远程控制化疗协同光动力治疗的ROS敏感型纳米药物递释系统的研究

Combined modality of chemotherapy and photodynamic therapy (PDT) is becoming one of the most attractive research fields in cancer therapy and brings new feasibilities for clinical treatment. Synergistic systems of chemotherapy and PDT still exists several defects including low drug loading efficiency, poor transportation stability and weak tumor-targeted release capability. A reactive oxygen species (ROS)-sensitive polymeric prodrug (mPEG-PAC-PMC-g-DOX) was synthesized based on polyethylene glycol (PEG), polycarbonate and doxorubicin (DOX) loading photosensitizer Ce6 by electrical charge interaction. When exposed to tumor-focused laser ray, Ce6 for photodynamic treatment generates ROS, which cut off ROS-sensitive bond thus release DOX. DOX was remotely controlled by light, at specific site, in accurate time and in manipulated release rate. The chemical structure of mPEG-PAC-PMC-g-DOX is characterized systematically and the micelles are evaluated in aspects of pharmaceutical property, photodynamic effect and DOX release triggered by ROS. The anti-tumor efficiency is studied from cell, organization and the animal level to screen the optimal nanostructure and to elucidate the key factors influencing formulation and drug efficacy. We aim to provide the physicochemical, biological and pharmacokinetic for synergistic chemotherapy and photodynamic therapy, and support further research and application in this field.

化疗协同光动力治疗（PDT）为肿瘤的临床治疗带来新的契机，是肿瘤治疗领域最为活跃的研究方向之一。现有的化疗-PDT协同体系存在负载率低、输送稳定性差和肿瘤定向释放能力弱的问题。本课题设计并合成了基于聚乙二醇、聚碳酸酯和阿霉素（DOX）的活性氧（ROS）敏感型聚合物前药（mPEG-PAC-PMC-g-DOX），以其为载体材料，通过静电作用包载光敏剂二氢卟吩e6，构建ROS敏感型纳米胶束。联合定位激光照射，借助PDT产生的有效治疗物质ROS，实现光远程控制DOX的定点、定时、定速释放，使化疗与PDT协同起效。应用现代技术手段，对mPEG-PAC-PMC-g-DOX的结构进行确证，评价ROS敏感型纳米胶束的制剂学性质、光动力效应和ROS触发DOX释放的能力，从细胞水平、组织水平及整体水平考察该系统的协同抗肿瘤效果，解析影响该系统发挥作用的载体因素和制剂因素，为化疗协同PDT制剂的研发提供依据。

本项目设计了一种聚合物纳米递释系统包载化药和光敏剂，充分利用光动治疗的优势，优化光化一体的共递送系统。首先，为了解决共载送效率低的问题，合成了聚合物通过ROS敏感键共价连接多柔比星聚合物（PEG-PBC-TKDOX）以包载光敏剂二氢卟酚e6（Ce6）。Ce6与DOX可通过π-π堆积相互作稳定包载于前药聚合物胶束中，共载两种药物的载药量高（分别>20 wt％），最佳粒径为（50 nm）。其次，在我们的设计中，PDT治疗时所施加的光照时不仅激发了Ce6产生活性氧（ROS），还通过远程控制激活了串联反应以释放药物。最后，我们设计一种自剪切型的聚合物载体（PEG-PBC-TKDOX），其包载疏水药物的聚碳酸酯骨架部分在ROS刺激下的可解聚使药物得以彻底释放。这种特性是通过将ROS敏感的侧链酮缩硫醇接枝到脂族聚碳酸酯的侧链得以实现的。当DOX通过酮缩硫醇键共价连接于该聚合物时，阿霉素的靶向性释放受到光的控制，很大程度上避免了全身给药的脱靶毒性。在实现光远程控制化疗药物的定点，定时，定速释放的同时，达到化疗与PDT协同作用的治疗效果。.应用多种手段对合成过程中的中间体和终产物聚合物前药的结构，以及ROS诱导的聚合物骨架断裂进行确证。评价了ROS敏感型纳米胶束的制剂学性质、ROS触发聚合物前药的释放性能。在细胞水平上发现，给以激光照射后，促进了DOX的胞内内定位于作用靶部位。从细胞水平和组织水平上证明了联合治疗可以提高药物在肿瘤部位的渗透。考察了该系统的协同抗肿瘤效果，评价了其在降低化疗药物全身毒性的优势。