Kim Won Jong, Christensen Lane V, Jo Seongbong, Yockman James W, Jeong Ji Hoon, Kim Yong-Hee, Kim Sung Wan
Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112-5820, USA.
Mol Ther. 2006 Sep;14(3):343-50. doi: 10.1016/j.ymthe.2006.03.022. Epub 2006 Jun 12.
Vascular endothelial growth factor (VEGF) is a multifunctional angiogenic growth factor that is a primary stimulant of the development and maintenance of a vascular network in the vascularization of solid tumors. It has been reported that a blockade of VEGF-mediated angiogenesis is a powerful method for tumor regression. RNA interference represents a naturally occurring biological strategy for inhibition of gene expression. In mammalian systems, however, the in vivo application of small interfering RNA (siRNA) is severely limited by the instability and poor bioavailability of unmodified siRNA molecules. In this study, we tested the hypothesis that a hydrophobically modified protein transduction domain, cholesteryl oligo-d-arginine (Chol-R9), may stabilize and enhance tumor regression efficacy of the VEGF-targeting siRNA. The noncovalent complexation of a synthetic siRNA with Chol-R9 efficiently delivered siRNA into cells in vitro. Moreover, in a mouse model bearing a subcutaneous tumor, the local administration of complexed VEGF-targeting siRNA, but not of scrambled siRNA, led to the regression of the tumor. Hence, we propose a novel and simple system for the local in vivo application of siRNA through Chol-R9 for cancer therapy.
血管内皮生长因子（VEGF）是一种多功能血管生成生长因子，是实体瘤血管化过程中血管网络发育和维持的主要刺激因子。据报道，阻断VEGF介导的血管生成是一种有效的肿瘤消退方法。RNA干扰是一种天然存在的抑制基因表达的生物学策略。然而，在哺乳动物系统中，未修饰的小干扰RNA（siRNA）分子的体内应用受到其不稳定性和低生物利用度的严重限制。在本研究中，我们测试了以下假设：疏水修饰的蛋白质转导结构域胆固醇基寡聚-d-精氨酸（Chol-R9）可能会稳定并增强靶向VEGF的siRNA的肿瘤消退效果。合成的siRNA与Chol-R9的非共价复合能够在体外有效地将siRNA递送至细胞内。此外，在携带皮下肿瘤的小鼠模型中，局部施用复合的靶向VEGF的siRNA而非乱序siRNA可导致肿瘤消退。因此，我们提出了一种新颖且简单的系统，通过Chol-R9在体内局部应用siRNA进行癌症治疗。
