Preclinical Evaluation of an Al18F-Radiolabeled Bicyclic Peptide Targeting Nectin-4.

IF 4.5 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
Molecular Pharmaceutics Pub Date : 2025-01-06 Epub Date: 2024-12-09 DOI:10.1021/acs.molpharmaceut.4c00858
Xiaojiang Duan, Zhuochen Zhang, Hongchuang Xu, Jingming Zhang, Yue Yan, Xing Yang
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引用次数: 0

Abstract

Precisely assessing nectin-4 expression in tumors is important in identifying patients who may benefit from nectin-4-targeted therapies. In our previous work, we developed a bicyclic peptide-based nectin-4-targeting radiotracer 68Ga-N188 and validated its nectin-4 detection efficacy. However, the relatively short half-life and low positron emission rate of 68Ga limit its further application. In this study, we constructed three novel nectin-4-targeting ligands N230-232 based on a bicyclic peptide structure and labeled with radionuclide 18F, which has a longer half-life and a higher positron emission rate, for PET imaging. Micro-PET/CT imaging-based screening showed that Al18F-N231 had the best imaging contrast with a tumor-to-muscle ratio of 10.97 ± 2.39. Further characterization demonstrated that ligand N231 had a high affinity to nectin-4 with a Kd of 4.29 nM, and Al18F-N231 had a good stability and safety profile in vivo. Biodistribution studies validated the specific binding of Al18F-N231 to nectin-4 in vivo, with tumor uptake in the nectin-4+ SW780 tumor group being 1.45- and 3.75-fold higher than that in the nectin-4- 5637 tumor group and blocking group, respectively. Based on the results of this work, Al18F-N231 has promising capability for noninvasive nectin-4 detection in vivo.

靶向Nectin-4的al18f放射性标记双环肽的临床前评价。
准确评估肿瘤中nectin-4的表达对于确定可能受益于nectin-4靶向治疗的患者非常重要。在我们之前的工作中,我们开发了一种基于双环肽的nectin-4靶向放射性示踪剂68Ga-N188,并验证了其检测nectin-4的有效性。然而,68Ga的半衰期较短,正电子发射率低,限制了其进一步的应用。在本研究中,我们基于双环肽结构构建了三个新的靶向连接素-4的配体N230-232,并以半衰期更长、正电子发射率更高的放射性核素18F标记,用于PET成像。基于Micro-PET/CT成像的筛查显示,Al18F-N231具有最佳的成像对比度,肿瘤与肌肉的比值为10.97±2.39。进一步表征表明,配体N231与连接蛋白-4具有较高的亲和力,Kd值为4.29 nM, Al18F-N231具有良好的体内稳定性和安全性。生物分布研究证实了Al18F-N231与nectin-4在体内的特异性结合,与nectin-4- 5637肿瘤组和阻断组相比,nectin-4+ SW780肿瘤组的肿瘤摄取分别高出1.45倍和3.75倍。基于本工作的结果,Al18F-N231具有在体内无创检测连接素-4的良好能力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular Pharmaceutics
Molecular Pharmaceutics 医学-药学
CiteScore
8.00
自引率
6.10%
发文量
391
审稿时长
2 months
期刊介绍: Molecular Pharmaceutics publishes the results of original research that contributes significantly to the molecular mechanistic understanding of drug delivery and drug delivery systems. The journal encourages contributions describing research at the interface of drug discovery and drug development. Scientific areas within the scope of the journal include physical and pharmaceutical chemistry, biochemistry and biophysics, molecular and cellular biology, and polymer and materials science as they relate to drug and drug delivery system efficacy. Mechanistic Drug Delivery and Drug Targeting research on modulating activity and efficacy of a drug or drug product is within the scope of Molecular Pharmaceutics. Theoretical and experimental peer-reviewed research articles, communications, reviews, and perspectives are welcomed.
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