Wang Kui, Kievit Forrest M, Chiarelli Peter A, Stephen Zachary R, Lin Guanyou, Silber John R, Ellenbogen Richard G, Zhang Miqin
Department of Materials Science and Engineering, University of Washington, Seattle, WA 98195, United States.
Department of Neurological Surgery, University of Washington, Seattle, WA 98195, United States.
Adv Funct Mater. 2021 Feb 3;31(6). doi: 10.1002/adfm.202007166. Epub 2020 Nov 6.
Temozolomide (TMZ) is the standard of care chemotherapy drug for treating glioblastomas (GBMs), the most aggressive cancer that affects people of all ages. However, its therapeutic efficacy is limited by the drug resistance mediated by a DNA repair protein, O-methylguanine-DNA methyltransferase (MGMT), which eliminates the TMZ-induced DNA lesions. Here we report the development of an iron oxide nanoparticle (NP) system for targeted delivery of siRNAs to suppress the TMZ-resistance gene (MGMT). We show that our NP is able to overcome biological barriers, bind specifically to tumor cells, and reduce MGMT expression in tumors of mice bearing orthotopic GBM serially-passaged patient-derived xenografts. The treatment with sequential administration of this NP and TMZ resulted in increased apoptosis of GBM stem-like cells, reduced tumor growth, and significantly-prolonged survival as compared to mice treated with TMZ alone. This study introduces an approach that holds great promise to improve the outcomes of GBM patients.
替莫唑胺（TMZ）是治疗胶质母细胞瘤（GBM）的标准护理化疗药物，GBM是影响各年龄段人群的最具侵袭性的癌症。然而，其治疗效果受到一种DNA修复蛋白O-甲基鸟嘌呤-DNA甲基转移酶（MGMT）介导的耐药性的限制，该蛋白可消除TMZ诱导的DNA损伤。在此，我们报告了一种用于靶向递送小干扰RNA（siRNA）以抑制TMZ耐药基因（MGMT）的氧化铁纳米颗粒（NP）系统的研发情况。我们表明，我们的NP能够克服生物屏障，特异性结合肿瘤细胞，并降低原位GBM连续传代患者来源异种移植小鼠肿瘤中的MGMT表达。与单独使用TMZ治疗的小鼠相比，序贯给予该NP和TMZ治疗可导致GBM干细胞样细胞凋亡增加、肿瘤生长减缓以及生存期显著延长。本研究引入了一种有望改善GBM患者治疗结果的方法。
