The induction of tumor apoptosis in B16 melanoma following STAT3 siRNA delivery with a lipid-substituted polyethylenimine
The induction of tumor apoptosis in B16 melanoma following STAT3 siRNA delivery with a lipid-substituted polyethylenimine
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DOI：
10.1016/j.biomaterials.2009.11.003
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发表时间：
2010-02-01
期刊：
影响因子：
14
通讯作者：
Uludag, Hasan
中科院分区：
文献类型：
--
作者：
Alshamsan, Aws;Hamdy, Samar;Uludag, Hasan
信号转导和转录激活因子3(STAT3)的持续激活已被证明在许多实体和血液肿瘤中具有多种致癌特征。在这项研究中，我们研究了硬脂酸(Sta)修饰的聚乙烯亚胺(PEI)纳米颗粒传递siRNA有效下调B16黑色素瘤细胞STAT3表达的可能性。与PEI复合体相比，PEI-sta复合体对B16细胞的STAT3沉默能力更强，同时可显著诱导IL-6的分泌和减少VEGF的产生。此外，在PEI-sta复合体中，细胞Caspase3活性(一种细胞凋亡活性的指标)的水平被发现比PEI复合体高2.5倍。当每天用50 nM的siRNA复合体处理细胞时，细胞活力在第三天剂量的PEI-sta复合体后急剧下降，仅为16%，而在相同时间段观察到的PEI复合体的活力为69%。体内实验结果一致地表明，与siRNA/PEI相比，siRNA/PEI-sta治疗后肿瘤生长和肿瘤重量显著下降。同时，肿瘤组织中IL-6水平和Caspase 3活性显著升高，而VEGF水平和STAT3活性显著降低。脂质修饰的PEI是一种很有前途的siRNA载体，而通过聚合物介导的siRNA传递下调STAT3是一种有效的癌症治疗策略，特别是当合适的传递系统可以增强siRNA的沉默活性时。(C)2009爱思唯尔有限公司。保留所有权利。
Persistent activation of signal transducer and activator of transcription 3 (STAT3) has been shown to impart several oncogenic features in many solid and blood tumors. In this study, we investigated the potential of nanoparticles based on polyethylenimine (PEI) modified with stearic acid (StA), to deliver siRNA for efficient STAT3 downregulation in B16 melanoma cells. The B16 cells were targeted with similar to 6-200 nM of siRNA complexes for 36 h. Compared to the PEI complexes, the PEI-StA complexes showed higher potency in STAT3 silencing in B16 cells accompanied by a significant induction of IL-6 secretion and a reduction of VEGF production. Moreover, with PEI-StA complexes, the level of the cellular Caspase 3 activity (an indicator of apoptotic activity) was found to be 2.5 times higher than that of PEI complexes. When the cells were treated with 50 nM of siRNA complexes on a daily basis, the cell viability was dramatically reduced reaching only to 16% after the third daily dose of PEI-StA complexes, as compared to the 69% viability observed with the PEI complexes at an equivalent time period. Consistently, in vivo results indicated significant regression in tumor growth and tumor weight after siRNA/PEI-StA treatment as compared to the siRNA/PEI. This was accompanied with significant increase in IL-6 levels and Caspase 3 activity, and a significant decrease in VEGF level and STAT3 activity in the tumor tissue. The lipid-modified PEI is a promising carrier for siRNA delivery and downregulation of STAT3 by polymer-mediated siRNA delivery is an effective strategy for cancer treatment especially when an optimum delivery system can potentiate the silencing activity of siRNA. (C) 2009 Elsevier Ltd. All rights reserved.