School of Pharmacy, Nottingham, NG7 2RD, UK.
Chem Soc Rev. 2013 Oct 21;42(20):7983-97. doi: 10.1039/c3cs35520a.
Small interfering ribonucleic acids (siRNAs) form potentially the most important class of next generation therapeutics. However, achieving their efficient delivery in the correct dose, time and location in the body remains a significant challenge. Rapid developments in the chemistries of siRNA formulations are enabling new strategies to overcome the core obstacles to delivery which include poor ribonuclease (RNase) resistance, short biological half-life, lack of tissue targeting, inefficient cellular uptake and undesirable toxicity. In this review we describe these principal challenges and evaluate recent approaches proposed to overcome the chemical, biochemical and physiological barriers. The role of the specific chemical structure of siRNA is considered and an overview of selected literature-reported siRNA formulations is provided. These include chemically-modified siRNAs and analogues, aptamer-siRNA chimeras, self-assembled nanoparticles, lipid and polymer complexes, bioconjugates and fusion protein complexes. We conclude the review with an outlook for the clinical use of this highly promising, but pharmaceutically challenging biotherapeutic.
小干扰核糖核酸（siRNAs）可能形成了下一代治疗药物中最重要的一类。然而，在体内以正确的剂量、时间和位置实现其有效递依然是一个重大挑战。siRNA 制剂化学的快速发展使新的策略能够克服递的核心障碍，包括对核糖核酸酶（RNase）的抗性差、生物半衰期短、缺乏组织靶向性、细胞摄取效率低和不良毒性。在这篇综述中，我们描述了这些主要挑战，并评估了最近提出的克服化学、生化和生理障碍的方法。我们还考虑了 siRNA 的特定化学结构的作用，并提供了选定的文献报道的 siRNA 制剂的概述。这些制剂包括化学修饰的 siRNAs 和类似物、适体-siRNA 嵌合体、自组装纳米颗粒、脂质和聚合物复合物、生物缀合物和融合蛋白复合物。最后，我们对这种极具前景但药物治疗具有挑战性的生物治疗剂的临床应用进行了展望。
