Center for Molecular Imaging and Nuclear Medicine, State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China.
ACS Appl Mater Interfaces. 2022 Aug 31;14(34):38617-38630. doi: 10.1021/acsami.2c12348. Epub 2022 Aug 16.
Chemo-/radioresistance is the most important reason for the failure of glioblastoma (GBM) treatment. Reversing the chemo-/radioresistance of GBM for boosting therapeutic efficacy is very challenging. Herein, we report a significant decrease in the chemo-/radioresistance of GBM by the generation of SO within a tumor, which was released on demand from the prodrug 5-amino-1,3-dihydrobenzo[]thiophene 2,2-dioxide (ATD) loaded on rare-earth-based scintillator nanoparticles (, NaYF:Ce@NaLuF:Nd@ATD@DSPE-PEG, ScNPs) under X-ray irradiation. Our novel X-ray-responsive ScNPs efficiently converted highly penetrating X-rays into ultraviolet rays for controlling the decomposition of ATD to generate SO, which effectively damaged the mitochondria of temozolomide-resistant U87 cells to lower the production of ATP and inhibit P-glycoprotein (P-gp) expression to reduce drug efflux. Meanwhile, the O-methylguanine-DNA methyltransferase (MGMT) of drug-resistant tumor cells was also reduced to prevent the repair of damaged DNA and enhance cell apoptosis and the efficacy of chemo-/radiotherapy. The tumor growth was obviously suppressed, and the mice survived significantly longer than untreated temozolomide-resistant GBM-bearing mice. Our work demonstrates the potential of SO in reducing chemo-/radioresistance to improve the therapeutic effect against resistant tumors if it can be well controlled and generated in tumor cells. It also provides insights into the rational design of stimuli-responsive drug delivery systems for the controlled release of drugs.
化疗/放疗耐药性是胶质母细胞瘤 (GBM) 治疗失败的最重要原因。逆转 GBM 的化疗/放疗耐药性以提高治疗效果极具挑战性。在此，我们报告了通过在肿瘤内产生 SO 来显著降低 GBM 的化疗/放疗耐药性，该 SO 是由负载在稀土基闪烁体纳米颗粒 (NaYF:Ce@NaLuF:Nd@ATD@DSPE-PEG，ScNPs) 上的前药 5-氨基-1,3-二氢苯并噻吩 2,2-二氧化物 (ATD) 在 X 射线照射下按需释放。我们的新型 X 射线响应性 ScNPs 可有效地将高穿透性 X 射线转化为紫外线，以控制 ATD 的分解以产生 SO，这有效地损伤替莫唑胺耐药 U87 细胞的线粒体以降低 ATP 的产生并抑制 P-糖蛋白 (P-gp) 的表达以减少药物外排。同时，耐药肿瘤细胞中的 O-甲基鸟嘌呤-DNA 甲基转移酶 (MGMT) 也减少，以防止受损 DNA 的修复，并增强细胞凋亡和化疗/放疗的疗效。肿瘤生长明显受到抑制，与未经处理的替莫唑胺耐药 GBM 荷瘤小鼠相比，小鼠的存活时间明显延长。我们的工作表明，如果能够在肿瘤细胞中得到很好的控制和产生，SO 具有降低化疗/放疗耐药性的潜力，以提高对耐药肿瘤的治疗效果。它还为设计用于控制药物释放的刺激响应性药物输送系统提供了深入的见解。
