Comparative Preclinical Evaluation of Peptide-Based Chelators for the Labeling of DARPin G3 with <sup>99m</sup>Tc for Radionuclide Imaging of HER2 Expression in Cancer
Non-invasive radionuclide imaging of human epidermal growth factor receptor type 2 (HER2) expression in breast, gastroesophageal, and ovarian cancers may stratify patients for treatment using HER2-targeted therapeutics. Designed ankyrin repeat proteins (DARPins) are a promising type of targeting pro...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/21/13443 |
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| author | Mariia Larkina Evgenii Plotnikov Ekaterina Bezverkhniaia Yulia Shabanova Maria Tretyakova Feruza Yuldasheva Roman Zelchan Alexey Schulga Elena Konovalova Anzhelika Vorobyeva Javad Garousi Torbjörn Gräslund Mikhail Belousov Vladimir Tolmachev Sergey Deyev |
| author_facet | Mariia Larkina Evgenii Plotnikov Ekaterina Bezverkhniaia Yulia Shabanova Maria Tretyakova Feruza Yuldasheva Roman Zelchan Alexey Schulga Elena Konovalova Anzhelika Vorobyeva Javad Garousi Torbjörn Gräslund Mikhail Belousov Vladimir Tolmachev Sergey Deyev |
| author_sort | Mariia Larkina |
| collection | DOAJ |
| description | Non-invasive radionuclide imaging of human epidermal growth factor receptor type 2 (HER2) expression in breast, gastroesophageal, and ovarian cancers may stratify patients for treatment using HER2-targeted therapeutics. Designed ankyrin repeat proteins (DARPins) are a promising type of targeting probe for radionuclide imaging. In clinical studies, the DARPin [<sup>99m</sup>Tc]Tc-(HE)<sub>3</sub>-G3 labeled using a peptide-based chelator His-Glu-His-Glu-His-Glu ((HE)<sub>3</sub>), 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 (E<sub>3</sub>C), Gly-Gly-Gly-Cys (G<sub>3</sub>C), and Gly-Gly-Gly-Ser-Cys connected via a (Gly-Gly-Gly-Ser)<sub>3</sub>-linker (designated as G3-(G<sub>3</sub>S)<sub>3</sub>C) would further improve the contrast of imaging using <sup>99m</sup>Tc-labeled derivatives of G3. The labeling of the new variants of G3 provided a radiochemical yield of over 95%. Labeled G3 variants bound specifically to human HER2-expressing cancer cell lines with affinities in the range of 1.9–5 nM. Biodistribution of [<sup>99m</sup>Tc]Tc-G3-G<sub>3</sub>C, [<sup>99m</sup>Tc]Tc-G3-(G<sub>3</sub>S)<sub>3</sub>C, and [<sup>99m</sup>Tc]Tc-G3-E<sub>3</sub>C in mice was compared with the biodistribution of [<sup>99m</sup>Tc]Tc-(HE)<sub>3</sub>-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, [<sup>99m</sup>Tc]Tc-(HE)<sub>3</sub>-G3 provided better contrast between tumors and the most frequent metastatic sites of HER2-expressing cancers and is therefore more suitable for clinical applications. |
| first_indexed | 2024-03-09T18:59:53Z |
| format | Article |
| id | doaj.art-b1a64337c5e043cb8be0635e815b0d3f |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T18:59:53Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b1a64337c5e043cb8be0635e815b0d3f2023-11-24T05:07:59ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123211344310.3390/ijms232113443Comparative Preclinical Evaluation of Peptide-Based Chelators for the Labeling of DARPin G3 with <sup>99m</sup>Tc for Radionuclide Imaging of HER2 Expression in CancerMariia Larkina0Evgenii Plotnikov1Ekaterina Bezverkhniaia2Yulia Shabanova3Maria Tretyakova4Feruza Yuldasheva5Roman Zelchan6Alexey Schulga7Elena Konovalova8Anzhelika Vorobyeva9Javad Garousi10Torbjörn Gräslund11Mikhail Belousov12Vladimir Tolmachev13Sergey Deyev14Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, RussiaResearch Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, RussiaResearch Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, RussiaResearch Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, RussiaResearch Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, RussiaResearch Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, RussiaResearch Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, RussiaResearch Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, RussiaResearch Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, RussiaDepartment of Immunology, Genetics and Pathology, Uppsala University, 75185 Uppsala, SwedenDepartment of Immunology, Genetics and Pathology, Uppsala University, 75185 Uppsala, SwedenDepartment of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, 11417 Stockholm, SwedenResearch Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, RussiaResearch Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, RussiaResearch Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, RussiaNon-invasive radionuclide imaging of human epidermal growth factor receptor type 2 (HER2) expression in breast, gastroesophageal, and ovarian cancers may stratify patients for treatment using HER2-targeted therapeutics. Designed ankyrin repeat proteins (DARPins) are a promising type of targeting probe for radionuclide imaging. In clinical studies, the DARPin [<sup>99m</sup>Tc]Tc-(HE)<sub>3</sub>-G3 labeled using a peptide-based chelator His-Glu-His-Glu-His-Glu ((HE)<sub>3</sub>), 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 (E<sub>3</sub>C), Gly-Gly-Gly-Cys (G<sub>3</sub>C), and Gly-Gly-Gly-Ser-Cys connected via a (Gly-Gly-Gly-Ser)<sub>3</sub>-linker (designated as G3-(G<sub>3</sub>S)<sub>3</sub>C) would further improve the contrast of imaging using <sup>99m</sup>Tc-labeled derivatives of G3. The labeling of the new variants of G3 provided a radiochemical yield of over 95%. Labeled G3 variants bound specifically to human HER2-expressing cancer cell lines with affinities in the range of 1.9–5 nM. Biodistribution of [<sup>99m</sup>Tc]Tc-G3-G<sub>3</sub>C, [<sup>99m</sup>Tc]Tc-G3-(G<sub>3</sub>S)<sub>3</sub>C, and [<sup>99m</sup>Tc]Tc-G3-E<sub>3</sub>C in mice was compared with the biodistribution of [<sup>99m</sup>Tc]Tc-(HE)<sub>3</sub>-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, [<sup>99m</sup>Tc]Tc-(HE)<sub>3</sub>-G3 provided better contrast between tumors and the most frequent metastatic sites of HER2-expressing cancers and is therefore more suitable for clinical applications.https://www.mdpi.com/1422-0067/23/21/13443radionuclideHER2DARPinSPECT<sup>99m</sup>Tcimaging |
| spellingShingle | Mariia Larkina Evgenii Plotnikov Ekaterina Bezverkhniaia Yulia Shabanova Maria Tretyakova Feruza Yuldasheva Roman Zelchan Alexey Schulga Elena Konovalova Anzhelika Vorobyeva Javad Garousi Torbjörn Gräslund Mikhail Belousov Vladimir Tolmachev Sergey Deyev Comparative Preclinical Evaluation of Peptide-Based Chelators for the Labeling of DARPin G3 with <sup>99m</sup>Tc for Radionuclide Imaging of HER2 Expression in Cancer International Journal of Molecular Sciences radionuclide HER2 DARPin SPECT <sup>99m</sup>Tc imaging |
| title | Comparative Preclinical Evaluation of Peptide-Based Chelators for the Labeling of DARPin G3 with <sup>99m</sup>Tc for Radionuclide Imaging of HER2 Expression in Cancer |
| title_full | Comparative Preclinical Evaluation of Peptide-Based Chelators for the Labeling of DARPin G3 with <sup>99m</sup>Tc for Radionuclide Imaging of HER2 Expression in Cancer |
| title_fullStr | Comparative Preclinical Evaluation of Peptide-Based Chelators for the Labeling of DARPin G3 with <sup>99m</sup>Tc for Radionuclide Imaging of HER2 Expression in Cancer |
| title_full_unstemmed | Comparative Preclinical Evaluation of Peptide-Based Chelators for the Labeling of DARPin G3 with <sup>99m</sup>Tc for Radionuclide Imaging of HER2 Expression in Cancer |
| title_short | Comparative Preclinical Evaluation of Peptide-Based Chelators for the Labeling of DARPin G3 with <sup>99m</sup>Tc for Radionuclide Imaging of HER2 Expression in Cancer |
| title_sort | comparative preclinical evaluation of peptide based chelators for the labeling of darpin g3 with sup 99m sup tc for radionuclide imaging of her2 expression in cancer |
| topic | radionuclide HER2 DARPin SPECT <sup>99m</sup>Tc imaging |
| url | https://www.mdpi.com/1422-0067/23/21/13443 |
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