Simultaneous Inhibition of Tumor Growth and Angiogenesis for Resistant Hepatocellular Carcinoma by Co-delivery of Sorafenib and Survivin Small Hairpin RNA

The development of multidrug resistance (MDR) in human hepatocellular carcinoma (HCC) is one of the major obstacles for successful chemotherapy of HCC. Co-delivery of sorafenib (SF) and survivin shRNA (shSur) was postulated to achieve synergistic effects in reversing MDR, suppressing tumor growth an...

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Bibliographic Details
Published in:Molecular pharmaceutics 2014-10, Vol.11 (10), p.3342-3351
Main Authors: Shen, Jianan, Sun, Huiping, Meng, Qingshuo, Yin, Qi, Zhang, Zhiwen, Yu, Haijun, Li, Yaping
Format: Article
Language:English
Subjects:
Animals
Carcinoma, Hepatocellular - drug therapy
Carcinoma, Hepatocellular - metabolism
Carcinoma, Hepatocellular - therapy
Cell Cycle - drug effects
Cell Cycle - genetics
Drug Resistance, Neoplasm
Humans
Inhibitor of Apoptosis Proteins - genetics
Liver Neoplasms - drug therapy
Liver Neoplasms - metabolism
Liver Neoplasms - therapy
Male
Mice
Mice, Inbred BALB C
Neovascularization, Pathologic
Niacinamide - analogs & derivatives
Niacinamide - therapeutic use
Phenylurea Compounds - therapeutic use
Repressor Proteins - genetics
RNA, Small Interfering - genetics
RNA, Small Interfering - physiology
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Summary:The development of multidrug resistance (MDR) in human hepatocellular carcinoma (HCC) is one of the major obstacles for successful chemotherapy of HCC. Co-delivery of sorafenib (SF) and survivin shRNA (shSur) was postulated to achieve synergistic effects in reversing MDR, suppressing tumor growth and angiogenesis. For this purpose, in this work, SF and shSur co-loaded pluronic P85-polyethyleneimine/d-α-tocopheryl polyethylene glycol 1000 succinate nanocomplexes (SSNs) were first designed and developed for the treatment of drug resistant HCC. The experimental results showed that SSNs could achieve effective cellular internalization and shSur transfection efficiency, induce significant downregulation of the survivin protein, and cause remarkable cell arrest and cell apoptosis. The tube formulation assay demonstrated that SSNs completely disrupted the enclosed capillary networks formed by human microvascular endothelial cells. The in vivo antitumor efficacy showed that SSNs were superior to that of other treatments on drug resistant hepatocellular tumor models. Therefore, it could be an efficient strategy to co-deliver SF and shSur for therapy of drug resistant HCC.
ISSN:1543-8384
1543-8392
DOI:10.1021/mp4006408