a Key Laboratory of Biomass Chemical Engineering of Ministry of Education and Center for Bionanoengineering, College of Chemical and Biological Engineering , Zhejiang University , Hangzhou , China.
b State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Medical School , Zhejiang University , Hangzhou , China.
J Drug Target. 2019 Mar;27(3):306-314. doi: 10.1080/1061186X.2018.1519028. Epub 2018 Sep 25.
Non-viral gene delivery is an attractive approach for the treatment of many diseases including cancer, benefiting from its safety and large-scale production concerns. However, the relatively low transfection efficacy compared with viral vectors restricts the clinical applications of non-viral gene vectors. Reactive oxygen species (ROS) triggered charge reversal polymers (named B-PDEAEA) presented improved transfection efficacy, because of fast release of plasmid DNA responding to enhanced oxidative stress in cancer cells. But inadequate dissociation can still occur owing to the insufficient intracellular ROS generation. Here, we report SAHA (vorinostat), which is a clinical histone deacetylase inhibitor and anticancer drug, induces the ROS accumulation in cancer cells, and facilitates the charge reversal process of B-PDEAEA and the cellular dissociation of the delivered gene from the vectors. As a result, SAHA remarkably increases the gene transfection efficacy in an ROS-dependent manner. Importantly, SAHA synergizes with B-PDEAEA mediated therapeutic gene TNF-related apoptosis-inducing ligand (TRAIL) delivery in inducing apoptosis of cancer cells. These findings support the first concept of improving the gene delivery efficacy of stimuli-responsive vectors through upregulating the cellular ROS via an FDA approved anticancer agent. Additionally, combination of SAHA and TRAIL gene therapy could be a potential strategy for cancer treatment.
非病毒基因传递是治疗许多疾病（包括癌症）的一种有吸引力的方法，其优点是安全性和大规模生产问题。然而，与病毒载体相比，其转染效率相对较低，限制了非病毒基因载体的临床应用。活性氧（ROS）触发的电荷反转聚合物（命名为 B-PDEAEA）由于快速释放质粒 DNA 以响应癌细胞中增强的氧化应激而表现出改善的转染效率。但是，由于细胞内 ROS 的产生不足，仍然可能发生解离不足。在这里，我们报告了 SAHA（伏立诺他），它是一种临床组蛋白去乙酰化酶抑制剂和抗癌药物，可诱导癌细胞中 ROS 的积累，促进 B-PDEAEA 的电荷反转过程和所递送基因从载体向细胞内的解离。结果，SAHA 以 ROS 依赖性方式显著增加基因转染效率。重要的是，SAHA 与 B-PDEAEA 介导的治疗性基因 TNF 相关凋亡诱导配体（TRAIL）递增效合，诱导癌细胞凋亡。这些发现支持了通过用 FDA 批准的抗癌药物上调细胞内 ROS 来提高刺激响应性载体的基因传递效率的第一个概念。此外，SAHA 和 TRAIL 基因治疗的联合可能是癌症治疗的一种潜在策略。
