Department of Chemistry, 1102 Natural Sciences 2, University of California, Irvine , California 92697-2025, United States.
J Am Chem Soc. 2013 Apr 3;135(13):4962-5. doi: 10.1021/ja400986u. Epub 2013 Mar 25.
In this study, we designed and synthesized a biodegradable dendronized polypeptide (denpol) platform for delivery of small interfering RNA (siRNA). The novel denpol architecture combines the multivalency of dendrimers and conformational flexibility of linear polymers for optimal siRNA binding. Multifunctional amino acids were incorporated onto the dendrons and the structure was tuned both systematically and combinatorially to select optimal vectors. By screening a focused library, we identified several denpols that can effectively deliver siRNA to NIH 3T3 cells in vitro and exhibit minimal toxicity. For comparison, the best-performing denpol showed significantly improved transfection efficiency over Lipofectamine in serum-containing media. Fluorescence intracellular trafficking studies indicated that amphiphilicity is important for cell uptake and that the buffering capacity of histidine facilitates endosomal membrane rupture and therefore enhances the transfection efficiency. The combination of high delivery efficiency in serum and low cytotoxicity suggests the denpol system as a promising new carrier for siRNA delivery.
在这项研究中，我们设计并合成了一种可生物降解的树枝状多肽（denpol）平台，用于递送小干扰 RNA（siRNA）。这种新型 denpol 结构结合了树状大分子的多价性和线性聚合物的构象灵活性，以实现最佳的 siRNA 结合。多功能氨基酸被整合到树枝上，并且结构被系统地和组合地进行了调整，以选择最佳的载体。通过筛选一个有针对性的文库，我们鉴定出了几种 denpol，它们可以有效地将 siRNA 递送到体外的 NIH 3T3 细胞中，并且表现出最小的毒性。相比之下，表现最好的 denpol 在含血清的培养基中显示出比 Lipofectamine 显著提高的转染效率。荧光细胞内转运动力学研究表明，两亲性对于细胞摄取很重要，组氨酸的缓冲能力有助于内体膜破裂，从而增强转染效率。在血清中具有高递送效率和低细胞毒性的结合表明 denpol 系统是一种很有前途的 siRNA 递送新载体。
