Liver-specific gene therapy of hepatocellular carcinoma by targeting human telomerase reverse transcriptase with pegylated immuno-lipopolyplexes.
【作者】 Yurong Hu,Yingying Shen,Baofang Ji,Shasha Yin,Xueling Ren,Tingting Chen,Yue Ma,Zhenzhong Zhang*,Yun Zhang,
【期刊名】 European Journal of Pharmaceutics and Biopharmaceutics
【影响因子】 2011年:4.269
【作者单位】 Zhengzhou Univ, Sch Pharm, 100 Sci Rd, Zhengzhou 450001, Henan Province, Peoples R China
【年，卷(期)：页码】2011.8.01,78(3):320-325
【关键词】hTERT; RNA interference; Hepatocellularcarcinoma; Pegylatedimmuno-lipopolyplexes; Apolipoprotein A-I promoter
【摘要】The purpose of this study is to explore the possibility and feasibility ofliver-specificgenetherapy. A shRNA expression plasmid against humantelomerasereversetranscriptase (hTERT) was constructed under the control ofliver-specific promoter apolipoprotein A-I (ApoAI), designated as pApoAI-shTERT, and its liver-specific cytotoxicity and inhibition oftelomerase activity were first evaluated in different cell lines, and its therapeutic effect was further studied in SMMC-7721 human liver tumor-bearing mice in vivo. The results showed that compared to pU6-shTERT, a shRNA expression plasmid against hTERT under the control of U6 promoter, pApoAI-shTERT only significantly diminished the cell viability in the telomerase positive hepatocarcinoma cells and showed no cytotoxicity in the telomerase negative cell lines as well as in the telomerase positive cell line of non-liver origin. Besides, pApoAI-shTERT only significantly reduced telomerase activity in the telomerase positive cell lines of liver origin. Intravenous administration ofpegylatedimmuno-lipopolyplexes (PILP) formulated green fluorescent protein (GFP) expression plasmid under the control of ApoAI into liver tumor-bearing mice resulted in restricted GFP expression in liver and liver tumor. The treatment of pApoAI-shTERT formulated as PILP caused a 56% increase in the life span of SMMC-7721 tumor-bearing mice in vivo relative to the control, which was in agreement with the reduced tumor size and down-regulated hTERT mRNA level in the tumors. We conclude that the vector pApoAI-shTERT was able to cause liver-specific and hTERT target-specific cytotoxicity, and utilizing PILP to deliver pApoAI-shTERT is a promising strategy for liver-specificgenetherapy. (C) 2011 Elsevier B.V. All rights reserved.
【全文链接】http://www.sciencedirect.com/science/article/pii/S0939641111000063
