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: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-11-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/21/13443 |
| Summary: | 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. |
|---|---|
| ISSN: | 1661-6596 1422-0067 |