title: Design of Ionizable Lipids To Overcome the Limiting Step of Endosomal Escape: Application in the Intracellular Delivery of mRNA, DNA, and siRNA.
abstract: The intracellular delivery of nucleic acid molecules is a complex process involving several distinct steps; among these the endosomal escape appeared to be of particular importance for an efficient protein production (or inhibition) into host cells. In the present study, a new series of ionizable vectors, derived from naturally occurring aminoglycoside tobramycin, was prepared using improved synthetic procedures that allow structural variations on the linker and hydrophobic domain levels. Complexes formed between the new ionizable lipids and mRNA, DNA, or siRNA were characterized by cryo-TEM experiments and their transfection potency was evaluated using different cell types. We demonstrated that lead molecule 30, bearing a biodegradable diester linker, formed small complexes with nucleic acids and provided very high transfection efficiency with all nucleic acids and cell types tested. The obtained results suggested that the improved and "universal" delivery properties of 30 resulted from an optimized endosomal escape, through the lipid-mixing mechanism.
authors.affiliation: In-Cell-Art , 21 rue de la Noue Bras de Fer, 44200 Nantes, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Habrant
authors.affiliation: Unité INSERM UMR1087, CNRS UMR 6291 , 8 quai Moncousu, 44007 Nantes, France.|Université de Nantes , L'institut du Thorax, 8 quai Moncousu, 44007 Nantes, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Peuziat
authors.affiliation: Unité INSERM UMR1087, CNRS UMR 6291 , 8 quai Moncousu, 44007 Nantes, France.|Université de Nantes , L'institut du Thorax, 8 quai Moncousu, 44007 Nantes, France.
authors.forename: Thibault
authors.initials: T
authors.lastname: Colombani
authors.affiliation: CBMN UMR-CNRS 5248 IECB, Université de Bordeaux 1-IPB , Allée Geoffroy Saint Hilaire, Pessac F-33600, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Dallet
authors.affiliation: In-Cell-Art , 21 rue de la Noue Bras de Fer, 44200 Nantes, France.
authors.forename: Johan
authors.initials: J
authors.lastname: Gehin
authors.affiliation: In-Cell-Art , 21 rue de la Noue Bras de Fer, 44200 Nantes, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Goudeau
authors.affiliation: In-Cell-Art , 21 rue de la Noue Bras de Fer, 44200 Nantes, France.
authors.forename: Bérangère
authors.initials: B
authors.lastname: Evrard
authors.affiliation: CBMN UMR-CNRS 5248 IECB, Université de Bordeaux 1-IPB , Allée Geoffroy Saint Hilaire, Pessac F-33600, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lambert
authors.affiliation: Unité INSERM UMR1087, CNRS UMR 6291 , 8 quai Moncousu, 44007 Nantes, France.|Université de Nantes , L'institut du Thorax, 8 quai Moncousu, 44007 Nantes, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Haudebourg
authors.affiliation: In-Cell-Art , 21 rue de la Noue Bras de Fer, 44200 Nantes, France.|Unité INSERM UMR1087, CNRS UMR 6291 , 8 quai Moncousu, 44007 Nantes, France.|Université de Nantes , L'institut du Thorax, 8 quai Moncousu, 44007 Nantes, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Pitard
mesh_terms: D000818:Animals; D060326:Chemistry Techniques, Synthetic; D020285:Cryoelectron Microscopy / Q000379:methods; D004247:DNA / Q000008:administration & dosage*; D016503:Drug Delivery Systems / Q000379:methods; D011992:Endosomes / Q000737:chemistry / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008055:Lipids / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D012333:RNA, Messenger / Q000008:administration & dosage*; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D051381:Rats; D013329:Structure-Activity Relationship; D014162:Transfection / Q000379:methods*
chemical_list: D005229:Fatty Acids, Monounsaturated; D008055:Lipids; D008081:Liposomes; D000644:Quaternary Ammonium Compounds; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C054005:N-(1-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium; D004247:DNA; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane