H2O2活化的高灵敏硼酸酯类前药对肿瘤细胞的识别及诊疗研究

项目名称： H2O2活化的高灵敏硼酸酯类前药对肿瘤细胞的识别及诊疗研究

项目编号： No.81501529

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 王鹏

作者单位： 中国药科大学

项目金额： 18万元

中文摘要： H2O2作为ROS的主要成员，调控肿瘤细胞生存、增殖、凋亡的全过程。本项目利用肿瘤细胞H2O2浓度明显高于正常细胞的特点，设计合成肿瘤组织H2O2高敏感特异性活化的抗肿瘤诊疗前药，实现对肿瘤细胞的识别和靶向治疗。我们拟采用本课题组设计优选出的靶向配体基团（RWR、RKY、DHA等）将前药分子靶向至肿瘤组织，然后被肿瘤细胞高浓度的H2O2活化，开启近红外成像功能并释放出抗肿瘤药物。本项目将优选出结构新颖的H2O2高灵敏Linker基团，用于探索肿瘤细胞荧光成像信息与胞内过氧化氢含量的内在关联，实现对肿瘤细胞的识别和诊断分期；通过采用生物相容性和光稳定性良好的DCM-NH2作为荧光报告基团，实现肿瘤靶向治疗过程中的在体实时监测。通过对肿瘤细胞H2O2敏感活化抗肿瘤前药的研究，不仅可以深入研究H2O2与肿瘤的关系，而且为最终实现肿瘤诊疗一体化提供新的思路。

中文关键词： 肿瘤靶向治疗；活体成像；分子探针；诊断显像

英文摘要： Reactive oxygen species (ROS) play important roles in the development and progression of cancer. Hydrogen peroxide (H2O2) as the principle member of ROS is a significant signaling molecule in cancer cells and regulates the survival, proliferation and apoptosis of tumor cells. Moreover, cancer cells produce higher amounts of H2O2 than normal cells. Herein, we developed highly efficient H2O2-activated theranostic prodrug that contained NIR fluorophore (DCM-NH2), anticancer drug (Doxifluridine) and targeting units (RWR, RKY, DHA, etc). This prodrug can be activated by endogenously produced H2O2 and release drug to the tumor cells. Different linker groups would be optimized and evaluated by both in vitro and in vivo experiments to obtain the ideal prodrug. The ideal linker group can be used to explore the relationships between fluorescence signal and the concentration of hydrogen peroxide in cancer cells. The study of this relationship can be applied to recognition and diagnosis of cancer cells. This research could also realize real-time monitoring of tumor during the targeted therapy. Such H2O2 in tumor microenvironment activated prodrug strategies have great potential for the diagnosis and treatment of cancer.

英文关键词： targeted cancer therapy;in-vivo imaging;molecular probe;diagnostic imaging