Department of Medical Imaging, Nuclear Medicine, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
Radboud University Nijmegen, Institute for Molecules and Materials, Systems Chemistry, Nijmegen, The Netherlands.
Theranostics. 2021 Jan 1;11(4):1527-1541. doi: 10.7150/thno.52166. eCollection 2021.
Incomplete resection of prostate cancer (PCa) occurs in 15%-50% of PCa patients. Disease recurrence negatively impacts oncological outcome. The use of radio-, fluorescent-, or photosensitizer-labeled ligands to target the prostate-specific membrane antigen (PSMA) has become a well-established method for the detection and treatment of PCa. Here, we developed and characterized multimodal [In]In-DOTA(GA)-IRDye700DX-PSMA ligands, varying in their molecular composition, for use in intraoperative radiodetection, fluorescence imaging and targeted photodynamic therapy of PCa lesions. PSMA-specificity of these ligands was determined in xenograft tumor models and on fresh human PCa biopsies. Ligand structure optimization showed that addition of the photosensitizer (IRDye700DX) and additional negative charges significantly increased ligand uptake in PSMA-expressing tumors. Moreover, an incubation study on human tumor biopsies confirmed the PSMA-specificity of these ligands on human samples, bridging the gap to the clinical situation. We developed a novel PSMA-targeting ligand, optimized for multimodal image-guided PCa surgery combined with targeted photodynamic therapy.
前列腺癌（PCa）患者中有 15%-50%存在前列腺癌不完全切除。疾病复发对肿瘤学结果有负面影响。放射性、荧光性或光敏剂标记配体靶向前列腺特异性膜抗原（PSMA）的使用已成为检测和治疗 PCa 的成熟方法。 在这里，我们开发并表征了多种模式的 [In]In-DOTA(GA)-IRDye700DX-PSMA 配体，其分子组成不同，用于 PCa 病变的术中放射检测、荧光成像和靶向光动力治疗。在异种移植肿瘤模型和新鲜人前列腺癌活检上确定了这些配体的 PSMA 特异性。配体结构优化表明，添加光敏剂（IRDye700DX）和额外的负电荷可显著增加 PSMA 表达肿瘤中的配体摄取。此外，对人肿瘤活检的孵育研究证实了这些配体在人样本上的 PSMA 特异性，弥合了与临床情况的差距。 我们开发了一种新型 PSMA 靶向配体，经过优化可用于多模态图像引导的 PCa 手术联合靶向光动力治疗。
