磁性纳米Fe_3O_4颗粒协同化疗药物及5溴汉防己甲素在荷瘤鼠体内逆转耐药的研究(英文)

Reversal of Multidrug Resistance in Xenograft Nude-mice by Magnetic Fe_3O_4 Nanoparticles Combined with Daunorubicin and 5-Bromotetrandrine

本研究探讨5溴汉防己甲素(5-BrTet)、磁性纳米Fe3O4(Fe3O4-MNP)协同化疗药在动物模型体内逆转耐药的作用及其作用机理。建立恶性血液病荷瘤鼠模型,将其随机分为5组。A组:生理盐水;B组:单用DNR;C组:5-BrTet复合DNR;D组:Fe3O4-MNPs复合DNR;E组:Fe3O4-MNPs复合DNR及5-BrTet。观察各组肿瘤生长特征,肿瘤重量、体积。取各组肿瘤以及心、肝、肾等脏器行组织病理观察。Western blot检测耐药肿瘤BCL-2,BAX,以及caspase-3表达。结果表明:对于K562移植瘤,B、C、D、E4个组之间肿瘤抑制率没有明显的差别。对于K562/A02移植瘤,Fe3O4-MNP复合DNR及5-BrTet可明显抑制移植瘤的增殖,促进肿瘤细胞凋亡;肿瘤组织病理观察显示肿瘤坏死明显。5-BrTet联合Fe3O4-MNP抑制K562/A02移植瘤的BCL-2蛋白的表达,下调BAX和caspas-3的表达。结论:在耐药肿瘤动物模型体内,FeO-MNPs协同DNR和5-BrTet具有很强的肿瘤抑制作用。

This study was aimed to investigate the reversal effect of 5-bromotetrandrine （5-BrTet） and magnetic nanoparticle of Fe3O4（ Fe3O4-MNPs） combined with DNR in vivo. The xenograft leukemia model with stable multiple drug resistance in nude mice was established. The two sub clones of K562 and K562/A02 cells were respectively inoculated subcutaneously into back of athymic nude mice （1×10^7 cells/each） to establish the leukemia xenograft models. Drug resistant and the sensitive tumor-beating nude mice were both assigned randomly into 5 groups： group A was treated with NS; group B was treated with DNR; group C was treated with nanoparticle of Fe3O4 combined with DNR; group D was treated with 5-BrTet combined with DNR; group E was treated with 5-bromotetrandrine and magnetic nanoparticle of Fe3O4 combined with DNR. The incidence of tumor formation, growth characteristics, weight and volume of tumor were observed. The histopathologic examination of tumors and organs were carried out. The protein levels of BCL-2, BAX, and Caspase-3 in resistant tumors were detected by Western blot. The results indicated that 5-BrTet and magnetic nanoparticle of Fe3O4 combined with DNR significantly suppressed growth of K562/A02 cell xenogaft tumor, histopathologic examination of tumors showed the tumors necrosis obviously. Application of 5-BrTet and magnetic nanoparticle of Fe3O4 inhibited the expression of BCL-2 protein and up regulated the expression of BAX, and Caspase-3 protein in K562/A02 cell xenograft tumor. It is concluded that 5-bromotetrandrine and magnetic nanoparticle of Fe304 combined with DNR have significant tumor-suppressing effect on MDR leukemia cell xenograft model.