title: Self-assembled lamellar complexes of siRNA with lipidic aminoglycoside derivatives promote efficient siRNA delivery and interference.
abstract: RNA interference requires efficient delivery of small double-stranded RNA molecules into the target cells and their subsequent incorporation into RNA-induced silencing complexes. Although current cationic lipids commonly used for DNA transfection have also been used for siRNA transfection, a clear need still exists for better siRNA delivery to improve the gene silencing efficiency. We synthesized a series of cationic lipids characterized by head groups bearing various aminoglycosides for specific interaction with RNA. siRNA complexation with such lipidic aminoglycoside derivatives exhibited three lipid/siRNA ratio-dependent domains of colloidal stability. Fluorescence and dynamic light-scattering experiments showed that cationic lipid/siRNA complexes were formed at lower charge ratios, exhibited a reduced zone of colloidal instability, and had smaller mean diameters compared with our previously described guanidinium-based cationic lipids. Cryo-transmission electron microscopy and x-ray-scattering experiments showed that, although the final in toto morphology of the lipid/siRNA complexes depended on the aminoglycoside type, there was a general supramolecular arrangement consisting of ordered lamellar domains with an even spacing of 67 A. The most active cationic lipid/siRNA complexes for gene silencing were obtained with 4,5-disubstituted 2-deoxystreptamine aminoglycoside derivatives and were characterized by the siRNA being entrapped in small particles exhibiting lamellar microdomains corresponding to siRNA molecules sandwiched between the lipid bilayers. These results clearly show that lipidic aminoglycoside derivatives constitute a versatile class of siRNA nanocarriers allowing efficient gene silencing.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U533, F-44035 Nantes, France.
authors.forename: Léa
authors.initials: L
authors.lastname: Desigaux
authors.forename: Matthieu
authors.initials: M
authors.lastname: Sainlos
authors.forename: Olivier
authors.initials: O
authors.lastname: Lambert
authors.forename: Raphael
authors.initials: R
authors.lastname: Chevre
authors.forename: Emilie
authors.initials: E
authors.lastname: Letrou-Bonneval
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Vigneron
authors.forename: Pierre
authors.initials: P
authors.lastname: Lehn
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Lehn
authors.forename: Bruno
authors.initials: B
authors.lastname: Pitard
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry*; D045744:Cell Line, Tumor; D003102:Colloids / Q000737:chemistry; D020285:Cryoelectron Microscopy; D049452:Green Fluorescent Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D053758:Nanoparticles / Q000737:chemistry*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000737:chemistry* / Q000235:genetics; D012542:Scattering, Radiation; D014162:Transfection; D014965:X-Rays
chemical_list: D000617:Aminoglycosides; D003102:Colloids; D008055:Lipids; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins