Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, Ministry of Education, Xi'an 710119, China.
National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an 710119, China.
Int J Mol Sci. 2022 Jul 20;23(14):7981. doi: 10.3390/ijms23147981.
Due to its noninvasive nature, site-confined irradiation, and high tissue penetrating capabilities, ultrasound (US)-driven sonodynamic treatment (SDT) has been proven to have broad application possibilities in neoplastic and non-neoplastic diseases. However, the inefficient buildup of sonosensitizers in the tumor site remarkably impairs SDT efficiency. The present work proposes a deep-penetrating sonochemistry nanoplatform (Pp18-lipos@SRA737&DOX, PSDL) comprising Pp18 liposomes (Pp18-lipos, Plipo), SRA737 (a CHK1 inhibitor), and doxorubicin (DOX) for the controlled formation of reactive oxygen species (ROS) and release of DOX and SRA737 upon US activation, therefore increasing chemotherapeutic effectiveness and boosting SDT efficacy. Therein, the antitumor activities of DOX have been attributed to its intercalation into the nucleus DNA and induction of cell apoptosis. CHK1 evolved to respond to DNA damage and repair the damage via cell cycle progression. SRA737 is a potent and orally bioavailable clinical drug candidate for inhibiting CHK1, demonstrating adjuvant anticancer effect in vitro and in vivo. It was interesting to find that SRA737 carried into Plipo@DOX could significantly alleviate G2/M cell cycle arrest and aggravate DNA double-strand injuries, resulting in significant cell death. The developed US-switchable nanosystem provides a promising strategy for augmenting sono-chemotherapy against breast cancer controllably and precisely.
由于其非侵入性、局部辐照和高组织穿透能力，超声（US）驱动的声动力学治疗（SDT）已被证明在肿瘤和非肿瘤疾病中有广泛的应用可能性。然而，声敏剂在肿瘤部位的低效积累显著降低了 SDT 的效率。本工作提出了一种深穿透声化学纳米平台（Pp18-脂质体@SRA737&DOX，PSDL），由 Pp18 脂质体（Pp18-脂质体，Plipo）、SRA737（CHK1 抑制剂）和阿霉素（DOX）组成，用于控制活性氧（ROS）的形成和 DOX 和 SRA737 的释放，从而提高化学治疗效果并增强 SDT 效果。其中，DOX 的抗肿瘤活性归因于其与核 DNA 的嵌入以及诱导细胞凋亡。CHK1 进化为响应 DNA 损伤并通过细胞周期进展修复损伤。SRA737 是一种有效的、口服生物可用的 CHK1 抑制剂临床候选药物，在体外和体内均显示出辅助抗癌作用。有趣的是，发现 SRA737 携带到 Plipo@DOX 中可以显著减轻 G2/M 细胞周期阻滞并加重 DNA 双链损伤，导致显著的细胞死亡。所开发的 US 开关纳米系统为可控和精确地增强针对乳腺癌的声化疗提供了有前途的策略。
