基于铜基金属有机框架的化学动力学疗法联合阿霉素抗口腔鳞癌作用及其机制研究

Doxorubicin⁃loaded Cu⁃doped metal⁃organic framework nanoparticles for driving synergetic chemodynamic anticancer therapy

目的:探讨基于铜基金属有机框架(Cu⁃MOF)的化学动力学疗法联合阿霉素(DOX)协同抗口腔鳞癌作用及其机制。方法:通过简单的搅拌合成法制备了纳米级的Cu⁃MOF,并将其作为纳米载体负载DOX(Cu⁃MOF@DOX);通过透射电子显微镜对Cu⁃MOF的形貌进行表征,利用CCK⁃8法检测Cu⁃MOF@DOX对口腔鳞癌细胞的杀伤效果,采用激光共聚焦显微镜观察口腔鳞癌细胞摄取纳米颗粒及细胞内活性氧(ROS)的生成情况,利用谷胱甘肽(GSH)试剂盒检测癌细胞中GSH消耗情况,利用Western blot检测凋亡蛋白BAX和Bcl⁃2的表达。结果:Cu⁃MOF形态较规则,分散较均匀;Cu⁃MOF@DOX具有显著的抑瘤作用,呈剂量依赖关系(P<0.05);与DOX相比,Cu⁃MOF、Cu⁃MOF@DOX组均消耗GSH(P<0.001)。与DOX组相比,Cu⁃MOF@DOX中的DOX被细胞摄取的更多,并在细胞内能够产生ROS,协同引起细胞凋亡。结论:Cu⁃MOF@DOX能够通过化学动力学疗法和化疗协同作用促进口腔鳞癌细胞凋亡,Cu⁃MOF@DOX在口腔鳞癌治疗方面具有较好的应用前景。

Objective:The exploration of the synergistic anti⁃tumor effects and mechanisms of doxorubicin(DOX)⁃loaded copper⁃based metal⁃organic framework(Cu⁃MOF@DOX)nanoplatform for cancer chemodynamic therapy.Methods:The nanoscale Cu⁃MOF was prepared by a facile stirring method,which acted as the nanocarrier for loading DOX.Transmission electron microscope(TEM)was used to characterize these Cu⁃MOF.CCK⁃8 assays were used to investigate the cytotoxicity of Cu⁃MOF@DOX againstoral cancer cells.Confocal laser scanning microscopy(CLSM)was used to study the cellular uptake of Cu⁃MOF and the generation of intracellular reactive oxygen species(ROS).The depletion of glutathione(GSH)in cancer cells by Cu⁃MOF@DOX was investigated by a GSH as⁃say kit.Western blotting analysis was used to investigate the expression of BAX and Bcl⁃2 of Cu⁃MOF@DOX⁃treated cancer cells.Re⁃sults:TEM image showed the uniform size distribution and good dispersibility of these Cu⁃MOF.Cu⁃MOF@DOX was able to kill oral cancer cells in a dose⁃dependent manner(P<0.05).Cu⁃MOF@DOX could deplete GSH and release DOX to synergistically kill cancer cells(P<0.001).Compared with DOX alone,the DOX in Cu⁃MOF@DOX could be more effective uptaken by cancer cells and pro⁃duced large amounts of ROS.Conclusions:Cu⁃MOF@DOX can effectively induce apoptosis of oral cancer cells through the synergistic effects of chemodynamic therapy and chemotherapy,which held good potential in oral cancer therapy.