Hepatocellular carcinoma (HCC) is one of the deadliest malignant tumors and the development of effective therapeutics against HCC is urgently needed. A novel quinazoline derivative 04NB-03 (Qd04) has been proved to be highly effective against HCC without obvious toxic side-effects. However, the poor water solubility and low bioavailability in vivo severely limit its clinical application. In addition, Qd04 kills tumor cells by inducing an accumulation of endogenous reactive oxygen species (ROS), which is highly impeded by the overexpression of glutathione (GSH) in tumor cells. Herein, we designed a disulfide cross-linked polyamino acid micelle to deliver Qd04 for HCC therapy. The disulfide linkage not only endowed a tumor-targeted delivery of Qd04 by responding to tumor cell GSH but also depleted GSH to achieve increased levels of ROS generation, which improved the therapeutic efficiency of Qd04. Both in vitro and in vivo results demonstrated that the synthesized nanodrug exerted good anti-hepatoma effects, which provided a potential application for HCC therapy in clinics.

中文翻译：

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用于靶向递送喹唑啉衍生物的还原敏感聚合物载体，以增强抗癌活性氧的产生

肝细胞癌（HCC）是最致命的恶性肿瘤之一，迫切需要开发针对 HCC 的有效治疗方法。新型喹唑啉衍生物04NB-03（Qd04）已被证明对HCC非常有效，且无明显毒副作用。但其水溶性差、体内生物利用度低严重限制了其临床应用。此外，Qd04通过诱导内源性活性氧（ROS）的积累来杀死肿瘤细胞，而肿瘤细胞中谷胱甘肽（GSH）的过度表达会严重阻碍内源性活性氧（ROS）的积累。在此，我们设计了一种二硫键交联的聚氨基酸胶束来递送 Qd04 用于 HCC 治疗。二硫键不仅可以通过响应肿瘤细胞GSH来实现Qd04的肿瘤靶向递送，而且还可以消耗GSH以实现ROS生成水平的增加，从而提高Qd04的治疗效率。体外和体内结果均表明合成的纳米药物具有良好的抗肝癌作用，为临床肝癌治疗提供了潜在的应用前景。