近红外光激发的TiO2基无机光敏剂及其肿瘤靶向光动力治疗研究

Compared with traditional organic photosensitizers, Titanium dioxide (TiO2) nanomaterials are excellent inorganic photosensitizer, and have the characteristics of stability, nontoxicity and long maintain time in body, which could have potential application in photodynamic therapy (PDT) for cancers. However, generally, TiO2 nanoparticles can only be excitateded by ultraviolet lights or shorter wave rays, the bad penetrability in body and the tissue damnification of ultraviolet lights restricted the application of TiO2 in PDT. In this project, an inorganic photosensitizer of TiO2-based nanomaterials (TiO2-NaYF4:Yb/Tm composite nanoparticles) labled with RGD peptide will be designed and synthesized, which could be excitateded by near-infrared laser. Under the excitation of 980 nm near-infrared laser, NaYF4:Yb/Tm nanoparticles emitted ultraviolet light, which could further excitated TiO2 for PDT. Based on HepG2 cells and mouse liver cancers, the targeted PDT reliability of inorganic photosensitizers was investigated. Moreover, using X-ray imaging techniques of Shanghai Synchrotron Radiation Facility, the visualization quantitative relationship between cell uptake dose of nanoparticles and PDT performance was constructed. Finally the PDT effect will be investigated by MRI techniques, and the PDT pinciple will also be illuminated. These results could provide some clues for the clinical applications of the inorganic photosensitizer based on TiO2-NaYF4:Yb/Tm composite nanoparticles excitateded by near-infrared laser.

与传统的有机光敏剂相比，纳米二氧化钛(TiO2)无机光敏剂具有性能稳定、无毒及体内维持时间长等优点，在恶性肿瘤的光动力治疗(PDT)中具有潜在应用。然而，TiO2需要紫外光或更短波长射线激发，紫外光较差的穿透能力以及对正常组织的损伤限制了其PDT应用。本项目设计并制备近红外光激发、RGD肽偶联的TiO2基无机光敏剂材料(TiO2-NaYF4:Yb/Tm复合纳米粒子)，利用NaYF4:Yb/Tm的紫外上转换发光性质，激发TiO2，实现近红外光激发下TiO2的靶向PDT功能；以人肝癌HepG2细胞以及小鼠肝癌模型为对象，研究980nm激光辐照下无机光敏剂靶向PDT功能的可靠性；采用上海光源的X射线荧光成像技术，构建纳米粒子的细胞摄取剂量与PDT性能的可视化定量表征方法；借助MRI诊断技术监测小鼠肿瘤的PDT效应，阐明PDT原理，为近红外光激发的TiO2基无机光敏剂在临床治疗中的应用提供依据。

TiO2基无机光敏剂在肿瘤光动力治疗中显示出重要潜力，但传统的TiO2需要紫外光激发，具有组织穿透浅和光损伤的缺点。本项目构建了上转换与TiO2复合的纳米结构，实现了TiO2在近红外光激发下的光动力治疗功能，解决了传统TiO2纳米材料在光动力治疗中的组织穿透浅和光损伤问题，并利用上海光源的X射线荧光成像技术研究了纳米粒子的细胞摄取。在本项目的执行过程中，主要从以下三方面开展研究：（1）设计并制备出上转换-TiO2复合纳米材料，通过实验调控与优化，实现了该复合纳米结构在980nm激发下的紫外上转换发光，为TiO2无机光敏剂在近红外激发下的光动力治疗奠定了基础；（2）制备了叶酸偶联的Gd基上转换-TiO2复合纳米材料，构建了具有磁共振成像和近红外光动力治疗双重功能的纳米探针，通过建立乳腺癌裸鼠模型，实现了对乳腺癌的体内靶向磁共振成像诊断和近红外光动力治疗，肿瘤抑制率达到88.6%；（3）制备了化疗药物阿霉素搭载的叶酸偶联的上转换-TiO2复合纳米材料，构建了具有近红外光动力治疗和化疗双重功能的纳米探针，通过构建耐药乳腺癌裸鼠模型，实现了对耐药乳腺癌的体内靶向近红外光动力治疗和化疗协同作用，肿瘤抑制率高达95%以上，逆转了乳腺癌的多药耐药性。依托本项目，在SCI期刊发表学术论文12篇（其中在国际Top期刊Biomaterials发表3篇），发表英文专著1章节，申请中国发明专利3项（其中已获授权1项），培养硕士研究生2名。本项目构建的近红外激发TiO2基无机光敏剂为实现TiO2的安全、无创和高效光动力治疗提供了新的思路。