Contrast enhanced MRI is commonly used in imaging and treatment planning of prostate cancer. However, no tumor targeting contrast agent is commercially available for accurate detection and characterization of prostate cancer with MRI. Extradomain B fibronectin (EDB-FN), an oncoprotein present in aggressive tumors, is a promising molecular target for detection and stratification of high-risk prostate cancer. In this work, we have identified four small peptides (GVK, IGK, SGV, and ZD2) specific to EDB-FN for tumor targeting. In silico simulations of the binding patterns and affinities of peptides to the EDB protein fragment revealed different binding site to different peptide in the ligand–receptor interactions. Tumor specificity and organ distribution of the peptides were assessed using fluorescence imaging in male mice bearing PC-3 human prostate cancer xenografts. Targeted contrast agents were synthesized by conjugating tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) to the peptides in the solid phase, followed by complexation with GdCl₃. The contrast agents were characterized by MALDI-TOF mass spectrometry and relaxivity measurements. All four peptide Gd–DOTA conjugates resulted in robust tumor contrast enhancement in MR imaging of the PC3 mouse prostate cancer model. The peptide Gd–DOTA conjugates specific to EDB-FN are promising targeted small molecular macrocyclic contrast agents for MR molecular imaging of prostate cancer.

中文翻译：

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合成和评估肽Gd-DOTA结合靶向域外B纤连蛋白的前列腺癌的磁共振分子成像。

对比增强MRI通常用于前列腺癌的成像和治疗计划。但是，尚无可商购的靶向肿瘤的造影剂用于通过MRI准确检测和表征前列腺癌。域外B纤连蛋白（EDB-FN）是侵袭性肿瘤中存在的一种癌蛋白，是检测和分层高危前列腺癌的有希望的分子靶标。在这项工作中，我们确定了EDB-FN特异的四种小肽（GVK，IGK，SGV和ZD2）用于肿瘤靶向。在计算机上肽与EDB蛋白片段的结合模式和亲和力的模拟显示，配体-受体相互作用中与不同肽的结合位点不同。使用携带有PC-3人前列腺癌异种移植物的雄性小鼠的荧光成像评估了肽的肿瘤特异性和器官分布。通过在固相中将四氮杂环十二烷-1,4,7,10-四乙酸（DOTA）与肽缀合，然后与GdCl ₃络合来合成靶向的造影剂。通过MALDI-TOF质谱和弛豫度测量来表征造影剂。在PC3小鼠前列腺癌模型的MR成像中，所有四种肽Gd-DOTA共轭物均能显着增强肿瘤的对比度。EDB-FN特异的肽Gd-DOTA缀合物是用于前列腺癌MR分子成像的有希望的靶向小分子大环造影剂。