咔唑基化合物在双光子光动力治疗中的作用机制研究

Two-photon photodynamic therapy (TPPDT) technique has gained much attention due to the high penetration depth in tissue and the capability of highly targeted treatment, as the excitation can be confined to small volumes at the laser focus. Photosensitizer has played an important role in TPPDT. However, the design of novel photosensitizer molecule and the development of TPPDT technique have been hindered due to the insufficient understanding of the photodynamic mechanism of PDT. In this project, the applicant aim to investigate the mechanism of TPPDT by using carbazole-based molecules. The investigation will be focused on the interaction and photodamage between carbazole-based photosensitizer and DNA, as well as the photodynamic effect of carbazole-based photosensitizer to living cancer cells. The carbazole-based photosensitizer has been demonstrated that it possesses excellent biocompatibility, affinity and two-photon absorption property, which is promising for TPPDT. Meanwhile, the tunable femtosecond laser will be employed in the TPPDT technique to provide the optimized wavelength according to the photosensitizer, which is expected to improve the excitation efficiency and the photodynamic effect in TPPDT. This study covers multiple research fields and would provide the new evidence for the molecular design of two-photon photosensitizer and the development of TPPDT technique based on the understanding of TPPDT mechanism, which would prompt the further application in biomedicine and biophotonics.

双光子光动力治疗(TPPDT)技术具有较强的组织穿透能力，有望实现对深层肿瘤的光动力治疗，具有十分广阔的应用前景。光敏剂在TPPDT中发挥着不可或缺的重要作用，但目前双光子光敏剂及其光动力治疗作用机制尚不明确，阻碍了光敏剂及TPPDT技术的发展。本项目立足于光敏剂TPPDT作用机制这一关键科学问题，采用具有良好的双光子吸收特性的新型咔唑基化合物，从分子结构特性出发，研究具有不同功能基团的咔唑基双光子光敏剂光损伤DNA能力及对肿瘤细胞的光动力活性，建立分子结构与光动力效应之间的关系，阐明其TPPDT作用机制；与此同时，利用宽波段连续可调谐飞秒激光，针对TPPDT光敏剂优选最佳激发波长，以提高单重态氧光激发效率，增强光动力活性。本项目具有化学、生物光子学等多学科交叉的特点及显著的创新性，将进一步指导TPPDT光敏剂的分子设计，为TPPDT技术在生物医学及生物光子学领域中的应用提供科学基础。

双光子光动力治疗技术具有较强的组织穿透能力，有望实现对深层肿瘤的光动力治疗，具有十分广阔的应用前景。光敏剂在双光子光动力治疗中发挥着不可或缺的重要作用，但目前双光子光敏剂及其光动力治疗作用机制尚不明确，阻碍了光敏剂及双光子光动力治疗技术的发展。本项目立足于光敏剂双光子光动力作用机制这一关键科学问题，采用具有良好的双光子吸收特性的新型咔唑基化合物，从分子水平上研究咔唑基双光子光敏剂分子与不同类型DNA的相互作用关系及光损伤DNA能力，在细胞水平上澄清咔唑基光敏剂分子对肿瘤细胞的光动力活性，阐明咔唑基双光子光敏剂分子的光动力治疗作用机制，为新型双光子光动力光敏剂的分子设计与双光子光动力技术的发展提供科学基础。通过本项目的研究工作，在ACS Applied Material Interfaces、 Journal of Material Chemistry C等国际核心刊物上发表高水平论文28篇，发明专利授权1项，培养研究生6名，博士后1名。