Delivery of miR-375 and doxorubicin hydrochloride by lipid-coated hollow mesoporous silica nanoparticles to overcome multiple drug resistance in hepatocellular carcinoma
Delivery of miR-375 and doxorubicin hydrochloride by lipid-coated hollow mesoporous silica nanoparticles to overcome multiple drug resistance in hepatocellular carcinoma
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通过脂质包被的中空介孔二氧化硅纳米粒子递送miR-375和盐酸阿霉素以克服肝细胞癌的多重耐药性
DOI：
10.2147/ijn.s135306
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发表时间：
2017
影响因子：
8
通讯作者：
Xu Chuanrui
中科院分区：
文献类型：
--
作者：
Xue Huiying;Yu Zhaoyang;Liu Yong;Yuan Weigang;Yang Tan;You Jia;He Xingxing;Lee Robert J.;Li Lei;Xu Chuanrui
p -糖蛋白（P-gp）过表达引起的多药耐药（MDR）是阻碍肝细胞癌（HCC）治疗的主要障碍。研究表明，miR-375通过抑制HCC中星形细胞升高基因1 （AEG-1）的表达来抑制P-gp的表达，并通过靶向AEG-1和YAP1诱导HCC细胞凋亡。在本研究中，我们制备了含有盐酸阿霉素（DOX）和miR-375 （LHD/miR-375）的脂质包被中空介孔二氧化硅纳米颗粒（LH），在体外和体内将这两种药物递送到MDR HCC细胞中。我们发现LHD/miR-375克服了药物外排，并将miR-375和DOX递送到MDR HepG2/ADR细胞或HCC组织中。由LHD/ MiR-375传递的MiR-375通过吞噬和网格蛋白和小泡介导的内吞作用被摄取。从晚期内体释放后，它抑制了HepG2/ADR细胞中P-gp的表达。miR-375和中空介孔二氧化硅纳米颗粒（HMSN）的协同作用导致HCC细胞对DOX的摄取显著增加，并阻止HCC细胞的生长。LHD/miR-375在肝癌异种移植和原发肿瘤中的抗肿瘤作用也得到了证实；然而，没有观察到明显的毒性。机制研究也表明，miR-375和DOX通过促进细胞凋亡发挥协同抗肿瘤作用。我们的研究表明，在HCC治疗中，使用HMSN递送miR-375是规避MDR的可行方法。因此，值得进一步开发潜在的临床应用。
Multidrug resistance (MDR) due to overexpression of P-glycoprotein (P-gp) is a major obstacle that hinders the treatment of hepatocellular carcinoma (HCC). It has been shown that miR-375 inhibits P-gp expression via inhibition of astrocyte elevated gene-1 (AEG-1) expression in HCC, and induces apoptosis in HCC cells by targeting AEG-1 and YAP1. In this study, we prepared lipid-coated hollow mesoporous silica nanoparticles (LH) containing doxorubicin hydrochloride (DOX) and miR-375 (LHD/miR-375) to deliver the two agents into MDR HCC cells in vitro and in vivo. We found that LHD/miR-375 overcame drug efflux and delivered miR-375 and DOX into MDR HepG2/ADR cells or HCC tissues. MiR-375 delivered by LHD/miR-375 was taken up through phagocytosis and clathrin- and caveolae-mediated endocytosis. Following release from late endosomes, it repressed the expression of P-gp in HepG2/ADR cells. The synergistic effects of miR-375 and hollow mesoporous silica nanoparticles (HMSN) resulted in a profound increase in the uptake of DOX by the HCC cells and prevented HCC cell growth. Enhanced antitumor effects of LHD/miR-375 were also validated in HCC xenografts and primary tumors; however, no significant toxicity was observed. Mechanistic studies also revealed that miR-375 and DOX exerted a synergistic antitumor effect by promoting apoptosis. Our study illustrates that delivery of miR-375 using HMSN is a feasible approach to circumvent MDR in the management of HCC. It, therefore, merits further development for potential clinical application.