Ghanaatgar Kasbi Sadaf, Savard Martin, Couture Frédéric, Dubuc Céléna, Dumulon-Perreault Véronique, Nepveu-Traversy Marie-Edith, Ait-Mohand Samia, Sabbagh Robert, Geha Sameh, Guérin Brigitte, Dory Yves, Gobeil Fernand
Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
Institute of Pharmacology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
Pharmaceutics. 2025 Sep 18;17(9):1215. doi: 10.3390/pharmaceutics17091215.
: This study explores the potential of the inducible G protein-coupled kinin B1 receptor (B1R) as a target for the diagnosis and treatment of prostate cancer (PCa) and aims to develop the first theranostic agent targeting hB1R for both molecular imaging and radionuclide therapy. : B1R expression was analyzed via qPCR and immunohistochemistry in human PCa cells and tissues specimens. A novel Cu/NOTA-conjugated peptide analog of the potent B1R antagonist R954 was synthetized and evaluated in vitro and in vivo. : B1R was confirmed to be expressed (RNA, protein) by varying degrees in all PCa cell lines and tissues investigated, with protein level significantly correlating with tumor grades. This finding was supported by similar analyses from the TCGA and MSKCC databases. In vitro, the Cu/NOTA-βAla-R954 conjugate showed nanomolar affinity/potency at hB1R, complete plasma stability over 24 h, significant cellular uptake (up to 33% of ID at 24 h), and dose-dependent anti-clonal growth effects. In vivo, the radioconjugate remained stable in circulation for up to 90 min and was primarily excreted intact via the kidneys following IV administration. Intravenous Cu/NOTA-βAla-R954 (7.5 MBq) effectively detected subcutaneous PCa xenografts via µPET imaging in male athymic nude mice. At a single higher dose (65 MBq; 50 µg/kg), it significantly reduced tumor growth without observable toxicity. This antitumor effect was associated with increased apoptosis (active caspase-3) and reduced proliferation (Ki67), as shown by immunohistochemistry. In contrast, the nonradioactive Cu/NOTA-βAla-R954 had no therapeutic effect at the same dose. : Our findings provide proof-of-concept for the potential theranostic use of Cu/NOTA-R954 in PCa, and potentially other types of B1R-positive solid cancers.
本研究探讨了可诱导的G蛋白偶联激肽B1受体（B1R）作为前列腺癌（PCa）诊断和治疗靶点的潜力，旨在开发首个靶向人B1R的用于分子成像和放射性核素治疗的诊疗试剂。通过qPCR和免疫组织化学分析人PCa细胞和组织标本中的B1R表达。合成了一种新型的与Cu/NOTA偶联的强效B1R拮抗剂R954的肽类似物，并在体外和体内进行评估。在所研究的所有PCa细胞系和组织中，均证实B1R有不同程度的表达（RNA、蛋白质），蛋白质水平与肿瘤分级显著相关。TCGA和MSKCC数据库的类似分析也支持了这一发现。在体外，Cu/NOTA-βAla-R954偶联物对人B1R显示出纳摩尔亲和力/效能，在24小时内血浆稳定性良好，有显著的细胞摄取（24小时时高达注射剂量的33%），以及剂量依赖性的抗克隆生长效应。在体内，放射性偶联物在循环中保持稳定长达90分钟，静脉注射后主要通过肾脏完整排泄。静脉注射Cu/NOTA-βAla-R954（7.5 MBq）可通过μPET成像有效检测雄性无胸腺裸鼠皮下的PCa异种移植瘤。在单一较高剂量（65 MBq；50 μg/kg）时，它能显著抑制肿瘤生长且无明显毒性。免疫组织化学显示，这种抗肿瘤作用与凋亡增加（活化的半胱天冬酶-3）和增殖减少（Ki67）有关。相比之下，相同剂量的非放射性Cu/NOTA-βAla-R954没有治疗效果。我们的研究结果为Cu/NOTA-R954在PCa以及可能的其他类型B1R阳性实体癌中的潜在诊疗应用提供了概念验证。
