorAttili, Bala
dc.contributor.authorSoloviev, Dmitry
dc.contributor.authorAigbirhio, Franklin
dc.contributor.authorLeeper, Finian. J.
dc.contributor.authorBrindle, Kevin M.
dc.contributor.authorNeves, André A.
dc.date.accessioned2020-12-09T17:19:18Z
dc.date.available2020-12-09T17:19:18Z
dc.date.issued2020-12-09
dc.date.submitted2020-07-27
dc.identifier.others13550-020-00738-7
dc.identifier.other738
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/314927
dc.description.abstractAbstract: Introduction: Trialing novel cancer therapies in the clinic would benefit from imaging agents that can detect early evidence of treatment response. The timing, extent and distribution of cell death in tumors following treatment can give an indication of outcome. We describe here an 18F-labeled derivative of a phosphatidylserine-binding protein, the C2A domain of Synaptotagmin-I (C2Am), for imaging tumor cell death in vivo using PET. Methods: A one-pot, two-step automated synthesis of N-(5-[18F]fluoropentyl)maleimide (60 min synthesis time, > 98% radiochemical purity) has been developed, which was used to label the single cysteine residue in C2Am within 30 min at room temperature. Binding of 18F-C2Am to apoptotic and necrotic tumor cells was assessed in vitro, and also in vivo, by dynamic PET and biodistribution measurements in mice bearing human tumor xenografts treated with a TRAILR2 agonist or with conventional chemotherapy. C2Am detection of tumor cell death was validated by correlation of probe binding with histological markers of cell death in tumor sections obtained immediately after imaging. Results: 18F-C2Am showed a favorable biodistribution profile, with predominantly renal clearance and minimal retention in spleen, liver, small intestine, bone and kidney, at 2 h following probe administration. 18F-C2Am generated tumor-to-muscle (T/m) ratios of 6.1 ± 2.1 and 10.7 ± 2.4 within 2 h of probe administration in colorectal and breast tumor models, respectively, following treatment with the TRAILR2 agonist. The levels of cell death (CC3 positivity) following treatment were 12.9–58.8% and 11.3–79.7% in the breast and colorectal xenografts, respectively. Overall, a 20% increase in CC3 positivity generated a one unit increase in the post/pre-treatment tumor contrast. Significant correlations were found between tracer uptake post-treatment, at 2 h post-probe administration, and histological markers of cell death (CC3: Pearson R = 0.733, P = 0.0005; TUNEL: Pearson R = 0.532, P = 0.023). Conclusion: The rapid clearance of 18F-C2Am from the blood pool and low kidney retention allowed the spatial distribution of cell death in a tumor to be imaged during the course of therapy, providing a rapid assessment of tumor treatment response. 18F-C2Am has the potential to be used in the clinic to assess early treatment response in tumors.
dc.languageen
dc.publisherSpringer Berlin Heidelberg
dc.rightsAttribution 4.0 International (CC BY 4.0)en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectOriginal Research
dc.subjectCell death
dc.subjectPET
dc.subjectC2Am
dc.subjectSynaptotagmin-I
dc.subjectTumor
dc.subjectTRAILR2
dc.title18 F-C2Am: a targeted imaging agent for detecting tumor cell death in vivo using positron emission tomography
dc.typeArticle
dc.date.updated2020-12-09T17:19:15Z
prism.issueIdentifier1
prism.publicationNameEJNMMI Research
prism.volume10
dc.identifier.doi10.17863/CAM.62036
dcterms.dateAccepted2020-11-23
rioxxterms.versionofrecord10.1186/s13550-020-00738-7
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidBrindle, Kevin M. [0000-0003-3883-6287]
dc.contributor.orcidNeves, André A. [0000-0003-2740-5166]
dc.identifier.eissn2191-219X
pubs.funder-project-idCancer Research UK (17242)
pubs.funder-project-idEngineering and Physical Sciences Research Council (16465)


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Attribution 4.0 International (CC BY 4.0)
Except where otherwise noted, this item's licence is described as Attribution 4.0 International (CC BY 4.0)