光控释ROS响应的靶向纳米载药系统用于肝门胆管癌光动力联合缺氧活化前药协同治疗研究

Photodynamic therapy (PDT) is an effective and local therapeutic technique for unresectable hilar cholangiocarcinoma (HCCA). The poor targeting and aggregation-induced quenching (ACQ) effect of traditional photosensitizers (PS), as well as the hypoxia of tumor tissue restrict the efficacy of PDT. In our previous study, We fully took advantage of an aggregation-induced emission (AIE) PS to fabricate targeted organic.theranostic AIE nanodots for image- guided PDT. The obtained AIE nanodots successfully overcome the ACQ effect and poor tumor targeting. However, how to utilize the hypoxic microenvironment of tumor after PDT and achieve precise controlled release of drugs have become other difficult problems that need to be tackled continually. We recently found that PDT could aggravate hypoxia in cholangiocarcinoma tissues and enhance the toxicity of hypoxia-activated prodrugs to HCCA cells. Furthermore, a ROS-responsive block copolymer, polyethylene glycol-thioketal-poly(lactic-co-glycolic acid) (PEG-TK-PLGA), was also synthesized. In this project, a photocontrolled ROS-responsive nano delivery system is intended to fabricate using PEG-TK-PLGA for the co-loading of AIE PS and hypoxia-activated prodrug. This nano system will achieve precise controlled drug release, effective utilization of hypoxic microenvironment after PDT, as well as synergistic effect of PDT and hypoxia-activated prodrug. This work will provide new strategy for improving the therapeutic effect of unresectable HCCA and have high value for future translational research.

光动力治疗(PDT)是不可切除肝门胆管癌的一种有效的局部治疗方法。传统光敏剂的靶向性差和聚集诱导淬灭效应，以及肿瘤组织的缺氧状态是制约PDT效果的关键。我们前期利用聚集诱导发光(AIE)光敏剂制备的靶向纳米探针克服了传统光敏剂靶向性差和聚集诱导淬灭问题，但如何利用好PDT后肿瘤缺氧微环境以及实现药物的精准控释成为需要继续攻克的难题。预实验发现PDT可加剧胆管癌组织缺氧并可增强缺氧活化前药对肿瘤细胞的毒性；此外合成了一种活性氧(ROS)可断裂的两亲性嵌段共聚物聚乙二醇-酮缩硫醇-聚乳酸羟基乙酸 (PEG-TK-PLGA)。拟以PEG-TK-PLGA为载体装载AIE光敏剂和缺氧活化前药制备对肝门胆管癌具有靶向作用的光控释ROS响应纳米载药系统，以实现对PDT后缺氧微环境的有效利用并实现药物的靶向递送、精准控释和协同治疗。本研究的完成对肝门胆管癌的治疗将提供新思路、新方法。

光动力治疗(PDT)是一种有效且微创的肿瘤局部治疗方法，但传统光敏剂靶向性差和聚集诱导淬灭效应是影响PDT疗效的重要因素；其次，PDT治疗后引起的缺氧微环境是导致肿瘤侵袭转移的重要原因。针对目前PDT治疗的以上不足之处，本项目首先合成一种ROS可断裂的两亲性嵌段共聚物PEG-TK-PLGA，其中响应基团酮缩硫醇(TK)可以调控纳米材料的ROS敏感性和释药性能。其次，利用PEG-TK-PLGA制备负载具有光敏特性的AIE分子TPETS和缺氧活化前药替拉扎明，初步阐明了纳米药物结构与其体内外响应性水解和释药特性间的关系。利用胆管癌小鼠动物模型，系统地评价了该纳米药物的体内外肿瘤靶向性、生物安全性、抗肿瘤作用及免疫激活效应。结果证明了ROS 响应性纳米药物对比非响应性药物具有更为显著的疗效。此外，抗肿瘤药物与AIE光敏剂的联合相较于单药具有更强效的抗肿瘤作用。除了对肿瘤细胞的直接杀伤，该纳米药物介导的光动力-化疗能诱发肿瘤细胞发生免疫原性细胞死亡，激发机体特异性的抗肿瘤免疫。上述成果为构建ROS响应性释药系统提供了优异的载体材料；同时阐明基于光动力-化疗联合的治疗方法有望成为抗肿瘤治疗的新策略。