68Ga 标记的聚乙二醇化 PSMA 多聚体改善前列腺癌药代动力学的影像学/结构研究,Pharmaceuticals

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68Ga 标记的聚乙二醇化 PSMA 多聚体改善前列腺癌药代动力学的影像学/结构研究
Pharmaceuticals ( IF 4.286 ) Pub Date : 2023-04-14 , DOI: 10.3390/ph16040589
Huihui Zhang ₁ , Maohua Rao ₁ , Huayi Zhao ₁ , Jianli Ren ₂ , Lan Hao ₂ , Meng Zhong ₃ , Yue Chen ₄ , Xia Yang ₅ , Yue Feng ₄ , Gengbiao Yuan ₁

Affiliation

PMSA（前列腺特异性膜抗原）是目前诊断和治疗 PCa（前列腺癌）最重要的靶标。在此，我们报道了一系列与 PEG 链结合的 68Ga/177Lu 标记的多聚体 PSMA 示踪剂，包括 [68Ga]Ga-DOTA-(1P-PEG4)、[68Ga]Ga-DOTA-(2P-PEG0)、[68Ga]Ga -DOTA-(2P-PEG4) 和 [68Ga]Ga/[177Lu]Lu-DOTA-(2P-PEG4)2，显示出多价效应和聚乙二醇化的优势，可实现更高的肿瘤积累和更快的肾脏清除。为了弄清楚基于 PSMA 多聚体和聚乙二醇化的结构优化如何影响探针的肿瘤靶向能力、生物分布和新陈代谢，我们检测了 PSMA 分子探针对 PC-3 PIP（PSMA 高表达 PC-3 细胞系）的亲和力, 并进行了药代动力学分析、生物分布检测、小动物 PET/CT 和 SPECT/CT 成像。结果表明，PEG4 和 PSMA 二聚体优化增强了探针在 PC-3 PIP 荷瘤小鼠模型中的肿瘤靶向能力。与PSMA单体相比，聚乙二醇化PSMA二聚体降低了血液中的消除半衰期，增加了肿瘤中的摄取，生物分布结果与PET/CT成像结果一致。[68Ga]Ga-DOTA-(2P-PEG4)2 表现出更高的肿瘤器官比。当用 lutetium-177 标记时，48 小时后在 PC-3 PIP 荷瘤小鼠模型中仍检测到相对较高的 DOTA-(2P-PEG4)2 积累，表明其肿瘤保留时间延长。鉴于DOTA-(2P-PEG4)2在成像上的优势、简单的合成过程和结构稳定性，有望成为未来临床实践中有前途的肿瘤靶向诊断分子探针。

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Imageological/Structural Study regarding the Improved Pharmacokinetics by 68Ga-Labeled PEGylated PSMA Multimer in Prostate Cancer

PMSA (prostate-specific membrane antigen) is currently the most significant target for diagnosing and treating PCa (prostate cancer). Herein, we reported a series 68Ga/177Lu-labeled multimer PSMA tracer conjugating with PEG chain, including [68Ga]Ga-DOTA-(1P-PEG4), [68Ga]Ga-DOTA-(2P-PEG0), [68Ga]Ga-DOTA-(2P-PEG4), and [68Ga]Ga/[177Lu]Lu-DOTA-(2P-PEG4)2, which showed an advantage of a multivalent effect and PEGylation to achieve higher tumor accumulation and faster kidney clearance. To figure out how structural optimizations based on a PSMA multimer and PEGylation influence the probe’s tumor-targeting ability, biodistribution, and metabolism, we examined PSMA molecular probes’ affinities to PC-3 PIP (PSMA-highly-expressed PC-3 cell line), and conducted pharmacokinetics analysis, biodistribution detection, small animal PET/CT, and SPECT/CT imaging. The results showed that PEG4 and PSMA dimer optimizations enhanced the probes’ tumor-targeting ability in PC-3 PIP tumor-bearing mice models. Compared with the PSMA monomer, the PEGylated PSMA dimer reduced the elimination half-life in the blood and increased uptake in the tumor, and the biodistribution results were consistent with PET/CT imaging results. [68Ga]Ga-DOTA-(2P-PEG4)2 exhibited higher tumor-to-organ ratios. When labeled by lutetium-177, relatively high accumulation of DOTA-(2P-PEG4)2 was still detected in PC-3 PIP tumor-bearing mice models after 48 h, indicating its prolonged tumor retention time. Given the superiority in imaging, simple synthetic processes, and structural stability, DOTA-(2P-PEG4)2 is expected to be a promising tumor-targeting diagnostic molecular probe in future clinical practice.

更新日期：2023-04-14

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