高尔基体靶向碳点/有序介孔碳纳米球荧光药物控释系统的构筑 及其抗肿瘤性能研究

Combined with fluorescence imaging and targeted technology, targeted fluorescence drug delivery system can achieve accurate imaging and targeted inhibition of tumor, which is a new strategy to improve the efficiency of chemotherapy and reduce toxic and side effects. This proposal plans to use the ordered mesoporous carbon nanospheres as drug carriers and load the chemotherapeutic drug doxorubicin by utilizing their rich pore structure. Adopting molecular design and heteroatom doping technology, Golgi apparatus-targeted carbon dots with high fluorescence quantum yield are prepared by taking cysteine and small molecules that rich in heteroatom as carbon sources through hydrothermal method. Golgi apparatus-targeted carbon dots are assembled on the surface of the ordered mesoporous carbon nanospheres by virtue of electrostatic action to realize the effective encapsulation of doxorubicin. The fluorescent controlled drug release system with tumor intracellular targeted and pH responsive controlled release performance is constructed for high-efficiency treatment of tumors.The effects of fluorescence characteristics, targeted and pH responsiveness on tumor precise imaging and targeting inhibition are studied at cellular level in vitro and mouse level in vivo, and the structure-activity relationship between targeted fluorescence drug delivery system and their application performance are established. The implementation of the project will form the preparation theory and technology of targeted fluorescent drug delivery system, and provide theoretical guidance and technical support for improving the efficiency of tumor treatment.

靶向荧光药物控释系统结合荧光成像和靶向技术可实现对肿瘤的精准成像与抑制，是提高肿瘤化疗效率和降低毒副作用的新策略。本项目拟以有序介孔碳纳米球为药物载体，利用其贯穿于结构内部的有序孔道结构装载化疗药物阿霉素；采用分子设计和杂原子掺杂技术，以半胱氨酸和富含杂原子的小分子为碳源，结合水热法制备具有高尔基体细胞器靶向性和高荧光量子产率的碳点；借助静电自组装技术在有序介孔碳纳米球表面组装高尔基体靶向碳点，实现对阿霉素的有效封装，构筑具有肿瘤细胞内靶向和pH响应控释性能的荧光药物控释系统，以用于肿瘤的高效治疗。从体外细胞和体内小鼠水平研究药物控释过程中的荧光特性、靶向性以及pH响应性对肿瘤的精准成像和靶向抑制性能影响机制，建立靶向荧光药物控释系统与应用性能之间的构效关系。项目的实施将形成靶向荧光药物控释系统的制备理论和技术，为提高肿瘤的治疗效率提供理论指导和技术支持。

本项目为解决肿瘤化疗过程中的靶向药物递送与精准成像的难题，一是设计亚细胞器高尔基体靶向碳量子点，通过其表面的半胱氨酸残基对肿瘤细胞内高尔基体的靶向作用，赋予其肿瘤细胞内的靶向性；以有序介孔碳纳米球为药物载体，将化疗药物直接靶向输运至肿瘤细胞内部并配合pH响应性药物控释机制，实现对化疗药物的可控递送和对肿瘤细胞的靶向治疗。二是构建具有精准成像辅助化疗的性能，利用高尔基体靶向碳量子点优异的发光特性，通过荧光成像技术监测药物复合体对化疗药物的可控输运，提高肿瘤的化疗效率并降低毒副作用。.通过这两方面的实验探索，制备了一系列用于高尔基体靶向成像的荧光碳量子点材料，与现有的高尔基体靶向探针对比，其皮尔森相关系数高达0.99，显示出良好的高尔基体精准成像性能。构建靶向荧光药物复合体材料，在活体小鼠水平上与无治疗对照组的肿瘤体积进行抑制效果比较，药物复合体材料处理20天后可抑制72.13%的肿瘤生长。对制备靶向荧光药物控释材料和文献中的同类材料进行比较分析、总结归纳，揭示本项目中合成材料的药物输送、控释与治疗机制，对实践规律进行分析厘清靶向荧光药物复合体材料在肿瘤靶向治疗中的内在机制，解决现阶段肿瘤治疗靶向性低、监测效果不足等难题，为肿瘤的高效低毒治疗提供一些有益的借鉴和启发。