Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China.
Mol Pharm. 2020 Aug 3;17(8):3000-3008. doi: 10.1021/acs.molpharmaceut.0c00416. Epub 2020 Jun 30.
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 αβ (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 Ga-radiolabeled peptide tracer targeting the α 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 Ga with greater than 99% radiochemical purity and a specific activity of 37 ± 5 MBq/nmol ( = 5). The expression level of integrin α 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 β 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. Ga-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, Ga-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.
胰腺癌恶性程度高，由于早期淋巴结、神经和血管转移，五年生存率仅为 5%。整合素 αβ（也称为晚期抗原-3，VLA-3）在许多肿瘤中过度表达，在肿瘤的形成、复发和转移中发挥重要作用。在本研究中，我们开发了一种针对 VLA-3α 亚基的 Ga 放射性标记肽示踪剂，并评估了其在胰腺癌正电子发射断层扫描（PET）成像中的潜在应用。NOTA-CK11 通过固相合成制备，并成功用 Ga 放射性标记，放射化学纯度大于 99%，比活度为 37±5MBq/nmol（=5）。通过流式细胞术和激光共聚焦显微镜观察，三种人胰腺癌细胞中整合素 α 的表达水平依次为 SW1990、BXPC-3 和 PANC-1，从高到低，而整合素 β 的表达水平则相对接近。当 VLA-3 表达水平最高的 SW1990 细胞用 FITC-CK11 染色时，流式细胞术和激光共聚焦显微镜下观察到强烈的荧光。然而，用过量 CK11 处理阻断组时，没有观察到明显的荧光。Ga-NOTA-CK11 显示出对 SW1990 细胞的明显放射性积累，并且可以被 CK11 成功阻断。随后在携带 SW1990 异种移植瘤的小鼠中进行小动物 PET 成像和生物分布研究证实，探针注射后 1 小时，其肿瘤摄取率高，肿瘤与血液的比值和肿瘤与肌肉的比值分别为 2.45±0.31 和 3.65±0.33。综上所述，我们成功开发了一种基于肽的成像剂 Ga-NOTA-CK11，它与 VLA-3 具有很强的结合亲和力，对 SW1990 细胞和异种移植瘤具有良好的靶向特异性，是一种很有前途的用于胰腺癌 VLA-3 表达 PET 成像的放射性示踪剂。
