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 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.
Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
Jianan
J
Shen
Huiping
H
Sun
Qingshuo
Q
Meng
Qi
Q
Yin
Zhiwen
Z
Zhang
Haijun
H
Yu
Yaping
Y
Li
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000628:therapy*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics*; D000077157:Sorafenib; D000077022:Survivin
C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D010671:Phenylurea Compounds; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D000077022:Survivin; D009536:Niacinamide; D000077157:Sorafenib
co-delivery; hepatocellular carcinoma; multidrug resistance; sorafenib; survivin shRNA