Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu 225009, P. R. China.
Hunan Provincial Key Laboratory of Micro & Nano Materials Interface Science, College of Chemistry and Chemical Engineering, Central South University, Changsha, Hunan 410083, P. R. China.
ACS Biomater Sci Eng. 2024 Jul 8;10(7):4601-4611. doi: 10.1021/acsbiomaterials.4c00704. Epub 2024 Jun 7.
Hepatocellular carcinoma (HCC) is one of the most lethal and highly malignant tumors. Sonodynamic therapy (SDT) is a new cancer treatment method. One of its unique advantages lies in the treatment of deep tumors due to its excellent tissue penetration ability caused by ultrasound (US). However, most sonosensitizers suffer from weak sonodynamic activity and poor tumor-targeting ability. In addition, small interfering RNA (siRNA) is a promising anticancer drug, and the efficacy of siRNA-based gene therapy largely depends on the cell impermeability of the gene carrier. Here, we designed and synthesized a cationic polythiophene derivative (PT2) that can be used as a siRNA carrier for gene therapy. Moreover, PT2 could generate singlet oxygen (O) and hydroxyl radicals (O) under US irradiation, which suggests that PT2 could be used for SDT. Our study discovered that NUDT1 promoted HCC proliferation and inhibited intracellular ROS production. Therefore, si-NUDT1 was designed and synthesized. NUDT1 silencing can inhibit the proliferation of tumor cells and increase the production of intracellular ROS to further improve the efficacy of SDT. Then, si-NUDT1 assembled with PT2 and DSPE-PEG-FA to prepare a novel tumor-targeting nanodrug (PT2-siRNA@PEG-FA) for synergic SDT and gene therapy of HCC.
肝细胞癌（HCC）是最致命和高度恶性的肿瘤之一。声动力学疗法（SDT）是一种新的癌症治疗方法。其独特的优势之一在于由于超声（US）引起的出色的组织穿透能力，可用于治疗深部肿瘤。但是，大多数声敏剂的声动力活性较弱，且对肿瘤的靶向能力较差。此外，小干扰 RNA（siRNA）是一种很有前途的抗癌药物，siRNA 基基因治疗的疗效在很大程度上取决于基因载体的细胞通透性。在这里，我们设计并合成了一种阳离子聚噻吩衍生物（PT2），可用作基因治疗的 siRNA 载体。此外，PT2 在超声照射下可以产生单线态氧（O）和羟基自由基（O），这表明 PT2 可用于 SDT。我们的研究发现，NUDT1 促进 HCC 的增殖并抑制细胞内 ROS 的产生。因此，设计并合成了 si-NUDT1。沉默 NUDT1 可以抑制肿瘤细胞的增殖并增加细胞内 ROS 的产生，从而进一步提高 SDT 的疗效。然后，将 si-NUDT1 与 PT2 和 DSPE-PEG-FA 组装在一起，制备了一种用于 HCC 的协同 SDT 和基因治疗的新型肿瘤靶向纳米药物（PT2-siRNA@PEG-FA）。
