title: Proton sponge trick for pH-sensitive disassembly of polyethylenimine-based siRNA delivery systems.
abstract: Small interfering RNAs offer novel opportunities to inhibit gene expression in a highly selective and efficient manner but depend on cytosolic translocation with synthetic delivery systems. The polyethylenimine (PEI) is widely used for plasmid DNA transfection. However, the water-soluble PEI does not form siRNA polyplexes stable enough in extracellular media for effective delivery. We previously showed that rendering PEI insoluble in physiological media, without modifying drastically its overall cationic charge density, by simple conjugation with natural hydrophobic alpha-amino acids, can lead to effective siRNA delivery in mammalian cells. In here, we comprehensively investigated the mechanism behind the excellent efficacy of the leading PEIY vector. Our data revealed that the underlining proton sponge property is key to the effectiveness of the tyrosine-polyethylenimine conjugate as it may allow both endosomal rupture and siRNA liberation via an optimal pH-sensitive dissolution of the PEIY self-aggregates. Altogether, these results should facilitate the development of novel and more sophisticated siRNA delivery systems.
authors.affiliation: Laboratoire de Conception et Application de Molecules Bioactives, CNRS-Universite de Strasbourg UMR 7199, Faculte de Pharmacie, 74, route du Rhin, 67400 Illkirch, France.
authors.forename: Gaelle
authors.initials: G
authors.lastname: Creusat
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Rinaldi
authors.forename: Etienne
authors.initials: E
authors.lastname: Weiss
authors.forename: Rkia
authors.initials: R
authors.lastname: Elbaghdadi
authors.forename: Jean-Serge
authors.initials: JS
authors.lastname: Remy
authors.forename: Rita
authors.initials: R
authors.lastname: Mulherkar
authors.forename: Guy
authors.initials: G
authors.lastname: Zuber
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D011992:Endosomes / Q000378:metabolism; D020868:Gene Silencing; D006461:Hemolysis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics; D011094:Polyethyleneimine / Q000737:chemistry* / Q000378:metabolism; D011522:Protons; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D044967:Serum / Q000378:metabolism; D012756:Sheep; D014764:Viral Proteins / Q000235:genetics
chemical_list: D015513:Oncogene Proteins; D011522:Protons; D034741:RNA, Small Interfering; D014764:Viral Proteins; D011094:Polyethyleneimine