Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences , Northwestern Polytechnical University , Xi'an , Shaanxi , China.
School of Computer Science , Northwestern Polytechnical University , Xi'an , Shaanxi , China.
Mol Pharm. 2019 Feb 4;16(2):689-700. doi: 10.1021/acs.molpharmaceut.8b00973. Epub 2019 Jan 14.
The excessive increase of intracellular reactive oxygen species (ROS) makes tumor cells usually in the state of oxidative stress. Although tumor cells can adapt to this state to a certain extent by upregulating antioxidant systems, the further ROS insults disrupt the transient intracellular redox balance, eventually leading to apoptosis and necrosis. Therefore, increasing the intracellular ROS level can effectively amplify the oxidative stress and induce apoptosis, which can be employed as a strategy for tumor treatment. Herein, a unique pH-responsive ROS inducing micellar system was reported in this study to specifically amplify the ROS signal in tumor cells. This micellar system was constructed by a new amphiphilic polymer, PIATCA, composed of poly(itaconic acid) (PIA) as the hydrophilic backbone, d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) as the hydrophobic side chain, and cinnamaldehyde (CA) as the ROS-generating agent, which were linked to PIA by the pH-sensitive hydrazone bond. PIATCA micelles could be degraded in the intracellular acidic environment through the hydrolysis of hydrazone bond and release CA. CA and TPGS could amplify oxidative stress cooperatively to kill MCF-7 human breast cells preferentially through the mitochondrial apoptosis pathway. Therefore, we anticipate that the PIATCA micelles could exert great potential in anticancer therapy.
细胞内活性氧（ROS）的过度增加使肿瘤细胞通常处于氧化应激状态。尽管肿瘤细胞可以通过上调抗氧化系统在一定程度上适应这种状态，但进一步的 ROS 损伤会破坏短暂的细胞内氧化还原平衡，最终导致细胞凋亡和坏死。因此，增加细胞内 ROS 水平可以有效地放大氧化应激并诱导细胞凋亡，这可以作为肿瘤治疗的一种策略。在此，本研究报道了一种独特的 pH 响应性 ROS 诱导胶束系统，用于特异性放大肿瘤细胞中的 ROS 信号。该胶束系统由一种新型两亲聚合物 PIATCA 构建而成，该聚合物由聚（衣康酸）（PIA）作为亲水主链、d-α-生育酚聚乙二醇 1000 琥珀酸酯（TPGS）作为疏水侧链和肉桂醛（CA）作为 ROS 生成剂组成，通过 pH 敏感的腙键连接到 PIA 上。PIATCA 胶束可以在细胞内酸性环境中通过腙键的水解而降解，并释放 CA。CA 和 TPGS 可以通过线粒体凋亡途径协同放大氧化应激，从而优先杀死 MCF-7 人乳腺癌细胞。因此，我们预计 PIATCA 胶束在癌症治疗中具有很大的潜力。
