title: Enhanced gene delivery to the lung using biodegradable polyunsaturated cationic phosphatidylcholine-detergent conjugates.
abstract: Lung diseases are among the more representative causes of mortality and morbidity worldwide and gene therapy is considered as a promising therapeutic approach for their treatment. However the design of efficient nucleic acid carriers for airway administration still is a challenge and there is a pressing need for new developments in this field. Herein, new synthetic DNA carriers based on the conjugation of a phospholipid and C12E4, a nonionic detergent, are developed. DNA complexes with phosphatidylcholine-detergent conjugates are administered in mouse airways, and transgene expression and inflammatory activity as an index of toxicity are investigated as a function of time, DNA dose, and presence of helper and stealth lipids. Introduction of a biodegradable linker between the phosphatidylcholine and detergent moieties significantly attenuates the severity of inflammatory response that characterizes cationic lipid-mediated gene transfer. Concurrent introduction of polyunsaturated fatty acid chains in the carrier scaffold improves transgene expression and further reduces airway inflammation. Finally, the biodegradable phosphatidylcholine-detergent conjugates favorably compare to GL67A, the gold standard for DNA delivery to the airway that is currently under clinical evaluation. Our findings indicate that the lipid formulations described herein may have great potential as nucleic acid carriers for gene therapy.
authors.affiliation: Laboratoire de Conception et Application de Molécules Bioactives, UMR 7199 CNRS⿿Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin⿿BP 60024, 67401 Illkirch, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Pierrat
authors.affiliation: Laboratoire de Conception et Application de Molécules Bioactives, UMR 7199 CNRS⿿Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin⿿BP 60024, 67401 Illkirch, France.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Kereselidze
authors.affiliation: Laboratoire de Conception et Application de Molécules Bioactives, UMR 7199 CNRS⿿Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin⿿BP 60024, 67401 Illkirch, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Lux
authors.affiliation: Laboratoire de Conception et Application de Molécules Bioactives, UMR 7199 CNRS⿿Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin⿿BP 60024, 67401 Illkirch, France. Electronic address: llebeau@unistra.fr.
authors.forename: Luc
authors.initials: L
authors.lastname: Lebeau
authors.affiliation: Laboratoire de Conception et Application de Molécules Bioactives, UMR 7199 CNRS⿿Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin⿿BP 60024, 67401 Illkirch, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Pons
mesh_terms: D000818:Animals; D003902:Detergents / Q000008:administration & dosage* / Q000378:metabolism; D018014:Gene Transfer Techniques; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010713:Phosphatidylcholines / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: D003902:Detergents; D010713:Phosphatidylcholines
keywords: Airway inflammation; Biodegradability; In vivo gene delivery; Lung transfection; Nanoparticle; Polyunsaturated cationic lipid