State Key Laboratory of Macromolecular Drugs and Large-scale Manufacturing, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
Department of Anesthesiology, The Second Clinical College of Wenzhou Medical University, Wenzhou, 325035, China.
Anal Chim Acta. 2024 Sep 1;1320:343035. doi: 10.1016/j.aca.2024.343035. Epub 2024 Jul 28.
Photodynamic therapy (PDT) is a pioneering and effective anticancer modality with low adverse effects and high selectivity. Hypochlorous acid or hypochlorite (HClO/ClO) is a type of inflammatory cytokine. The abnormal increase of ClO in tumor cells is related to tumor pathogenesis and may be a "friend" for the design and synthesis of responsive phototherapy agents. However, preparing responsive phototherapy agents for all-in-one noninvasive diagnosis and simultaneous in situ therapy in a complex tumor environment is highly desirable but still remains an enormously demanding task.
An acceptor-π bridge-donor-π bridge-acceptor (A-π-D-π-A) type photosensitizer TPTPy was designed and synthesized based on the phenothiazine structure which was used as the donor moiety as well as a ClO responsive group. TPTPy was a multifunctional mitochondria targeted aggregation-induced emission (AIE) photosensitizer which could quickly and sensitively respond to ClO with fluorescence "turn on" performance (19-fold fluorescence enhancement) and enhanced type I reactive oxygen species (ROS) generation to effectively ablate hypoxic tumor cells. The detection limit of TPTPy to ClO was calculated to be 185.38 nM. The well-tailored TPTPy anchoring to mitochondria and producing ROS in situ could disrupt mitochondria and promote cell apoptosis. TPTPy was able to image inflammatory cells and tumor cells through ClO response. In vivo results revealed that TPTPy was successfully utilized for PDT in tumor bearing nude mice and exhibited excellent biological safety for major organs.
A win-win integration strategy was proposed to design a tumor intracellular ClO responsive photosensitizer TPTPy capable of both type I and type II ROS production to achieve photodynamic therapy of tumor. This work sheds light on the win-win integration design by taking full advantage of the characteristics of tumor microenvironment to build up responsive photosensitizer for in situ PDT of tumor.
光动力疗法（PDT）是一种具有低副作用和高选择性的开创性有效抗癌方法。次氯酸或次氯酸盐（HClO/ClO）是一种炎症细胞因子。肿瘤细胞中 ClO 的异常增加与肿瘤发病机制有关，可能是设计和合成响应型光疗剂的“朋友”。然而，在复杂的肿瘤环境中，为非侵入性诊断和原位治疗的一体化设计响应型光疗剂仍然是一项极具挑战性的任务。
基于吩噻嗪结构设计并合成了一种受体-π 桥-供体-π 桥-受体（A-π-D-π-A）型光敏剂 TPTPy，该结构同时作为供体部分和 ClO 响应基团。TPTPy 是一种多功能线粒体靶向聚集诱导发射（AIE）光敏剂，能够快速且灵敏地响应 ClO，表现出荧光“开启”性能（荧光增强 19 倍）和增强的 I 型活性氧（ROS）生成，从而有效地消融缺氧肿瘤细胞。TPTPy 对 ClO 的检测限计算为 185.38 nM。精心设计的 TPTPy 锚定在线粒体上并原位产生 ROS 可以破坏线粒体并促进细胞凋亡。TPTPy 能够通过 ClO 响应对炎症细胞和肿瘤细胞进行成像。体内结果表明，TPTPy 成功地用于荷瘤裸鼠的 PDT，并对主要器官表现出优异的生物安全性。
提出了一种双赢的整合策略，设计了一种能够产生 I 型和 II 型 ROS 的肿瘤细胞内 ClO 响应型光敏剂 TPTPy，以实现肿瘤的光动力治疗。这项工作充分利用肿瘤微环境的特点，构建响应型光敏剂用于肿瘤的原位 PDT，为响应型光疗剂的双赢整合设计提供了思路。
