Di Gioia Sante, Conese Massimo
Department of Biomedical Sciences, University of Foggia, Viale L. Pinto 1, Foggia, Italy.
Drug Des Devel Ther. 2009 Feb 6;2:163-88. doi: 10.2147/dddt.s2708.
Nonviral gene delivery is now considered a promising alternative to viral vectors. Among nonviral gene delivery agents, polyethylenimine (PEI) has emerged as a potent candidate for gene delivery to the lung. PEI has some advantages over other polycations in that it combines strong DNA compaction capacity with an intrinsic endosomolytic activity. However, intracellular (mainly the nuclear membrane) and extracellular obstacles still hamper its efficiency in vitro and in vivo, depending on the route of administration and the type of PEI. Nuclear delivery has been increased by adding nuclear localization signals. To overcome nonspecific interactions with biological fluids, extracellular matrix components and nontarget cells, strategies have been developed to protect polyplexes from these interactions and to increase target specificity and gene expression. When gene delivery into airway epithelial cells of the conducting airways is necessary, aerosolization of complexes seems to be better suited to guarantee higher transgene expression in the airway epithelial cells with lower toxicity than observed with either intratracheal or intravenous administration. Aerosolization, indeed, is useful to target the alveolar epithelium and pulmonary endothelium. Proof-of-principle that PEI-mediated gene delivery has therapeutic application to some genetic and acquired lung disease is presented, using as genetic material either plasmidic DNA or small-interfering RNA, although optimization of formulation and delivery protocols and limitation of toxicity need further studies.
非病毒基因递送如今被认为是病毒载体的一种有前景的替代方法。在非病毒基因递送载体中，聚乙烯亚胺（PEI）已成为向肺部递送基因的有力候选者。与其他聚阳离子相比，PEI具有一些优势，即它兼具强大的DNA压缩能力和内在的溶酶体溶解活性。然而，细胞内（主要是核膜）和细胞外的障碍仍会阻碍其在体外和体内的效率，这取决于给药途径和PEI的类型。通过添加核定位信号提高了核递送效率。为了克服与生物流体、细胞外基质成分和非靶细胞的非特异性相互作用，已开发出多种策略来保护多聚体免受这些相互作用的影响，并提高靶向特异性和基因表达。当需要将基因递送至传导气道的气道上皮细胞时，复合物雾化似乎更适合保证气道上皮细胞中更高的转基因表达，且毒性低于气管内或静脉内给药。事实上，雾化有助于靶向肺泡上皮和肺内皮。本文展示了PEI介导的基因递送在一些遗传性和获得性肺部疾病中具有治疗应用的原理证明，使用质粒DNA或小干扰RNA作为遗传物质，尽管制剂和递送方案的优化以及毒性限制仍需进一步研究。
