College of Chemical Engineering, Nanjing Forestry University; Jiangsu Key Lab for the Chemistry and Utilization of Agro-Forest Biomass, Nanjing 210037, People's Republic of China.
School of Chemistry and Chemical Engineering, Southeast University, Nanjing 210089, People's Republic of China.
Mol Pharm. 2019 Dec 2;16(12):4929-4939. doi: 10.1021/acs.molpharmaceut.9b00819. Epub 2019 Nov 8.
Breaking the threshold of intracellular reactive oxygen species (ROS) levels can cause nonspecific oxidative damage to proteins and lead to the Fenton reaction-mediated exogenous ROS production to be a new promising anticancer strategy. However, the problems, including the inefficient transport of metal catalysts and insufficient endogenous hydrogen peroxide (HO) content in cells, still need to be improved. In this study, a functional nanosystem encapsulated with benzothiazole complexes (FeTB) and the photosensitizer indocyanine green (ICG) was designed for highly effective antitumor therapy. The surface of the nanocarriers was modified with dihydroartemisinin (DHA)-grafted polyglutamic acid. The induced hyperthermia enables the lipid-polymer shell to depolymerize, releasing FeTB. The released FeTB could kill tumor cells in two different ways by inhibiting DNA replication and catalyzing HO to produce active •OH. Moreover, the conjugated DHA could increase the amount of peroxides in tumor cells and significantly enhance the ROS yield. This work has provided solid evidence that the present nanosystem enables a significant effect on tumor killing through the combined inhibition of DNA replication and ROS-mediated oxidative damage by regulation of the tumor microenvironment, providing a ROS-mediated high-efficiency antitumor strategy.
打破细胞内活性氧（ROS）水平的阈值会导致蛋白质发生非特异性氧化损伤，并引发芬顿反应介导的外源性 ROS 产生，成为一种有前途的新抗癌策略。然而，包括金属催化剂的传输效率低下和细胞内过氧化氢（HO）含量不足在内的问题仍有待改善。在这项研究中，设计了一种封装苯并噻唑配合物（FeTB）和光敏剂吲哚菁绿（ICG）的功能纳米系统，用于高效的抗肿瘤治疗。纳米载体的表面用二氢青蒿素（DHA）接枝聚谷氨酸进行修饰。诱导的热疗使脂质-聚合物壳解聚，释放 FeTB。释放的 FeTB 可以通过抑制 DNA 复制和催化 HO 产生活性 •OH 来杀死肿瘤细胞。此外，共轭的 DHA 可以增加肿瘤细胞中的过氧化物量，并显著增强 ROS 的产生。这项工作为通过调节肿瘤微环境来抑制 DNA 复制和 ROS 介导的氧化损伤的联合作用对肿瘤杀伤的显著效果提供了确凿的证据，为 ROS 介导的高效抗肿瘤策略提供了依据。
