Polyethylenimines for RNAi-mediated gene targeting in vivo and siRNA delivery to the lung.

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.