氧化锌基智能诊疗一体化增效光敏剂的构建及其抗皮肤鳞癌作用与协同机制研究

PDT is superior to any other techniques such as chemotherapy, radiation, and surgery for the effective treatment of cancer because of its limitative therapeutic area, high treatment efficiency and less side effects. Photosensitizer plays a key role in PDT which can induce the generation of ROS from cells. However, low ROS yield, poor targeting property, less injury and high cost are the defects of the reported photosensitizer, which seriously restrict the application of PDT in clinic. Herein, UV-toxic and -fluorescent Fe3O4@ZnO NCs grafted with antibody were employed as a new kind of theranostic photosensitizer on which loaded brusatol and linked siRNA. The release of brusatol can be controlled by UV-radiation due to the hydrophobic/hydrophilic state transformation of zinc oxide and that of the Nrf2-siRNA can be controlled by UV-radiation due to the photodegradative linkage. The novel photosensitizer is in hope of diagnosis of cancer in vitro as well as realizing PDT, light controlled chemotherapy and gene therapy simultaneously under ultraviolet light treatment. The anti-cancer effect of squamous cell carcinoma of skin was investigated in vitro and in vivo. Moreover, the koinonia molecular mechanism of Nrf2 signaling pathway induced ROS accumulation and its influence on the cellular damage were explored. In view of the sufficient theoretical basis and experimental data studied in this study on the molecular, cellular and animal level, it can be inferred that such new theranostic photosensitizer could greatly improve the targeting and ROS yield and reduce the side effect and therapeutic cost which holds the immense potential in PDT for clinic use.

光动力治疗(PDT)因作用范围可限定，治疗效率高，毒副作用小等特点而备受青睐。光敏剂是PDT的核心要素，但现有光敏剂ROS产率低，靶向性差，制备成本高，严重制约PDT的临床应用。本项目拟选择廉价且具有磁性，能在紫外光照射下表面发生亲/疏水性变化并发射荧光，诱导产生ROS的Fe3O4@ZnO NCs为光敏剂基元，连接靶向抗体后负载鸦胆子苦醇和Nrf2-siRNA，制备一种新型诊疗一体化光敏剂，以达到体外显像诊断，体内靶向输送，智能光控PDT，光控化疗和基因治疗联合作用增效目的。以皮肤鳞癌为模型，分别从细胞和动物水平考察光敏剂的抑癌效果。选择鳞癌细胞的Nrf2信号通路，研究联合作用对信号通路的影响而导致胞内ROS产率变化与细胞损伤的关系，以期阐明联合作用的分子机制。本项目成功实施可将诊断和治疗一体化，提高光敏剂诱导ROS产率及其靶向性，大大降低医疗成本，具有重大的理论意义和潜在的临床价值。

光动力治疗因作用范围可限定，治疗效率高，毒副作用小等特点而备受青睐。光敏剂是的核心要素，但现有光敏剂ROS产率低，靶向性差，制备成本高，严重制约光动力治疗的临床应用。本项目首先将Fe3O4@ZnO NCs表面负载鸦胆子苦醇并用光降解链连接Nrf2-siRNA，同时连接抗EGFR抗体，构建一种能够利用外界磁场引导到癌症病灶区域并精确寻靶癌细胞，通过紫外光照射激发ZnO诱导ROS产生以及控释鸦胆子苦醇和siRNA，调控细胞Nrf2信号通路，协同ZnO光毒性增加ROS累积的智能诊疗一体化光敏剂。通过皮肤鳞癌动物模型实验，发现该光敏剂抑制肿瘤生长的效果良好。因此，本项目制备的新型光敏剂基本具备理想光敏剂的特征，弥补目前临床使用光敏剂ROS产率低，靶向性差，制备成本高等缺点，同时能够便捷地实现诊疗一体化，并能从分子、细胞以及动物水平上为其临床应用提供充分的理论基础和实验数据。项目的成功实施大力推进光动力治疗技术的发展，实验结果具有重大的理论意义和潜在的临床价值。