富勒烯/卟啉类衍生物纳米组装体系的肿瘤靶向光动力性质研究

Controllable assembling is an important technique to achieve multifunctionality of materials. Both fullerene and porphyrin derivatives could produce reactive oxygen species (ROS) under the light irradiation to kill diseased cells effectively, and have become the most potential candidates currently as photosensitizers. The assembly of fullerene and porphyrin will make their performance complementary and produce synergistic effect in photodynamic therapy (PDT); the introduction of targeting molecule will further benefit the enrichment of the assembly in diseased tissue via molecular recognition mechanism, and thus increase the subsequent PDT effect and further reduce the side effect. This project aims to design novel fullerenes-based photosensitizer with good biocompatibility, high ROS production, and improved tumor-specificity by controllable assembly. The breast cancer cells will be used as a model to optimize the fullerenes-based PDT treatment, such as the dosage of assembly, the time and power of light irradiation, as well as the cell killing mechanism and corresponding structure-activity relationship. We expect to provide important information in the highly selective and efficient PDT and lay foundation for the auxiliary cancer treatment.

构建自组装纳米体系是物质实现多功能化的重要手段。富勒烯衍生物和卟啉分子在光照条件下均能产生活性氧，可有效地杀死病变细胞，是目前最具潜力的光动力学治疗试剂,二者的可控组装可以性能互补，在肿瘤的光动力治疗上起到加合增效的作用；而与靶向分子的组装可提高功能分子的肿瘤选择性，进一步降低毒副作用。本项目旨在利用靶标分子（赫赛汀或叶酸等）的识别特异性、富勒烯的易装载性和衍生物的亲水亲脂性、卟啉分子在光疗窗口的强吸收特性，通过它们之间的可控组装构建光疗窗口光谱吸收强、生物相容性好、且具有双重光动力功效的新型靶向光敏剂。拟采用接种乳腺癌细胞的荷瘤小鼠为动物模型，研究其有效的光疗窗口、合适的光疗剂量、肿瘤组织选择性及生物分布和代谢行为，揭示组装体系结构与功能之间的构效关系，进一步克服富勒烯和卟啉在光动力治疗肿瘤应用中的不足，为发展恶性肿瘤等疾病的辅助治疗新方法奠定物质基础。

本项目围绕肿瘤微环境特性，首先构建了活性氧和谷胱甘肽双响应的纳米组装载体，实现模型药物在细胞水平和小鼠活体水平的程序释放，可显著提高药物的生物利用率，并降低毒副作用。其次，探索了富勒烯（C70）与酞菁的自组装行为，设计合成了PEG修饰的富勒烯衍生物、磁共振成像小分子组装体系，得到生物相容性好、对肿瘤组织富集程度高、可在磁共振成像介导下实施光动力治疗的多功能纳米光敏剂；此外，可以巧妙的缩短富勒烯注射和施加光照的时间间隔，充分利用血管中丰富的氧气，高效破坏肿瘤血管，克服了传统光动力肿瘤治疗中由于肿瘤部位乏氧而降低光动力疗效的问题。最后，设计合成了其它类型的富勒烯衍生物，拓展富勒烯光动力组装体系，并可利用富勒烯自由基清除特性及与生物分子结合特性，通过局部给药的方式，实现矽肺模型小鼠的有效治疗。