Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Comparative Preclinical Evaluation of Peptide-Based Chelators for Labeling of DARPin G3 with 99mTc for Radionuclide Imaging of HER2 Expression in Cancer

Maria Larkina
,
Evgenii Plotnikov
,
Ekaterina Bezverkhniaia
ORCID logo ,
Yulia Shabanova
,
Maria Tretyakova
,
Feruza Yuldasheva
,
Roman Zelchan
,
Alexey Schulga
ORCID logo ,
Elena Konovalova
,
Anzhelika Vorobyeva
ORCID logo ,
Javad Garousi
ORCID logo ,
Torbjörn Gräslund
ORCID logo ,
Mikhail Belousov
,
Vladimir Tolmachev
* ORCID logo ,
Sergey M. Deyev
ORCID logo
Version 1 : Received: 4 October 2022 / Approved: 6 October 2022 / Online: 6 October 2022 (08:09:37 CEST)

A peer-reviewed article of this Preprint also exists.

Larkina, M.; Plotnikov, E.; Bezverkhniaia, E.; Shabanova, Y.; Tretyakova, M.; Yuldasheva, F.; Zelchan, R.; Schulga, A.; Konovalova, E.; Vorobyeva, A.; Garousi, J.; Gräslund, T.; Belousov, M.; Tolmachev, V.; Deyev, S. Comparative Preclinical Evaluation of Peptide-Based Chelators for the Labeling of DARPin G3 with 99mTc for Radionuclide Imaging of HER2 Expression in Cancer. Int. J. Mol. Sci. 2022, 23, 13443. Larkina, M.; Plotnikov, E.; Bezverkhniaia, E.; Shabanova, Y.; Tretyakova, M.; Yuldasheva, F.; Zelchan, R.; Schulga, A.; Konovalova, E.; Vorobyeva, A.; Garousi, J.; Gräslund, T.; Belousov, M.; Tolmachev, V.; Deyev, S. Comparative Preclinical Evaluation of Peptide-Based Chelators for the Labeling of DARPin G3 with 99mTc for Radionuclide Imaging of HER2 Expression in Cancer. Int. J. Mol. Sci. 2022, 23, 13443.

Abstract

Non-invasive radionuclide imaging of human epidermal growth factor receptor type 2 (HER2) expression in breast, gastroesopha-geal and ovarian cancers may stratify patients for treatment using HER2-targeted therapeutics. Designed ankyrin repeat proteins (DARPins) are a promising type of targeting probes for radionuclide imaging. In clinical studies, the DARPin [99mTc]Tc-(HE)3-G3, labeled using a peptide-based chelator His-Glu-His-Glu-His-Glu ((HE)3), provided clear imaging of HER2 expressing breast cancer 2-4 h after injection. The goal of this study was to evaluate if the use of cysteine-containing peptide-based chelators Glu-Glu-Glu-Cys (E3C), Gly-Gly-Gly-Cys (G3C), and Gly-Gly-Gly-Ser-Cys connected via a (Gly-Gly-Gly-Ser)3-linker (designated as G3-(G3S)3C) would further improve the contrast of imaging using 99mTc-labeled derivatives of G3. The labeling of the new variants of G3 provided a radiochemical yield over 95%. Labeled G3 variants bound specifically to human HER2-expressing cancer cell lines with affinity in the range 1.9-5 nM. Biodistribution of [99mTc]Tc-G3-G3C, [99mTc]Tc-G3-(G3S)3C, and [99mTc]Tc-G3-E3C in mice was compared with the biodistribution of [99mTc]Tc-(HE)3-G3. It was found that the novel variants provide specific accumulation in HER2-expressing human xenografts and enable discrimination between tumors with high and low HER2 expression. However, [99mTc]Tc-(HE)3-G3 provided better contrast between tumors and the most frequent metastatic sites of HER2-expressing cancers and is therefore more suitable for clinical applications.

Keywords

radionuclide; HER2; DARPin; SPECT; 99mTc; imaging; cancer

Subject

Medicine and Pharmacology, Pharmacology and Toxicology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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