基于新型荧光共轭聚合物的肿瘤细胞信号转导通路调控研究

The studies on tumor cell signaling transduction are of great importance to understand the mechanism of tumor formation and development，which offers new potential targets for tumor diagnosis and therapy. New fluorescent conjugated polymer is an important kind of polymer materials and able to sentisize the generation of reactive oxygen species (ROS). Conjugated polymer-based photodynamic regulation method can be used to rapidly regulate the cell signaling pathway with high temporal and spatial resolution. In this project, we plan to design and synthesize a series of conjugated polymers with photosensitized property.These conjugated polymers and certain targeting molecule will be assembled together to form a new targeting system by non covalent or covalent bond. Further, their physicochemical properties will be comprehensively characterized. In the following stage, the regulatory effects of fluorescent targeting system toward the target proteins on the surface and inside of tumor cells will be investigated under irradiation by cytological, molecular biological and immunological technology. The changes of morphology and behaviors of the treated cells will be observed and detected. On the other hand, in order to regulate the multiple targets in cell signal transduction, the fluorescent conjugated polymers containing small molecule inhibitors will be employed to treat the tumor cell under irradiation. The fluorescent polymer-based photodynamic regulation method will elucidate the cell signaling transduction mechanism and open up another way to enhance the selectivity and therapeutic effect of small molecule inhibitors.

细胞信号转导机制的研究对于揭示肿瘤的发病机理具有重要意义，能够为肿瘤诊断和治疗提供潜在靶位。荧光共轭聚合物可以作为一类重要的调控细胞信号蛋白的高分子材料，在光照的条件下，它可以通过敏化氧分子，产生活性氧物种，直接、迅速地对肿瘤细胞信号转导途径进行调控，因而具有较高的时间和空间分辨率。本项目设计、合成一系列具有光敏性质的共轭聚合物，将这些聚合物以共价键或非共价键形式与靶向分子连接，获得能识别细胞信号蛋白的靶向共轭聚合物体系，并对其物理化学性质进行全面表征。我们将进一步利用细胞生物学、分子生物学和免疫学方法，研究该体系对细胞表面和细胞内靶蛋白的光动力调控作用，以及对肿瘤细胞系形态和行为影响。同时，我们将用侧链中含有小分子药物基团的载药共轭聚合物对肿瘤细胞进行多位点的光动力调控。这种以共轭聚合物为基础的光动力调控方法将为阐明肿瘤细胞信号转导途径，增强小分子药物的选择性和抗癌效果提供一种新方法。

肿瘤细胞信号转导过程的光动力调控对于发展有效的抗肿瘤方法具有重要意义。荧光共轭聚合物作为一种新型的光动力反应试剂，能够被致敏产生活性氧物质。.本项目已经设计、合成了具有光敏性质的系列荧光共轭聚合物，包括1）设计合成阳离子聚酯结构聚合物（PIOT），它通过静电相互作用与透明质酸形成纳米粒子；2）侧链带有酪氨酸激酶抑制剂的水溶性聚噻吩（PTL）；3）末端带有药物分子普乐沙福（plerixafor）的共轭聚合物PFPNP-PLE；4）四种新型水溶性聚噻吩衍生物 (PT, PT-DDA, PT-ADA, and PT-ADA-PPR)；5)通过click反应产生侧链带有季氨盐及叠氮基团的聚噻吩；6)表达毒素的大肠杆菌和荧光共轭聚合物的多功能微生物毒素胶囊。在系统地研究这些共轭聚合物理化性质基础上，不但实现了对肿瘤细胞信号途径的光调控，而且实现了对细胞内亚结构的定位追踪和成像。我们最终证实这些共轭聚合物对多种肿瘤细胞系的生长和转移等功能具有显著的抑制作用。此研究将为抗肿瘤的靶向性光动力治疗提供重要的理论基础。