Low-molecular weight chitosan/vascular endothelial growth factor short hairpin RNA for the treatment of hepatocellular carcinoma
Low-molecular weight chitosan/vascular endothelial growth factor short hairpin RNA for the treatment of hepatocellular carcinoma
复制标题
低分子量壳聚糖/血管内皮生长因子短发夹RNA用于治疗肝细胞癌。
DOI：
10.1016/j.lfs.2012.09.015
复制
发表时间：
2012-12-10
期刊：
影响因子：
6.1
通讯作者：
Zhang, Junfeng
中科院分区：
文献类型：
--
作者：
Huang, Zhen;Dong, Lei;Zhang, Junfeng
目的：血管内皮生长因子（VEGF）已被证明是肝细胞癌（HCC）血管生成和肿瘤生长的关键驱动力。作为一种新兴的阻断这种血管生成刺激因子的方法，RNA干扰（RNAi）技术得到了迅速发展，但由于小RNA的低细胞摄取和差的稳定性而阻碍了其在体内的应用。以低分子量壳聚糖（LMWC）为载体，构建了针对VEGF的短发夹状RNA（shRNA）基因递送系统。本研究旨在探讨LMWC/shRNA纳米复合物是否能有效抑制肿瘤细胞和肿瘤组织中VEGF的表达，并抑制不同肝癌模型中肿瘤的生长。主要方法：采用转染实验和Real-time qPCR检测LMWC/shRNA复合物对Hepa 1-6小鼠肝癌细胞的转染效率和基因抑制活性。结果：LMWC/VEGF shRNA复合物能显著抑制肝癌细胞和肝癌组织中VEGF的表达。将LMWC/shRNA复合物静脉注射到原位移植性肝癌小鼠体内，可明显增强并延长shRNA在肿瘤部位的沉积。通过瘤内或静脉注射LMWC/VEGF shRNA复合物的管理证明了更有效的抑制肿瘤血管生成和肿瘤生长在不同的HCC模型相比，裸shRNA.Significance：这项研究表明，使用LMWC作为一个潜在的载体的RNA干扰药物在肝癌治疗的可行性。(C)2012 Elsevier Inc. All rights reserved.
Aims: Vascular endothelial growth factor (VEGF) has been shown to be a key driving force for angiogenesis and tumor growth in hepatocellular carcinoma (HCC). As an emerging approach to block this angiogenic stimulator, the RNA interference (RNAi) technique has rapidly developed but is hindered for in vivo applications due to low cellular uptake and poor stability of small RNA. Based on low molecular weight chitosan (LMWC), a gene delivery system of short hairpin RNA (shRNA) directed against VEGF was constructed. The objective of this study was to investigate whether LMWC/shRNA nano-complexes can effectively inhibit VEGF expression in cancer cells and tumor tissues and suppress tumor growth in different HCC models.Main methods: The transfection experiment and Real-time qPCR assay were used to evaluate the transfection efficiency and gene suppression activity of LMWC/shRNA complexes in Hepa 1-6 murine hepatocarcinoma cells. The therapeutic effect of LMWC/ VEGF shRNA was further tested in ectopic and orthotopic liver cancer models.Key findings: LMWC/VEGF shRNA complexes significantly inhibited VEGF expression of HCC cells and liver tumor tissues. LMWC obviously enhanced and prolonged the deposition of shRNA at the tumor site when LMWC/shRNA complexes were intravenously injected into orthotopic allograft liver tumor-bearing mice. The administration of LMWC/VEGF shRNA complexes by intratumoral or intravenous injection demonstrated more effective suppression of tumor angiogenesis and tumor growth in different HCC models compared with naked shRNA.Significance: This study demonstrated the feasibility of using LMWC as a potential carrier for RNA interference drugs in liver cancer therapy. (C) 2012 Elsevier Inc. All rights reserved.