title: Arsonium-containing lipophosphoramides, poly-functional nano-carriers for simultaneous antibacterial action and eukaryotic cell transfection.
abstract: Gene therapy of diseases like cystic fibrosis (CF) would consist of delivering a gene medicine towards the lungs via the respiratory tract into the target epithelial cells. Accordingly, poly-functional nano-carriers are required in order to overcome the various successive barriers of such a complex environment, such as airway colonization with bacterial strains. In this work, the antibacterial effectiveness of a series of cationic lipids is investigated before evaluating its compatibility with gene transfer into human bronchial epithelial cells. Among the various compounds considered, some bearing a trimethyl-arsonium headgroup demonstrate very potent biocide effects towards clinically relevant bacterial strains. In contrast to cationic lipids exhibiting no or insufficient antibacterial potency, arsonium-containing lipophosphoramides can simultaneously inhibit bacteria while delivering DNA into eukaryotic cells, as efficiently and safely as in absence of bacteria. Moreover, such vectors can demonstrate antibacterial activity in vitro while retaining high gene transfection efficiency to the nasal epithelium as well as to the lungs in mice in vivo. Arsonium-containing amphiphiles are the first synthetic compounds shown to achieve efficient gene delivery in the presence of bacteria, a property particularly suitable for gene therapy strategies under infected conditions such as within the airways of CF patients.
authors.affiliation: Unité INSERM 1078; SFR ScInBioS, Université de Bretagne Occidentale, Université Européenne de Bretagne, Faculté de Médecine et des Sciences de la Santé, 22 avenue Camille Desmoulins, 29238 Brest, France. Tony.LeGall@univ-brest.fr.
authors.forename: Tony
authors.initials: T
authors.lastname: Le Gall
authors.forename: Mathieu
authors.initials: M
authors.lastname: Berchel
authors.forename: Sophie
authors.initials: S
authors.lastname: Le Hir
authors.forename: Aurore
authors.initials: A
authors.lastname: Fraix
authors.forename: Jean Yves
authors.initials: JY
authors.lastname: Salaün
authors.forename: Claude
authors.initials: C
authors.lastname: Férec
authors.forename: Pierre
authors.initials: P
authors.lastname: Lehn
authors.forename: Paul-Alain
authors.initials: PA
authors.lastname: Jaffrès
authors.forename: Tristan
authors.initials: T
authors.lastname: Montier
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001152:Arsenicals / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D002460:Cell Line; D004337:Drug Carriers; D005057:Eukaryotic Cells / Q000378:metabolism*; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry; D051379:Mice; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D053758:Nanoparticles / Q000737:chemistry*; D009861:Onium Compounds / Q000737:chemistry / Q000494:pharmacology*; D063088:Phosphoramides / Q000737:chemistry / Q000494:pharmacology*; D014162:Transfection / Q000379:methods*
chemical_list: D000900:Anti-Bacterial Agents; D001152:Arsenicals; D004337:Drug Carriers; D008055:Lipids; D008081:Liposomes; D009861:Onium Compounds; D063088:Phosphoramides
keywords: antibacterial; gene delivery; multimodal therapy; nano-carrier; poly-functional