Synthesis and Preclinical Evaluation of a 68Ga-Radiolabeled Peptide Targeting Very Late Antigen-3 for PET Imaging of Pancreatic Cancer.,Molecular Pharmaceutics

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Synthesis and Preclinical Evaluation of a 68Ga-Radiolabeled Peptide Targeting Very Late Antigen-3 for PET Imaging of Pancreatic Cancer.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-06-16 , DOI: 10.1021/acs.molpharmaceut.0c00416
Huiling Li _{1,

2} , Lujie Yuan _{1,

2,

3} , Yu Long _{1,

2} , Hanyi Fang _{1,

2} , Mengting Li _{1,

2} , Qingyao Liu _{1,

2} , Xiaotian Xia _{1,

2} , Chunxia Qin _{1,

2} , Yongxue Zhang _{1,

2} , Xiaoli Lan _{1,

2} , Yongkang Gai _{1,

2}

Affiliation

Pancreatic cancer is highly malignant and has a five-year survival rate of 5% due to an early lymph node, nerve, and vascular metastasis. Integrin α₃β₁ (also called very late antigen-3, VLA-3) is overexpressed in many tumors and plays a vital role in tumor formation, recurrence, and metastasis. In this study, we developed a ⁶⁸Ga-radiolabeled peptide tracer targeting the α₃ unit of VLA-3 and evaluated its potential application in positron emission computed tomography (PET) imaging of pancreatic cancer. NOTA-CK11 was prepared by solid-phase synthesis and successfully radiolabeled with ⁶⁸Ga with greater than 99% radiochemical purity and a specific activity of 37 ± 5 MBq/nmol (n = 5). The expression level of integrin α₃ in three human pancreatic cancer cells was evaluated with the order of SW1990, BXPC-3, and PANC-1 from high to low, while the expression level of integrin β₁ was relatively close. When SW1990 cells with the highest expression level of VLA-3 were stained with FITC–CK11, strong fluorescence was observed by flow cytometry and under a laser confocal microscope. However, no significant fluorescence was observed in the blocking group when treated with excessive CK11. ⁶⁸Ga-NOTA-CK11 showed significant radioactivity accumulation in SW1990 cells and was blocked by CK11 successfully. Subsequent small-animal PET imaging and biodistribution studies in mice bearing SW1990 xenografts confirmed its high tumor uptake with a good tumor-to-blood ratio and tumor-to-muscle ratio (2.45 ± 0.31 and 3.65 ± 0.33, respectively) at 1 h post injection of the probe. In summary, we successfully developed a peptide-based imaging agent, ⁶⁸Ga-NOTA-CK11, that showed a strong binding affinity with VLA-3 and good target specificity for SW1990 cells and xenografted pancreatic tumor, rending it a promising radiotracer for PET imaging of VLA-3 expression in pancreatic cancer.

中文翻译：

用于胰腺癌 PET 成像的靶向极晚期抗原 3 的 68Ga 放射性标记肽的合成和临床前评估。

胰腺癌恶性程度高，由于早期淋巴结、神经、血管转移，五年生存率为5%。整合素α ₃ β ₁ （也称为极晚期抗原3，VLA-3）在许多肿瘤中过度表达，在肿瘤形成、复发和转移中发挥着至关重要的作用。在本研究中，我们开发了一种针对 VLA-3 α ₃单元的⁶⁸ Ga 放射性标记肽示踪剂，并评估了其在胰腺癌正电子发射计算机断层扫描 (PET) 成像中的潜在应用。 NOTA-CK11 采用固相合成法制备，并成功用⁶⁸ Ga 进行放射性标记，放射化学纯度大于 99%，比活度为 37 ± 5 MBq/nmol ( n = 5)。三种人胰腺癌细胞中整合素α ₃的表达水平从高到低依次为SW1990、BXPC-3、PANC-1，而整合素β ₁的表达水平较为接近。当VLA-3表达水平最高的SW1990细胞用FITC-CK11染色时，流式细胞仪和激光共聚焦显微镜下观察到强荧光。然而，当用过量的CK11处理时，在阻断组中没有观察到明显的荧光。 ⁶⁸ Ga-NOTA-CK11在SW1990细胞中表现出明显的放射性积累，并被CK11成功阻断。随后在带有 SW1990 异种移植物的小鼠中进行的小动物 PET 成像和生物分布研究证实了其在移植后 1 小时具有良好的肿瘤与血液比率和肿瘤与肌肉比率（分别为 2.45 ± 0.31 和 3.65 ± 0.33）的高肿瘤摄取注射探针。总之，我们成功开发了一种基于肽的显像剂⁶⁸ Ga-NOTA-CK11，它与 VLA-3 具有很强的结合亲和力，对 SW1990 细胞和异种移植胰腺肿瘤具有良好的靶特异性，使其成为 PET 成像的一种有前途的放射性示踪剂胰腺癌中 VLA-3 的表达。

更新日期：2020-08-03

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