TY - JOUR
T1 - Molecular design of radiocopper-labelled Affibody molecules
AU - Tolmachev, Vladimir
AU - Grönroos, Tove J.
AU - Yim, Cheng Bin
AU - Garousi, Javad
AU - Yue, Ying
AU - Grimm, Sebastian
AU - Rajander, Johan
AU - Perols, Anna
AU - Haaparanta-Solin, Merja
AU - Solin, Olof
AU - Ferdani, Riccardo
AU - Orlova, Anna
AU - Anderson, Carolyn J.
AU - Karlström, Amelie Eriksson
N1 - Funding Information:
We thank Marko Vehmanen for support with the ex vivo measurements of biodistribution. This research was financially supported by grants from the Swedish Cancer Society [Grants CAN 2015/350 and 2014/474], Swedish Research Council [Grants 2015–02353, 2013–5135, and 2015–02509], and Hospital District of Southwest Finland (EVO).
Publisher Copyright:
© 2018 The Author(s).
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - The use of long-lived positron emitters 64Cu or 61Cu for labelling of Affibody molecules may improve breast cancer patients' stratification for HER-targeted therapy. Previous animal studies have shown that the use of triaza chelators for 64Cu labelling of synthetic Affibody molecules is suboptimal. In this study, we tested a hypothesis that the use of cross-bridged chelator, CB-TE2A, in combination with Gly-Glu-Glu-Glu spacer for labelling of Affibody molecules with radiocopper would improve imaging contrast. CB-TE2A was coupled to the N-terminus of synthetic Affibody molecules extended either with a glycine (designation CB-TE2A-G-ZHER2:342) or Gly-Glu-Glu-Glu spacer (CB-TE2A-GEEE-ZHER2:342). Biodistribution and targeting properties of 64Cu-CB-TE2A-G-ZHER2:342 and 64Cu-CB-TE2A-GEEE-ZHER2:342 were compared in tumor-bearing mice with the properties of 64Cu-NODAGA-ZHER2:S1, which had the best targeting properties in the previous study. 64Cu-CB-TE2A-GEEE-ZHER2:342 provided appreciably lower uptake in normal tissues and higher tumor-to-organ ratios than 64Cu-CB-TE2A-G-ZHER2:342 and 64Cu-NODAGA-ZHER2:S1. The most pronounced was a several-fold difference in the hepatic uptake. At the optimal time point, 6 h after injection, the tumor uptake of 64Cu-CB-TE2A-GEEE-ZHER2:342 was 16 ± 6%ID/g and tumor-to-blood ratio was 181 ± 52. In conclusion, a combination of the cross-bridged CB-TE2A chelator and Gly-Glu-Glu-Glu spacer is preferable for radiocopper labelling of Affibody molecules and, possibly, other scaffold proteins having high renal re-absorption.
AB - The use of long-lived positron emitters 64Cu or 61Cu for labelling of Affibody molecules may improve breast cancer patients' stratification for HER-targeted therapy. Previous animal studies have shown that the use of triaza chelators for 64Cu labelling of synthetic Affibody molecules is suboptimal. In this study, we tested a hypothesis that the use of cross-bridged chelator, CB-TE2A, in combination with Gly-Glu-Glu-Glu spacer for labelling of Affibody molecules with radiocopper would improve imaging contrast. CB-TE2A was coupled to the N-terminus of synthetic Affibody molecules extended either with a glycine (designation CB-TE2A-G-ZHER2:342) or Gly-Glu-Glu-Glu spacer (CB-TE2A-GEEE-ZHER2:342). Biodistribution and targeting properties of 64Cu-CB-TE2A-G-ZHER2:342 and 64Cu-CB-TE2A-GEEE-ZHER2:342 were compared in tumor-bearing mice with the properties of 64Cu-NODAGA-ZHER2:S1, which had the best targeting properties in the previous study. 64Cu-CB-TE2A-GEEE-ZHER2:342 provided appreciably lower uptake in normal tissues and higher tumor-to-organ ratios than 64Cu-CB-TE2A-G-ZHER2:342 and 64Cu-NODAGA-ZHER2:S1. The most pronounced was a several-fold difference in the hepatic uptake. At the optimal time point, 6 h after injection, the tumor uptake of 64Cu-CB-TE2A-GEEE-ZHER2:342 was 16 ± 6%ID/g and tumor-to-blood ratio was 181 ± 52. In conclusion, a combination of the cross-bridged CB-TE2A chelator and Gly-Glu-Glu-Glu spacer is preferable for radiocopper labelling of Affibody molecules and, possibly, other scaffold proteins having high renal re-absorption.
UR - http://www.scopus.com/inward/record.url?scp=85046069525&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85046069525&partnerID=8YFLogxK
U2 - 10.1038/s41598-018-24785-2
DO - 10.1038/s41598-018-24785-2
M3 - Article
C2 - 29695813
AN - SCOPUS:85046069525
VL - 8
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 6542
ER -