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Article

Influence of the Position and Composition of Radiometals and Radioiodine Labels on Imaging of Epcam Expression in Prostate Cancer Model Using the DARPin Ec1

1
Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia
2
Molecular Immunology Laboratory, Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia
3
Bio-Nanophotonic Lab., Institute of Engineering Physics for Biomedicine (PhysBio), National Research Nuclear University “MEPhI”, 115409 Moscow, Russia
4
Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden
5
Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, 114 17 Stockholm, Sweden
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Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden
7
Department of Pharmaceutical Analysis, Siberian State Medical University (SSMU), 2, Moscow Trakt, 634050 Tomsk, Russia
8
Science for Life Laboratory, Uppsala University, 751 23 Uppsala, Sweden
*
Author to whom correspondence should be addressed.
Contributed equally.
Academic Editors: Salvatore Cappabianca and Craig N Craig Robson
Cancers 2021, 13(14), 3589; https://doi.org/10.3390/cancers13143589
Received: 23 June 2021 / Revised: 13 July 2021 / Accepted: 15 July 2021 / Published: 17 July 2021
Metastasis-targeting therapy might improve outcomes in oligometastatic prostate cancer. Epithelial cell adhesion molecule (EpCAM) is overexpressed in 40–60% of prostate cancer cases and might be used as a target for specific delivery of toxins and drugs. Radionuclide molecular imaging could enable non-invasive detection of EpCAM and stratification of patients for targeted therapy. Designed ankyrin repeat proteins (DARPins) are scaffold proteins, which can be selected for specific binding to different targets. The DARPin Ec1 binds strongly to EpCAM. To determine an optimal design of Ec1-based probes, we labeled Ec1 at two different positions with four different nuclides (68Ga, 111In, 57Co and 125I) and investigated the impact on Ec1 biodistribution. We found that the C-terminus is the best position for labeling and that 111In and 125I provide the best imaging contrast. This study might be helpful for scientists developing imaging probes based on scaffold proteins.
The epithelial cell adhesion molecule (EpCAM) is intensively overexpressed in 40–60% of prostate cancer (PCa) cases and can be used as a target for the delivery of drugs and toxins. The designed ankyrin repeat protein (DARPin) Ec1 has a high affinity to EpCAM (68 pM) and a small size (18 kDa). Radiolabeled Ec1 might be used as a companion diagnostic for the selection of PCa patients for therapy. The study aimed to investigate the influence of radiolabel position (N- or C-terminal) and composition on the targeting and imaging properties of Ec1. Two variants, having an N- or C-terminal cysteine, were produced, site-specifically conjugated to a DOTA chelator and labeled with cobalt-57, gallium-68 or indium-111. Site-specific radioiodination was performed using ((4-hydroxyphenyl)-ethyl)maleimide (HPEM). Biodistribution of eight radiolabeled Ec1-probes was measured in nude mice bearing PCa DU145 xenografts. In all cases, positioning of a label at the C-terminus provided the best tumor-to-organ ratios. The non-residualizing [125I]I-HPEM label provided the highest tumor-to-muscle and tumor-to-bone ratios and is more suitable for EpCAM imaging in early-stage PCa. Among the radiometals, indium-111 provided the highest tumor-to-blood, tumor-to-lung and tumor-to-liver ratios and could be used at late-stage PCa. In conclusion, label position and composition are important for the DARPin Ec1. View Full-Text
Keywords: radionuclide; EpCAM; DARPin; PET; SPECT; imaging; prostate; cancer radionuclide; EpCAM; DARPin; PET; SPECT; imaging; prostate; cancer
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MDPI and ACS Style

Deyev, S.M.; Xu, T.; Liu, Y.; Schulga, A.; Konovalova, E.; Garousi, J.; Rinne, S.S.; Larkina, M.; Ding, H.; Gräslund, T.; Orlova, A.; Tolmachev, V.; Vorobyeva, A. Influence of the Position and Composition of Radiometals and Radioiodine Labels on Imaging of Epcam Expression in Prostate Cancer Model Using the DARPin Ec1. Cancers 2021, 13, 3589. https://doi.org/10.3390/cancers13143589

AMA Style

Deyev SM, Xu T, Liu Y, Schulga A, Konovalova E, Garousi J, Rinne SS, Larkina M, Ding H, Gräslund T, Orlova A, Tolmachev V, Vorobyeva A. Influence of the Position and Composition of Radiometals and Radioiodine Labels on Imaging of Epcam Expression in Prostate Cancer Model Using the DARPin Ec1. Cancers. 2021; 13(14):3589. https://doi.org/10.3390/cancers13143589

Chicago/Turabian Style

Deyev, Sergey M., Tianqi Xu, Yongsheng Liu, Alexey Schulga, Elena Konovalova, Javad Garousi, Sara S. Rinne, Maria Larkina, Haozhong Ding, Torbjörn Gräslund, Anna Orlova, Vladimir Tolmachev, and Anzhelika Vorobyeva. 2021. "Influence of the Position and Composition of Radiometals and Radioiodine Labels on Imaging of Epcam Expression in Prostate Cancer Model Using the DARPin Ec1" Cancers 13, no. 14: 3589. https://doi.org/10.3390/cancers13143589

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