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.
Int J Mol Sci. 2023 Oct 11;24(20):15088. doi: 10.3390/ijms242015088.
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 Cu, log 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-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.
免疫检查点抑制剂疗法针对癌症患者的 PD-1/PD-L1 轴，是一种有前途的肿瘤治疗方法。然而，仍有大量的无反应者，这给患者和医疗系统带来了负担。因此，一种预测治疗效果的诊断工具将有助于患者分层。分子成像通过提供 PD-L1 表达的全身定量评估，提供了这种诊断工具，从而支持治疗决策。合成了四种含有用于放射性金属化的连接子-螯合剂系统的 PD-L1 放射性配体候选物，以及三种亲水性单元-一个磺酸基和两个膦酸基。用 Cu 标记后，确定的 log 值小于-3.03，并在 48 小时后确认了超过 94%的完整化合物的蛋白酶稳定性。使用两种不同的测定法测定了结合亲和力，结果显示高达 13 nM 的高亲和力。在荷瘤小鼠中进行了 µPET/CT 成像，以研究 PD-L1 特异性肿瘤摄取和放射性配体的药代动力学特征。这些结果产生了意想不到的体内分布，例如 PD-L1 阳性肿瘤中的低肿瘤摄取、高肝脏摄取以及在骨/骨髓和潜在的滑膜间隙中的积累。这些影响可能是由 Ca 亲和力和/或与巨噬细胞的结合引起的。尽管膦酸提供了高水溶性，但必须仔细考虑它们的掺入，以避免破坏放射性配体的药代动力学行为。
