MiR-375 and Doxorubicin Co-delivered by Liposomes for Combination Therapy of Hepatocellular Carcinoma

被引:63
作者
Fan, Yin-Ping [1 ]
Liao, Jia-Zhi [1 ]
Lu, Ya-Qi [1 ]
Tian, De-An [1 ]
Ye, Feng [2 ]
Zhao, Peng-Xuan [3 ]
Xiang, Guang-Ya [3 ]
Tang, Wang-Xian [1 ]
He, Xing-Xing [1 ]
机构
[1] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Inst Liver Dis, Wuhan 430030, Peoples R China
[2] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Pediat, Wuhan 430030, Peoples R China
[3] Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Pharm, Wuhan 430030, Peoples R China
来源
MOLECULAR THERAPY-NUCLEIC ACIDS | 2017年 / 7卷
基金
中国国家自然科学基金;
关键词
CANCER; SIRNA; MECHANISMS; SYSTEMS; AGENTS; CELLS;
D O I
10.1016/j.omtn.2017.03.010
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Doxorubicin (DOX) is one of the most frequently used anticancer drugs and the front line option for hepatocellular carcinoma (HCC) treatment. However, the clinical applications of DOX are restricted largely due to its toxicity and chemoresistance. Here, we report that miR-375 and DOX were co-delivered by liposomes (named L-miR-375/DOX-NPs) for combination therapy of HCC and drug resistance reversion of DOX. In vitro, L-miR-375/DOX-NPs could deliver DOX and miR375 efficiently and simultaneously into HCC cells and ensure the successful release of mature miR-375 and DOX. Then, the released miR-375 suppressed the malignant hallmarks of HCC by significantly decreasing the expression of AEG-1, YAP1, and ATG7, while the released DOX evidently accelerated cell apoptosis and blocked cycle at a G2/M stage by activating the P53/Bax/Bcl-2, caspase-3, and P-JNK, P-P38 pathway. Furthermore, miR-375 dramatically inhibited drug resistance of DOX by reducing the expression of multidrug resistance gene 1 (MDR1). In vivo, L-miR-375/DOX-NPs exhibited enhanced anti-tumor efficiency in xenograft HCC mouse models with mild adverse effects compared with doxorubicin or miR-375 alone. In conclusion, our research demonstrated that L-miR-375/DOX-NPs had significant synergetic anti-tumor effects and added values in overcoming drug resistance, which may represent a promising approach for the therapy of HCC.
引用
收藏
页码:181 / 189
页数:9
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