核壳结构超支化共轭聚合物的双光子荧光增强及光动力治疗

Design and construction of the polymeric nanomaterials with two-photo emission enhancement properties are currently one of the important strategies for the photodynamic therapy. In the current stage, two-photo nanomaterials suffer from low two-photo emission properties, poor water-solubility, weak photostability and nonspecific targeting. To overcome these shortcomings, a novel kind of stimuli-responsive hyperbranched conjugated polymer with core-shell structure and two-photo emission enhancement properties will be developed in this project for photodynamic therapy by utilization of the steric hindrance of highly branched polymers to prevent from the aggregation of hydrophobic moieties. Firstly, hyperbranched conjugated polymers with controlled branching structure will be synthesized through cross-coupling polymerization, and then the hyperbranched conjugated polymers with core-shell structure will be obtained by the surface modification with flexible thermo-responsive hyperbranched polymers. Such hyperbranched polymers with a hyperbranched conjugated core and many flexible hyperbranched arms can form the unimolecular micelles in good solvents. Base on the unique self-assembly mechanism of highly branched polymers from unimolecular micelles to multi-micelle aggregates in an aqueous solution, the polymeric micelles with two-photo emission enhancement properties can be readily obtained. The relationship between two-photo emission properties and polymeric structures including the branched structure and self-assembled behavior of hyperbranched conjugated polymers will be investigated systematically. Finally, the photodynamic therapy will be carried out after the surface grafting of anti-cancer photo-sensitizer onto hyperbranched conjugated copolymers with core-shell structure. Benefiting from the thick tissue penetration depth and the fast heating effect of near infrared, the photodynamic therapy of hyperbranched conjugated copolymers with anti-cancer photo-sensitizer will be initiated and controlled through the photo-responsive properties. Consequently, the inhibition of tumor cells will be realized by the cooperative action between hyperbranched conjugated copolymers and anti-cancer photo-sensitizer, which will be verified by in vitro and in vivo evaluations. If this project works, it is no doubt that the two-photo emission nanomaterials can be used as drug carriers for promoting the development of tumor therapy.

构建双光子荧光增强的聚合物纳米材料是发展光动力治疗的重要途径。现有的双光子纳米材料存在荧光强度低、水溶性差、光稳定性弱及非特异性靶向等问题，本项目拟利用高度支化空间拓扑结构阻断疏水分子相互聚集，研制新型双光子荧光增强的核壳结构超支化共轭聚合物，并用于肿瘤光动力治疗。采用交叉偶联聚合反应技术，制备结构可控的超支化共轭聚合物，在此基础上合成温度响应性超支化聚合物修饰的超支化共轭聚合物。借助高度支化聚合物特有的单分子胶束的多胶束聚集自组装，获得双光子荧光增强的功能性聚合物纳米胶束。系统阐明超支化共轭聚合物的支化结构和自组装行为对双光子荧光性能的影响。将抗肿瘤光敏剂接枝到核壳结构超支化共轭聚合物表面，利用红外光的组织穿透性和热效应触发并控制光动力治疗，实现对肿瘤细胞的特异性识别和有效抑制。通过上述系统研究，将有助于丰富双光子荧光材料作为药物载体的尝试，为肿瘤光动力治疗提供新途径。

构建双光子荧光增强的聚合物纳米材料是发展光动力治疗的重要途径。现有的双光子纳米材料存在荧光强度低、水溶性差、光稳定性弱及非特异性靶向等问题，本项目利用高度支化空间拓扑结构阻断疏水分子相互聚集，研制新型双光子荧光增强的核壳结构超支化共轭聚合物，并用于肿瘤光动力治疗。我们通过Wittig交叉偶联法，以N-(正己基)-3,6-二醛基咔唑和1,3,5-(三苯基膦基)溴代均三甲苯为单体，合成了末端为醛基的超支化共轭聚合物。醛基在硼氢化钠的还原下，可得末端为羟基的超支化共轭聚合物（HCP-OH）。之后，我们以HCP-OH、三羟基乙烷、三羟基丙烷和1,4-丁二醇二缩水甘油醚为单体，在氢化钾引发下，利用氧阴离子开环聚合，得到了温度响应性超支化聚醚修饰的超支化共轭聚合物。借助高度支化聚合物特有的单分子胶束的多胶束聚集自组装，获得了双光子荧光增强的功能性聚合物纳米胶束，系统阐明了超支化共轭聚合物的支化结构和自组装行为对双光子荧光性能的影响。我们利用聚合物末端存在的大量羟基，通过酯化反应将抗肿瘤光敏剂二氢卟吩Ce6接枝到核壳结构超支化共轭聚合物表面，利用红外光的组织穿透性和热效应触发并控制光动力治疗，实现对肿瘤细胞的特异性识别和有效抑制。通过上述系统研究，利用温度响应性超支化聚合物修饰的超支化共轭聚合物单分子胶束的独特理化性质，将双光子激活荧光共振能量转移与近红外光热效应相结合，提高了光动力治疗的效果，有助于丰富双光子荧光材料作为药物载体的尝试，为肿瘤光动力治疗提供了新途径。在上述工作基础上，我们进一步优化开发了各种体系。在国家自然科学基金的资助下，本项目共发表标注基金资助的SCI收录论文 58篇，授权国家发明专利3项，申请国际发明专利1项、国家发明专利13项；除此之外，参加了若干次国内和国际重要学术会议，出站博士后1名，毕业博士研究生6名、硕士研究生4名，另有多名博士和硕士研究生在读。