Optimization of ZD2 Peptide Targeted Gd(HP-DO3A) for Detection and Risk-Stratification of Prostate Cancer with MRI.,ACS Medicinal Chemistry Letters

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Optimization of ZD2 Peptide Targeted Gd(HP-DO3A) for Detection and Risk-Stratification of Prostate Cancer with MRI.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-06-06 , DOI: 10.1021/acsmedchemlett.8b00172
Nadia R Ayat ₁ , Jing-Can Qin ₁ , Han Cheng ₁ , Sarah Roelle ₁ , Songqi Gao _{1,

2} , Yajuan Li ₂ , Zheng-Rong Lu ₁

Affiliation

The aim of this work is to optimize a peptide targeted macrocyclic MRI contrast agent for detection and risk-stratification of aggressive prostate cancer. The optimized agent was prepared using click chemistry in the presence of CuSO4 and ascorbate at room temperature. The T1 and T2 relaxivities of ZD2-N3-Gd(HP-DO3A) are 5.44 and 7.10 mM-1 s-1 at 1.4 T, and 5.53 and 7.81 mM-1 s-1 at 7 T, respectively, higher than the previously reported ZD2-Gd(HP-DO3A). The specific tumor enhancement of the agent was investigated in male nude mice bearing aggressive PC3 human prostate cancer xenografts and slow-growing LNCaP tumor xenografts. Contrast enhanced MR images were acquired using a 2D spin-echo sequence and a 3D FLASH sequence with a 7 T small animal scanner. ZD2-N3-Gd(HP-DO3A) produced robust contrast enhancement in aggressive PC3 tumors and little enhancement in slow-growing LNCaP tumors. It produced 400% and 100% CNR increases in the T1-weighted 2D spin-echo MR images and 3D FLASH images of PC3 tumors, respectively, for at least 30 min at a dose of 0.1 mmol/kg. In contrast, less than 20% CNR increase was observed in the LNCaP tumors with both sequences. The optimized targeted contrast agent has higher relaxivities and are effective to detect aggressive PC3 tumors and differentiate the aggressive cancer from the slow-growing LNCaP prostate cancer in contrast enhanced MRI. ZD2-N3-Gd(HP-DO3A) has the promise for accurate detection and risk-stratification of aggressive prostate cancer.

中文翻译：

ZD2 肽靶向 Gd(HP-DO3A) 的优化，用于 MRI 前列腺癌的检测和风险分层。

这项工作的目的是优化肽靶向大环 MRI 造影剂，用于侵袭性前列腺癌的检测和风险分层。优化的试剂是在室温下在 CuSO4 和抗坏血酸存在下使用点击化学制备的。 ZD2-N3-Gd(HP-DO3A)的T1和T2弛豫率在1.4 T时分别为5.44和7.10 mM-1 s-1，在7 T时分别为5.53和7.81 mM-1 s-1，高于先前的结果报道了ZD2-Gd(HP-DO3A)。在携带侵袭性 PC3 人类前列腺癌异种移植物和缓慢生长的 LNCaP 肿瘤异种移植物的雄性裸鼠中研究了该药物的特异性肿瘤增强作用。使用 7 T 小动物扫描仪使用 2D 自旋回波序列和 3D FLASH 序列获取对比增强 MR 图像。 ZD2-N3-Gd(HP-DO3A) 在侵袭性 PC3 肿瘤中产生强烈的对比度增强，而在缓慢生长的 LNCaP 肿瘤中产生很少的增强。在 0.1 mmol/kg 的剂量下，它在 T1 加权 2D 自旋回波 MR 图像和 3D FLASH 图像中分别产生 400% 和 100% CNR 增加，持续至少 30 分钟。相比之下，在具有这两种序列的 LNCaP 肿瘤中观察到 CNR 增加不到 20%。优化后的靶向造影剂具有更高的弛豫度，可有效检测侵袭性PC3肿瘤，并在对比增强MRI中区分侵袭性癌症与缓慢生长的LNCaP前列腺癌。 ZD2-N3-Gd(HP-DO3A) 有望准确检测侵袭性前列腺癌并进行风险分层。

更新日期：2018-06-06

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