共轭寡聚物的设计、合成及其靶向抗肿瘤活性研究

It is significant to develop biocompatible bio-composite materials and controllably regulate their biological functions for diagnosis and treatment of serious diseases. The object of this proposal is to develop multifunctional conjugated oligomer bio-composite materials which could be used to target tumor cells, load antitumor drugs and image tumor cells. A series of conjugated oligomers are designed to connect targeting ligand and antitumor drug. Targeting ligand in the conjugated oligomer specifically binds to the tumor cells with receptor overexpression, and then the conjugated oligomer containing drug enters cells followed by the hydrolysis of ester bond between conjugated oligomer and antitumor drug by esterase in the cytoplasm to finally kill the tumor cells. Meanwhile the self-luminous conjugated oligomer could exhibit imaging function in the process of interaction between conjugated-oligomer-based bio-composite and tumor cells. The cytotoxicity of conjugated oligomers with different main chains will be evaluated to obtain a good compatible conjugated oligomer to prepare conjugated oligomer bio-composite with high targeting antitumor efficiency and fluorescent imaging function. These researches will provide new thinking on development of chemical and biomedical applications of conjugated oligomer bio-composite.

发展新型具有良好生物相容性的生物复合材料并实现其生物功能可控调控在重大疾病的诊断以及防治方面具有重要意义。本项目旨在发展具有靶向、载药和荧光成像功能的共轭寡聚物生物复合材料，进而研究其靶向抗肿瘤活性与细胞成像。设计、合成一系列具有不同主链结构并在末端共价键合靶向配体和药物的水溶性共轭寡聚物。利用靶向配体与过表达受体的肿瘤细胞特异性结合，键合药物的共轭寡聚物进入细胞，在细胞内酯酶的水解作用下，键合在共轭寡聚物上的药物释放，在细胞内发挥药效。共轭寡聚物的自发光性质可使其在与肿瘤细胞作用过程中实现示踪功能，同时实现对肿瘤细胞成像的研究。通过对比不同主链结构的共轭寡聚复合物的生物相容性，筛选出具有良好生物相容性的共轭寡聚物结构，制备具有高效靶向抗肿瘤以及荧光成像功能的多功能生物复合材料，拓展共轭寡聚物生物复合材料在化学、生物医药交叉领域的应用。

肿瘤与病原菌感染导致的全球死亡率逐年增加，而抗肿瘤药物及抗生素使肿瘤细胞与病原微生物产生多药耐药性，对肿瘤及病原菌感染等重大疾病的诊断及防治一直是科学家们关注的重要课题。本项目合成制备了多种共轭材料用于肿瘤细胞的成像、动态监测及病原微生物的杀伤研究，开展了并取得了如下创新性成果：1）制备了高量子产率固态发光共轭纳米材料，荧光量子产率达到17%，具有较大的斯托克斯位移，减少成像时材料的自吸收，成功用于肿瘤细胞成像，同时可对肿瘤细胞分裂行为进行动态监测，为研究肿瘤细胞的行为奠定基础。2）合成了侧链带有咪唑盐的聚合物，成功用于致病的大肠杆菌和金黄色葡萄球菌的高效选择性杀伤。3）合成均聚阳离子聚对苯撑乙烯，可特异性对肿瘤细胞溶酶体成像，与商用溶酶体染料具有98%的重合定位，且能够对肿瘤细胞进行长期成像，而商用溶酶体染料会很快被肿瘤细胞排出体外。这些研究成果为进一步肿瘤及病原菌感染防治提供了新思路。