Comparative Preclinical Evaluation of HYNIC-Modified Designed Ankyrin Repeat Proteins G3 for the 99m Tc-Based Imaging of HER2-Expressing Malignant Tumors.

Autor: Larkina M; Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia.; Department of Pharmaceutical Analysis, Siberian State Medical University, 634050 Tomsk, Russia., Varvashenya R; Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia.; Department of Pharmaceutical Analysis, Siberian State Medical University, 634050 Tomsk, Russia., Yuldasheva F; Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia., Plotnikov E; Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia., Bezverkhniaia E; Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia., Tretyakova M; Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia., Zelchan R; Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia.; Department of Nuclear Medicine, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634009 Tomsk, Russia., Schulga A; Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia.; Molecular Immunology Laboratory, Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia., Konovalova E; Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia.; Molecular Immunology Laboratory, Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia., Vorobyeva A; Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden., Belousov M; Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia.; Department of Pharmaceutical Analysis, Siberian State Medical University, 634050 Tomsk, Russia., Orlova A; Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden., Tolmachev V; Department of Immunology, Genetics and Pathology, Uppsala University, 75185 Uppsala, Sweden., Deyev S; Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia.; Molecular Immunology Laboratory, Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia.
Jazyk: angličtina
Zdroj: Molecular pharmaceutics [Mol Pharm] 2024 Apr 01; Vol. 21 (4), pp. 1919-1932.
DOI: 10.1021/acs.molpharmaceut.3c01173
Abstrakt: HER2 status determination is a necessary step for the proper choice of therapy and selection of patients for the targeted treatment of cancer. Targeted radiotracers such as radiolabeled DARPins provide a noninvasive and effective way for the molecular imaging of HER2 expression. This study aimed to evaluate tumor-targeting properties of three 99m Tc-labeled DARPin G3 variants containing Gly-Gly-Gly-Cys (G 3 C), (Gly-Gly-Gly-Ser) 3 -Cys ((G 3 S) 3 C), or Glu-Glu-Glu-Cys (E 3 C) amino acid linkers at the C-terminus and conjugated to the HYNIC chelating agent, as well as to compare them with the clinically evaluated DARPin G3 labeled with 99m Tc(CO) 3 using the (HE) 3 -tag at the N-terminus. The labeling of DARPin G3-HYNIC variants provided radiochemical yields in the range of 50-80%. Labeled variants bound specifically to human HER2-expressing cancer cell lines with affinities in the range of 0.5-3 nM. There was no substantial influence of the linker and HYNIC chelator on the binding of 99m Tc-labeled DARPin G3 variants to HER2 in vitro; however, [ 99m Tc]Tc-G3-(G 3 S) 3 C-HYNIC had the highest affinity. Comparative biodistribution of [ 99m Tc]Tc-G3-G 3 C-HYNIC, [ 99m Tc]Tc-G3-(G 3 S) 3 C-HYNIC, [ 99m Tc]Tc-G3-E 3 C-HYNIC, and [ 99m Tc]Tc-(HE) 3 -G3 in healthy CD1 mice showed that there was a strong influence of the linkers on uptake in normal tissues. [ 99m Tc]Tc-G3-E 3 C-HYNIC had an increased retention of activity in the liver and the majority of other organs compared to the other conjugates. The tumor uptake of [ 99m Tc]Tc-G3-(G 3 S) 3 C-HYNIC and [ 99m Tc]Tc-(HE) 3 -G3 in Nu/j mice bearing SKOV-3 xenografts was similar. The specificity of tumor targeting in vivo was demonstrated for both tracers. [ 99m Tc]Tc-G3-(G 3 S) 3 C-HYNIC provided comparable, although slightly lower tumor-to-lung, tumor-to spleen and tumor-to-liver ratios than [ 99m Tc]Tc-(HE) 3 -G3. Radiolabeling of DARPin G3-HYNIC conjugates with 99m Tc provided the advantage of a single-step radiolabeling procedure; however, the studied HYNIC conjugates did not improve imaging contrast compared to the 99m Tc-tricarbonyl-labeled DARPin G3. At this stage, [ 99m Tc]Tc-(HE) 3 -G3 remains the most promising candidate for the clinical imaging of HER2-overexpressing cancers.
Databáze: MEDLINE
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