Institute of Pharmacology, Philipps-University, Marburg, Germany.
Eur J Pharm Biopharm. 2011 Apr;77(3):438-49. doi: 10.1016/j.ejpb.2010.11.007. Epub 2010 Nov 18.
RNA interference (RNAi) is a promising strategy to inhibit the expression of pathologically relevant genes, which show aberrant (over-)expression, e.g. in tumors or other pathologies. The induction of RNAi relies on small interfering RNAs (siRNAs), which trigger the specific mRNA degradation. Their instability and poor delivery into target tissues including the lung, however, so far severely limits the therapeutic use of siRNAs and requires the development of nanoscale delivery systems. Polyethylenimines (PEIs) are synthetic polymers, which are able to form non-covalent complexes with siRNAs. These nanoscale complexes ('nanoplexes') allow the protection of siRNAs from nucleolytic degradation, their efficient cellular uptake through endocytosis and intracellular release through the 'proton sponge effect'. Chemical modifications of PEIs as well as the coupling of cell/tissue-specific ligands are promising approaches to increase the biocompatibility, specificity and efficacy of PEI-based nanoparticles. This review article gives a comprehensive overview of pre-clinical in vivo studies on the PEI-mediated delivery of therapeutic siRNAs in various animal models. It discusses the chemical properties of PEIs and PEI modifications, and their influences on siRNA knockdown efficacy, on adverse effects of the polymer or the nanoplex and on siRNA biodistribution in vivo. Beyond systemic application, PEI-based complexation allows the local siRNA application to the lung. Biodistribution studies demonstrate cellular uptake of PEI-complexed, but not of naked siRNAs in the lung with little systemic availability of the siRNAs, indicating the usefulness of this approach for the targeting of genes, which are pathologically relevant in lung tumors or lung metastases. Taken together, (i) PEI and PEI derivatives may represent an efficient delivery platform for siRNAs, (ii) siRNA-mediated induction of RNAi is a promising approach for the knockdown of pathologically relevant genes, and (iii) when sufficiently addressing biocompatibility issues, the locoregional delivery of PEI/siRNA complexes may become an attractive therapeutic strategy for the treatment of lung diseases with little systemic side effects.
RNA 干扰 (RNAi) 是一种很有前途的策略，可以抑制病理性相关基因的表达，这些基因表现出异常（过度）表达，例如在肿瘤或其他病变中。RNAi 的诱导依赖于小干扰 RNA（siRNAs），它能触发特定的 mRNA 降解。然而，它们的不稳定性和向包括肺在内的靶组织的传递能力很差，这极大地限制了 siRNA 的治疗用途，并需要开发纳米级递药系统。聚乙二烯亚胺（PEI）是一种合成聚合物，能够与 siRNA 形成非共价复合物。这些纳米级复合物（“纳米复合物”）可以保护 siRNA 免受核酸酶降解，通过内吞作用有效地将其摄取到细胞内，并通过“质子海绵效应”在细胞内释放。PEI 的化学修饰以及与细胞/组织特异性配体的偶联是提高基于 PEI 的纳米颗粒的生物相容性、特异性和疗效的有前途的方法。本文综述了在各种动物模型中，关于 PEI 介导的治疗性 siRNA 传递的临床前体内研究。它讨论了 PEI 的化学性质和修饰，以及它们对 siRNA 敲低效果、聚合物或纳米复合物的不良影响以及 siRNA 在体内的生物分布的影响。除了全身应用外，基于 PEI 的复合物允许将 siRNA 局部应用于肺部。生物分布研究表明，PEI 复合物摄取细胞，但肺内的裸 siRNA 不摄取，siRNA 的全身可用性很小，这表明该方法对肺肿瘤或肺转移中病理性相关基因的靶向具有有用性。总之，（i）PEI 和 PEI 衍生物可能是 siRNA 的有效递药平台，（ii）siRNA 介导的 RNAi 诱导是一种很有前途的方法，可以敲低病理性相关基因，（iii）当充分解决生物相容性问题时，PEI/siRNA 复合物的局部递药可能成为治疗肺部疾病的一种有吸引力的治疗策略，其全身副作用较小。
