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

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.

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。

恶性肿瘤仍然是危害人类健康的主要杀手，针对癌症的早期诊断及其治疗成为当前国际研究的热点。ROS 被认为是肿瘤发生、发展和复发的重要因素。相比正常细胞，肿瘤细胞能够通过自身诱导氧化应激，使肿瘤细胞内的ROS 特别是H2O2 水平增加，肿瘤细胞内过氧化氢的浓度明显高于正常细胞。利用这一特点，本项目首先设计合成了六个含有不同Linker基团的抗肿瘤诊疗前药，并通过体外过氧化氢响应速率和选择性实验筛选得到一个过氧化氢响应最快的前药分子，并对其响应机制进行了研究。随后，经过体外肿瘤细胞成像性和靶向性研究，发现该前药分子对整合素受体高表达的肿瘤细胞具有更好的靶向性。最后，体内肿瘤成像性和抗肿瘤活性表明前药分子不仅对整合素受体高表达的肿瘤具有明显的靶向性，而且表现出良好的抑瘤作用和较低的毒副作用。本项目综合运用分子影像学与化学生物学技术，优选出了结构新颖的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；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，实现了肿瘤靶向治疗过程中的在体实时监测。本项目最终获得了一个H2O2高灵敏的抗肿瘤前药分子，为最终实现肿瘤诊疗一体化提供了新的思路。.