Arginine-Terminated Generation 4 PAMAM Dendrimer as an Effective Nanovector for Functional siRNA Delivery in Vitro and in Vivo
Arginine-Terminated Generation 4 PAMAM Dendrimer as an Effective Nanovector for Functional siRNA Delivery in Vitro and in Vivo
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DOI：
10.1021/bc4005156
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发表时间：
2014-03-01
影响因子：
4.7
通讯作者：
Peng, Ling
中科院分区：
文献类型：
--
作者：
Liu, Cheng;Liu, Xiaoxuan;Peng, Ling
RNA干扰的成功治疗实施关键取决于能够安全有效地递送小干扰RNA（siRNA）的系统。树枝状聚合物由于其独特的明确的树枝状纳米结构而成为siRNA递送的有吸引力的纳米载体，其中限制了有趣的协同性和多价性。我们以前已经证明，结构灵活的三乙醇胺（TEA）核心聚（酰胺基胺）（PAMAM）的高世代树枝状聚合物是有效的nanovectors siRNA交付在体外和体内。在本研究中，我们已经开发了精氨酸终止的树枝状聚合物，目的是结合和利用TEA核心PAMAM树枝状聚合物的独特siRNA递送特性和富含精氨酸的基序的细胞穿透优势。该家族的第4代树枝状聚合物（G（4）Arg）与siRNA形成稳定的树枝状复合物，与其不含精氨酸的树枝状聚合物对应物相比，导致siRNA的细胞摄取改善。此外，G（4）Arg被证明是用于siRNA递送的优良纳米载体，在体外和体内前列腺癌模型中产生有效的基因沉默和抗癌作用，并且没有可辨别的毒性。因此，在树枝状聚合物的表面上引入精氨酸残基是提高递送效率的一个有吸引力的选择，同时，树枝状聚合物G（4）Arg构成了用于有效siRNA递送的非常有前途的纳米载体，并具有进一步治疗应用的巨大潜力。
Successful therapeutic implementation of RNA interference critically depends on systems able to safely and efficiently deliver small interfering RNA (siRNA). Dendrimers are emerging as appealing nanovectors for siRNA delivery by virtue of their unique well-defined dendritic nanostructure within which is confined an intriguing cooperativity and multivalency. We have previously demonstrated that structurally flexible triethanolamine (TEA) core poly(amidoamine) (PAMAM) dendrimers of high generations are effective nanovectors for siRNA delivery in vitro and in vivo. In the present study, we have developed arginine-terminated dendrimers with the aim of combining and harnessing the unique siRNA delivery properties of the TEA-core PAMAM dendrimer and the cell-penetrating advantages of the arginine-rich motif. A generation 4 dendrimer of this family (G(4)Arg) formed stable dendriplexes with siRNA, leading to improved cell uptake of siRNA by comparison with its nonarginine bearing dendrimer counterpart. Moreover, G(4)Arg was demonstrated to be an excellent nanocarrier for siRNA delivery, yielding potent gene silencing and anticancer effects in prostate cancer models both in vitro and in vivo with no discernible toxicity. Consequently, importing an arginine residue on the surface of a dendrimer is an appealing option to improve delivery efficiency, and at the same time, the dendrimer G(4)Arg constitutes a highly promising nanovector for efficacious siRNA delivery and holds great potential for further therapeutic applications.