Moschos S A, Williams A E, Lindsay M A
Biopharmaceutics Research Group, Airways Disease, National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK.
Biochem Soc Trans. 2007 Aug;35(Pt 4):807-10. doi: 10.1042/BST0350807.
The therapeutic application of siRNA (short interfering RNA) shows promise as an alternative approach to small-molecule inhibitors for the treatment of human disease. However, the major obstacle to its use has been the difficulty in delivering these large anionic molecules in vivo. A potential approach to solving this problem is the chemical conjugation of siRNA to the cationic CPPs (cell-penetrating peptides), Tat-(48-60) (transactivator of transcription) and penetratin, which have been shown previously to mediate protein and peptide delivery in a host of animal models. In this transaction, we review recent studies on the utility of siRNA for the investigation of protein function in the airways/lung. We show that, despite previous studies showing the utility of cationic CPPs in vitro, conjugation of siRNA to Tat-(48-60) and penetratin failed to increase residual siRNA-mediated knockdown of p38 MAPK (mitogen-activated protein kinase) (MAPK14) mRNA in mouse lung in vivo. Significantly, we will also discuss potential non-specific actions and the induction of immunological responses by CPPs and their conjugates and how this might limit their application for siRNA-mediated delivery in vivo.
小干扰RNA（siRNA）的治疗应用有望成为治疗人类疾病的小分子抑制剂的替代方法。然而，其应用的主要障碍在于在体内递送这些带负电荷的大分子存在困难。解决这一问题的一种潜在方法是将siRNA与阳离子细胞穿透肽（CPP）进行化学偶联，如Tat-（48-60）（转录反式激活因子）和穿膜肽，先前已证明它们能在许多动物模型中介导蛋白质和肽的递送。在此论述中，我们回顾了近期关于siRNA在气道/肺中蛋白质功能研究方面应用的研究。我们发现，尽管先前的研究表明阳离子CPP在体外有用，但在体内将siRNA与Tat-（48-60）和穿膜肽偶联未能增加小鼠肺中siRNA介导的p38丝裂原活化蛋白激酶（MAPK）（MAPK14）mRNA的残留敲低。值得注意的是，我们还将讨论CPP及其偶联物的潜在非特异性作用和免疫反应诱导，以及这可能如何限制它们在体内siRNA介导递送中的应用。
