| Autor: |
Krutzek F; Helmholtz Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Medicinal Radiochemistry, Bautzner Landstraße 400, 01328 Dresden, Germany., Donat CK; Helmholtz Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Medicinal Radiochemistry, Bautzner Landstraße 400, 01328 Dresden, Germany., Stadlbauer S; Helmholtz Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Medicinal Radiochemistry, Bautzner Landstraße 400, 01328 Dresden, Germany.; School of Science, Faculty of Chemistry and Food Chemistry, Technical University Dresden, 01069 Dresden, Germany. |
| Jazyk: |
angličtina |
| Zdroj: |
International journal of molecular sciences [Int J Mol Sci] 2023 Oct 11; Vol. 24 (20). Date of Electronic Publication: 2023 Oct 11. |
| DOI: |
10.3390/ijms242015088 |
| Abstrakt: |
Immune checkpoint inhibitor therapy targeting the PD-1/PD-L1 axis in cancer patients, is a promising oncological treatment. However, the number of non-responders remains high, causing a burden for the patient and the healthcare system. Consequently, a diagnostic tool to predict treatment outcomes would help with patient stratification. Molecular imaging provides said diagnostic tool by offering a whole-body quantitative assessment of PD-L1 expression, hence supporting therapy decisions. Four PD-L1 radioligand candidates containing a linker-chelator system for radiometalation, along with three hydrophilizing units-one sulfonic and two phosphonic acids-were synthesized. After labeling with 64 Cu, log D 7.4 values of less than -3.03 were determined and proteolytic stability confirmed over 94% intact compound after 48 h. Binding affinity was determined using two different assays, revealing high affinities up to 13 nM. µPET/CT imaging was performed in tumor-bearing mice to investigate PD-L1-specific tumor uptake and the pharmacokinetic profile of radioligands. These results yielded an unexpected in vivo distribution, such as low tumor uptake in PD-L1 positive tumors, high liver uptake, and accumulation in bone/bone marrow and potentially synovial spaces. These effects are likely caused by Ca 2+ -affinity and/or binding to macrophages. Despite phosphonic acids providing high water solubility, their incorporation must be carefully considered to avoid compromising the pharmacokinetic behavior of radioligands. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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