基于EGFR靶向的PET/荧光肿瘤分子成像研究

The signal transduction networks of epidermal growth factor receptor (EGFR) was considered that associate with many former cancer lesionsand malignant tumors, and the research on molecular probes of EGFR make great significance in/play a important role in the diagnosis of cancer and the formation mechanism of early cancer. This project is based on the design of Off-On switch mode molecular targeted fluorescent probes. These probes include three parts which are recognition groups, connected groups and fluorescenc groups. Firstly, the mature EGFR targeted drugs are used to be recognition groups which could purchase from markets directly. The second, link groups which have good water solubility will be choosed. The third, the fluorescence groups should have highly fluorescence quantum yield rate. The fluorescence groups and recognition groups are connected with link groups. 18F labeled is introduced into the molecular backbone structure of the EGFR molecular targeted drugs, and 18F-labeled probes can be achieved PET scan imaging to get the corresponding probemolecule which having dual targeting and good biocompatibility. According to intramolecular photoinduced electron transfer theory, the fluorescence is off state when the probe is not combined with targeting EGFR, and the probes are showing the folded state. However, when the probe is combined with targeting EGFR, the fluorescence is on, and the probes are showing the enhanced state. The recognition groups are valid part of the medicine, so that the probe has both recognition and therapeutic effect, can realize to diagnosis and treatment at the same time.

表皮生长因子受体（EGFR）的信号转导和许多癌症前病变和恶性肿瘤有关，研究可以识别EGFR的分子探针对于癌症的早期诊断以及研究肿瘤的形成机理都具有十分重要的意义。本项目设计Off-On开关式分子靶向荧光探针，用市场中技术成熟的靶向药物的分子骨架作为识别基团，通过具有良好水溶性的链接基团与具有较高荧光量子产率的荧光基团相连，在EGFR分子靶向药物的分子骨架结构中引入18F标记，得到在复杂生命体系中特异性识别EGFR的PET/荧光双信号响应分子探针，探针具有良好靶向性、高灵敏度和生物兼容性。基于分子内光诱导电子转移原理，探针未与EGFR靶向结合时，呈现折叠状态，荧光为off状态，降低背景荧光，探针结合EGFR靶向后识别基团与靶点作用于细胞的内表面，折叠构象伸展，使得探针荧光恢复，点亮肿瘤细胞。识别基团为成药的有效部分，同时兼具治疗作用，实现诊疗一体。

受体酪氨酸激酶是一类重要的肿瘤标记物，其信号转导和许多癌症前病变和恶性肿瘤有关，研究可以识别受体酪氨酸激酶的分子探针对于癌症的早期诊断以及研究肿瘤的形成机理都具有十分重要的意义。本项目针对探针在生命体系中识别灵敏度低的问题，将荧光量子产率较高的荧光团罗丹明B和荧光素等与选择性识别基团相结合，构筑构象转化的荧光探针，屏蔽生命体内水分子的影响，实现生命体系微量元素高灵敏度检测及细胞成像。针对在复杂生命体系中高选择性识别困难的特点，通过将FDA认证靶向药物的分子骨架作为识别基团，构筑对特定肿瘤标志物具有专一靶向识别的探针，实现受体酪氨酸激酶高选择性肿瘤细胞膜及活体荧光成像。设计开关式构象转化荧光探针，引入FDA认证的靶向药物舒尼替尼分子骨架作为识别基团提高探针的靶向性。通过具有良好水溶性的链接基团将识别基团与具有较高荧光量子产率的荧光基团芘等相连，得到在复杂生命体系中特异性识别受体酪氨酸激酶的荧光探针，探针具有良好靶向性、高灵敏度和生物兼容性。探针未与受体酪氨酸激酶作用时，荧光为off状态，降低背景荧光，探针结合受体酪氨酸激酶后构象转化，探针线状分子结构利于其在细胞膜表面高密度排列，荧光为on状态，实现受体酪氨酸激酶肿瘤细胞的细胞膜及活体荧光成像。项目负责人以第一作者发表标注基金号的SCI收录论文6篇，其中影响因子大于4的文章4篇，代表性研究成果J. Am. Chem. Soc. 2018. 140: 5882-5885.被选为当期的封面文章。