The systemic delivery of siRNAs by a cell penetrating peptide, low molecular weight protamine
The systemic delivery of siRNAs by a cell penetrating peptide, low molecular weight protamine
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DOI：
10.1016/j.biomaterials.2009.11.001
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发表时间：
2010-02-01
期刊：
影响因子：
14
通讯作者：
Park, Yoon-Jeong
中科院分区：
文献类型：
--
作者：
Choi, Young-Suk;Lee, Jue Yeon;Park, Yoon-Jeong
小干扰rna (sirna)，用于特异性下调靶基因，已获得相当大的兴趣作为一个有吸引力的新型药物广泛的临床应用。然而，这些sirna携带的多阴离子电荷会抑制细胞摄取，从而限制对基因调控的影响。本文作者描述了一种含有细胞穿透肽的肽/siRNA复合物，这种复合物来源于天然鱼精蛋白，称为低分子量鱼精蛋白（LMWP）。用于治疗癌症。在LMWP/siRNA复合物与癌细胞孵育后不久，荧光标记的siRNA与肽一起定位在细胞质中。使用LMWP实现的siRNA的细胞摄取增加导致模型蛋白荧光素酶以及治疗性癌症靶点血管内皮生长因子（VEGF）表达显著下调。在荷瘤小鼠的体内研究进一步证明，该肽可以携带siRNA并在肿瘤内定位，通过系统应用肽复合物抑制VEGF的表达，从而抑制肿瘤生长。此外，在LMWP/siRNA复合物处理下，血清炎症细胞因子包括干扰素(IFN)- α和白细胞介素(IL)-12水平未检测到升高，表明LMWP/siRNA的全身递送没有可测量的免疫刺激作用。基于lmwp的全身递送方法可能是一种可靠和安全的方法，可以最大限度地提高治疗性siRNA治疗癌症和其他疾病的有效性。2009爱思唯尔有限公司版权所有。
Small interfering RNAs (siRNAs), used for specific down-regulation of targeted genes, have garnered considerable interest as an attractive new class of drugs for broad clinical applications. The polyanionic charges carried by these siRNAs, however, restrain cellular uptake and consequently limit effects on gene regulation. Herein the authors describe a peptide/siRNA complex containing the cell penetrating peptide derived from natural protamine, termed low molecular weight protamine (LMWP). for the treatment of cancer. Fluorescently-tagged siRNAs were localized with the peptide in the cytoplasm shortly after incubation of LMWP/siRNA complex with carcinoma cells. The increased cell uptake of siRNA that was achieved using the LMWP resulted in significant down-regulation of model protein luciferase as well as therapeutic cancer target, vascular endothelial growth factor (VEGF) expression. In vivo studies with tumor-bearing mice further demonstrated that the peptide could carry and localize siRNA inside tumors and inhibit the expression of VEGF through systemic application of the peptide complex, thereby suppressing tumor growth. In addition, no detectable increase in the serum level of inflammatory cytokines including interferon (IFN)-alpha and interleukin (IL)-12 was observed under the LMWP/siRNA complex treatment, indicating systemic delivery of LMWP/siRNA did not exert measurable immunostimulatory effect. The LMWP-based systemic delivery method could be a reliable and safe approach to maximize effectiveness of therapeutic siRNA for treatment of cancer and other diseases. (C) 2009 Elsevier Ltd. All rights reserved.