Eder Ann-Christin, Matthias Jessica, Schäfer Martin, Schmidt Jana, Steinacker Nils, Bauder-Wüst Ulrike, Domogalla Lisa-Charlotte, Roscher Mareike, Haberkorn Uwe, Eder Matthias, Kopka Klaus
Department of Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Department of Nuclear Medicine, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
Pharmaceuticals (Basel). 2022 Feb 22;15(3):267. doi: 10.3390/ph15030267.
The development of PSMA-targeting low-molecular-weight hybrid molecules aims at advancing preoperative imaging and accurate intraoperative fluorescence guidance for improved diagnosis and therapy of prostate cancer. In hybrid probe design, the major challenge is the introduction of a bulky dye to peptidomimetic core structures without affecting tumor-targeting properties and pharmacokinetic profiles. This study developed a novel class of PSMA-targeting hybrid molecules based on the clinically established theranostic agent PSMA-617. The fluorescent dye-bearing candidates of the strategically designed molecule library were evaluated in in vitro assays based on their PSMA-binding affinity and internalization properties to identify the most favorable hybrid molecule composition for the installation of a bulky dye. The library's best candidate was realized with IRDye800CW providing the lead compound. Glu-urea-Lys-2-Nal-Chx-Lys(IRDye800CW)-DOTA (PSMA-927) was investigated in an in vivo proof-of-concept study, with compelling performance in organ distribution studies, PET/MRI and optical imaging, and with a strong PSMA-specific tumor uptake comparable to that of PSMA-617. This study provides valuable insights about the design of PSMA-targeting low-molecular-weight hybrid molecules, which enable further advances in the field of peptidomimetic hybrid molecule development.
靶向前列腺特异性膜抗原（PSMA）的低分子量杂合分子的研发旨在推进术前成像及精确的术中荧光引导，以改善前列腺癌的诊断与治疗。在杂合探针设计中，主要挑战在于将体积较大的染料引入拟肽核心结构，同时又不影响肿瘤靶向特性和药代动力学特征。本研究基于临床已确立的诊疗试剂PSMA-617开发了一类新型的靶向PSMA的杂合分子。基于其PSMA结合亲和力和内化特性，在体外试验中对经策略性设计的分子库中带有荧光染料的候选物进行评估，以确定安装体积较大染料的最适宜杂合分子组成。用IRDye800CW实现了该分子库的最佳候选物，从而得到先导化合物。对Glu-尿素-Lys-2-Nal-Chx-Lys(IRDye800CW)-DOTA（PSMA-927）进行了体内概念验证研究，其在器官分布研究、PET/MRI和光学成像中表现出色，并且具有与PSMA-617相当的强烈的PSMA特异性肿瘤摄取。本研究为靶向PSMA的低分子量杂合分子的设计提供了有价值的见解，这能够推动拟肽杂合分子研发领域的进一步发展。
