Arsonium-Containing Lipophosphoramides, Poly-Functional Nano-Carriers for Simultaneous Antibacterial Action and Eukaryotic Cell Transfection

• Published in: Advanced healthcare materials 2013-11, Vol.2 (11), p.1513-1524
• Main Authors: Le Gall, Tony, Berchel, Mathieu, Le Hir, Sophie, Fraix, Aurore, Salaün, Jean Yves, Férec, Claude, Lehn, Pierre, Jaffrès, Paul-Alain, Montier, Tristan
• Format: Article
• Language: English
• Subjects: Airways; Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; antibacterial; Antiinfectives and antibacterials; Arsenicals - chemistry; Arsenicals - pharmacology; Bacteria; Bacteria - drug effects; Cationic; Cell Line; Cystic fibrosis; Drug Carriers; Eukaryotic Cells - metabolism; gene delivery; Gene therapy; Genes; Humans; Lipids - chemistry; Liposomes - chemistry; Mice; Microbial Sensitivity Tests; Microbial Viability - drug effects; multimodal therapy; nano-carrier; Nanoparticles - chemistry; Nanostructure; Onium Compounds - chemistry; Onium Compounds - pharmacology; Patients; Phosphoramides - chemistry; Phosphoramides - pharmacology; poly-functional; Transfection - methods
• ISSN: 2192-2640; 2192-2659
• DOI: 10.1002/adhm.201200478

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. In contrast to compounds exhibiting no (Z+ = N+) or insufficient (Z+ = P+) antibacterial effectiveness, arsonium (Z+ = As+)‐containing lipophosphoramides can simultaneously inhibit bacteria while safely and efficiently delivering DNA into eukaryotic cells, thereby leading to luciferase (Luc) reporter gene expression. Such poly‐functional nano‐carriers may therefore be particularly suitable for gene therapy strategies under infected conditions such as within the airways of cystic fibrosis patients.