School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province, China, Zhengzhou University, Zhengzhou 450001, China.
Nano Lett. 2020 Nov 11;20(11):8102-8111. doi: 10.1021/acs.nanolett.0c03042. Epub 2020 Oct 16.
Multidrug resistance (MDR) of a tumor is the main cause of failure of clinical chemotherapy. Herein, we report a simple, yet versatile, tumor-targeting "calcium ion nanogenerator" (TCaNG) to reverse drug resistance by inducing intracellular Ca bursting. Consequently, the TCaNG could induce Ca bursting in acidic lysosomes of tumor cells and then reverse drug resistance according to the following mechanisms: (i) Ca specifically accumulates in mitochondria, suppressing cellular respiration and relieving tumor hypoxia, thus inhibiting P-glycoprotein biosynthesis by downregulating HIF-1α expression. (ii) Ca-bursting-induced respiratory depression blocks intracellular ATP production, which further leads to the P-gp incompetence. As a result, the TCaNG could decrease the IC of DOX to MCF-7/ADR cells by approximately 30 times and reduce the proliferation of drug-resistant tumors by approximately 13 times without obvious side effects. This simple, safe, and effective "Ca bursting" strategy holds the potential for clinical application in tumor treatment.
肿瘤的多药耐药性（MDR）是临床化疗失败的主要原因。在此，我们报告了一种简单而通用的肿瘤靶向“钙离子纳米发电机”（TCaNG），通过诱导细胞内 Ca 爆发来逆转耐药性。因此，TCaNG 可以在酸性溶酶体中诱导 Ca 爆发，然后根据以下机制逆转耐药性：（i）Ca 特异性地积累在线粒体中，抑制细胞呼吸并缓解肿瘤缺氧，从而通过下调 HIF-1α 表达抑制 P-糖蛋白的生物合成。（ii）Ca 爆发诱导的呼吸抑制阻止了细胞内 ATP 的产生，这进一步导致 P-gp 失活。结果，TCaNG 可以将 DOX 对 MCF-7/ADR 细胞的 IC 降低约 30 倍，并减少耐药性肿瘤的增殖约 13 倍，而没有明显的副作用。这种简单、安全、有效的“Ca 爆发”策略具有在肿瘤治疗中临床应用的潜力。
