J Biomed Nanotechnol. 2014 Jun;10(6):1130-6. doi: 10.1166/jbn.2014.1823.
The endogenous RNA interference (RNAi) pathway enables control of pathologies caused by the dysregulation of proteins. Several biological molecules are active in RNAi including short interfering ribonucleic acid (siRNA). The effective utilization of siRNA as a therapeutic agent has been marked with distinct challenges, namely in intracellular delivery and achieving a sufficient dosage to affect protein expression. A delivery strategy we have developed to improve safety and efficacy of siRNA includes complexing siRNA with nanostructured polymers delivery systems (NSPs). These NSPs are synthesized via atom transfer radical polymerization (ATRP) and combine several important advances in polymer architecture for siRNA delivery. This includes shielding the cationic charge of the NSP with a poly(ethylene glycol) (PEG) shell to promote cell viability in MC3T3-E1.4 pre-osteoblasts, and minimize the inflammatory response in a C57BL/6 mouse model. In our gene knockdown experiments targeting glyceraldehyde 3-phosphate dehydrogenase Gapdh expression, star polymer and nanogel polyplexes suppressed Gapdh mRNA to levels comparable to cells treated with Lipofectamine RNAiMAX lipoplexes.
内源性 RNA 干扰 (RNAi) 途径可控制蛋白质失调引起的病理。几种生物分子在 RNAi 中起作用，包括短干扰核糖核酸 (siRNA)。siRNA 作为一种治疗剂的有效利用存在明显的挑战，即细胞内递药和达到足够的剂量以影响蛋白质表达。我们开发的一种改善 siRNA 安全性和疗效的递药策略包括将 siRNA 与纳米结构聚合物递药系统 (NSP) 复合。这些 NSP 是通过原子转移自由基聚合 (ATRP) 合成的，并结合了聚合物结构设计在 siRNA 递药方面的几个重要进展。这包括用聚乙二醇 (PEG) 壳屏蔽 NSP 的阳离子电荷，以提高 MC3T3-E1.4 前成骨细胞的细胞活力，并在 C57BL/6 小鼠模型中最小化炎症反应。在我们针对甘油醛 3-磷酸脱氢酶 Gapdh 表达的基因敲低实验中，星形聚合物和纳米凝胶聚阳离子复合物将 Gapdh mRNA 水平抑制到与用 Lipofectamine RNAiMAX 脂质体处理的细胞相当的水平。
