Zhou Jiayan, Sun Chunyang, Yu Chunshui
Department of Radiology and Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital Tianjin 300052 P. R. China
RSC Adv. 2020 May 27;10(34):19997-20008. doi: 10.1039/d0ra02053b. eCollection 2020 May 26.
Highly-controllable release consisting of preventing unnecessary drug leakage at physiologically normal tissues and triggering sufficient drug release at tumor sites is the main aim of nanoparticle-based tumor therapy. Developing drug-conjugation strategies with covalent bonds in response to a characteristic stimulus, such as reactive oxygen species (ROS) generated by photodynamic therapy (PDT) has attracted much attention. ROS can not only cause cytotoxicity, but also trigger the cleavage of ROS-responsive linkers. Therefore, it is feasible to design a new model of controlled drug release the breakage of ROS-responsive linkers and degradation of nanoparticles. The self-supply of the stimulus and highly-controllable drug release can be achieved by encapsulation of photosensitizer (PS) and chemotherapeutic drugs simultaneously without any support of tumor endogenous stimuli. Therefore, we used thioketal (TK) linkers as the responsive linkers due to their reaction with singlet oxygen (O, SO), a type of ROS. They were conjugated to the side groups of polyphosphoesters (PPE) click chemistry to acquire the core cross-linked SO-responsive PPE nanoparticles poly(thioketal phosphoesters) (TK-PPE). TK-PPE coated with the photosensitizer chlorin e6 (Ce6) and chemotherapeutic drug doxorubicin (DOX) simultaneously were prepared and named as TK-PPE. TK-PPE kept stable due to the high stability of the TK-linkers in the normal physiological environment. With self-production of SO as the stimulating factor from the encapsulated Ce6, highly-controlled drug release was achieved. After incubation of tumor cells, 660 nm laser irradiation induced SO generation, resulting in the cleavage of TK-linkers and boosted-release of DOX. Highly-controllable drug release of TK-PPE through self-production of stimulus increased antitumor efficacy, offering a promising avenue for clinical on-demand chemotherapy.
基于纳米颗粒的肿瘤治疗的主要目标是实现高度可控的药物释放，即在生理正常组织中防止不必要的药物泄漏，并在肿瘤部位触发足够的药物释放。开发基于共价键的药物共轭策略以响应特定刺激，如光动力疗法（PDT）产生的活性氧（ROS），已引起广泛关注。ROS不仅能引起细胞毒性，还能触发ROS响应连接子的断裂。因此，设计一种新的可控药物释放模型——ROS响应连接子的断裂和纳米颗粒的降解是可行的。通过同时封装光敏剂（PS）和化疗药物，无需肿瘤内源性刺激的任何支持，即可实现刺激的自我供应和高度可控的药物释放。因此，我们使用硫酮（TK）连接子作为响应连接子，因为它们能与一种ROS——单线态氧（O，SO）发生反应。通过点击化学将它们与聚磷酸酯（PPE）的侧基共轭，以获得核心交联的SO响应PPE纳米颗粒——聚（硫酮磷酸酯）（TK-PPE）。同时包被光敏剂二氢卟吩e6（Ce6）和化疗药物阿霉素（DOX）的TK-PPE被制备出来，并命名为TK-PPE。由于TK连接子在正常生理环境中的高稳定性，TK-PPE保持稳定。以封装的Ce6产生的SO作为刺激因子，实现了高度可控的药物释放。在肿瘤细胞孵育后，660nm激光照射诱导SO生成，导致TK连接子断裂和DOX的加速释放。通过刺激的自我产生实现TK-PPE的高度可控药物释放提高了抗肿瘤疗效，为临床按需化疗提供了一条有前景的途径。
