靶向上皮细胞粘附分子的新型肝癌诊断探针的研制及应用研究

Epithelial cell adhesion molecule (EpCAM) is involved in the regulation of cell adhesion, migration, proliferation and differentiation, and is closely related to the occurrence and development of hepatic carcinoma(HCC), indicating that it could be a potential target for HCC diagnosis. Based on our previous study，EpCAM targeted antibody has some limitations in the application of clinical diagnosis, therefore new kind ligand with excellent properties is in great need. Aptamer, with the properties of high specificity, strong affinity, good biological safety, and easy chemical synthesis, has become a new direction in the development of EpCAM targeted probes. However, the aptamer probes targeted to EpCAM so far is mostly optical probes, which have the following prominent problems in the clinical application: firstly it is vulnerable to be degraded by nuclease; secondly the signal’s penetration is poor and the analysis of the image can’t be quantified. In order to solve the problems above, this study intends to employ the capping and base substitution strategies to modify the aptamer’s structure, and label the aptamer with Ga-68, then evaluate the biological properties and diagnostic efficiency of the probe by radionuclide imaging. This project will provide new direction to design novel aptamer probe and new idea for the early diagnosis of HCC.

上皮细胞黏附分子(EpCAM)参与调节细胞黏附、迁移、增殖、分化，与肝癌的发生、发展密切相关，是对肝癌进行早期诊断的潜在靶标。基于课题组前期研究，EpCAM靶向的抗体尚不能满足临床诊断需求，亟需寻找性质优良的新型靶向配体。核酸适配体因特异性高、亲和力强、生物安全性好、易于化学合成与修饰等优势，成为EpCAM靶向探针发展的新方向。但是，目前靶向EpCAM的核酸适配体探针多为光学探针，其在临床应用中存在以下突出问题：①结构上易遭受核酸酶的降解；②成像上信号穿透力差、不能定量分析。针对上述问题，本研究拟联合采用加帽策略和碱基替换策略，对核酸适配体进行结构修饰，并对核酸适配体进行Ga-68标记，用核素显像的技术手段对探针的生物学性能和肝癌诊断效能进行定量研究。本项目的实施将为设计新型核酸适配体探针提供新方向，为肝癌的早期诊断提供新思路。

上皮细胞黏附分子(EpCAM)参与调节细胞黏附、迁移、增殖、分化，与肿瘤的发生、发展密切相关，是对肿瘤进行早期诊断的潜在靶标。基于课题组前期研究，EpCAM靶向的抗体尚不能满足临床诊断需求，亟需寻找性质优良的新型靶向配体。核酸适配体因特异性高、亲和力强、生物安全性好、易于化学合成与修饰等优势，成为EpCAM靶向探针发展的新方向。但是，目前靶向EpCAM的核酸适配体探针多为光学探针，其在临床应用中存在以下突出问题：①结构上易遭受核酸酶的降解；②成像上信号穿透力差、不能定量分析。针对上述问题，本项目先后运用加帽策略叠加碱基替换策略制备得到NOTA-SYLN，以及运用白蛋白搭载策略制备得到NMEB-SYL3C和DMEB-SYL3C。通过对新型探针进行核素标记以及体内、外试验评价，结果证实，运用加帽策略叠加碱基替换策略制备得到的NOTA-SYLN，依然存在体内稳定性差、代谢迅速、肿瘤摄取低等缺点，而运用白蛋白搭载策略对核酸适配体SYL3C进行结构修饰后，可以有效提高核酸适配体在体内的稳定性，改善体内代谢动力学性质，进而显著提升肿瘤的摄取水平。本研究开发的放射性EpCAM靶向探针具有良好的肿瘤诊疗应用前景，为肿瘤诊疗一体化研究和个体化诊疗提供了新的方向。