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.

Lipid‐Based Quaternary Ammonium Sophorolipid Amphiphiles with Antimicrobial and Transfection Activities

“…These results are promising for medical applications in which transfection efficiencies or micelle formation need to be combined with good antimicrobial properties. To further explore the application possibilities, the simultaneous antimicrobial action and transfection efficiency could be assessed by evaluating the transfection of eukaryotic cells in the presence of prokaryotic cells …”

“…To furthere xplore the application possibilities, the simultaneous antimicrobial action and transfection efficiency could be assessed by evaluating the transfection of eukaryoticc ells in the presence of prokaryotic cells. [36] Experimental Section Synthetic procedures Sophorolipid amines 9a nd 10:I na5 0mLf lask, peracetylated sophorolipid aldehyde 3 or 8 (2.02 mmol, 1equiv) was dissolved in methanol (25 mL) and the amine (2.02 mmol, 1equiv), NaBH 3 CN (0.25 g, 4.04 mmol, 2equiv), and acetic acid (0.58 mL, 10.09 mmol, 5equiv) were added sequentially.F or reaction with pentadecylamine, the sophorolipid aldehyde and amine were stirred for 1hat room temperature (18 8C) prior to the addition of NaBH 3 CN and AcOH to avoid as econd reductive amination. The reaction mixture was stirred overnight at room temperature, concentrated under reduced pressure, and dissolved in ethyl acetate.…”

Ruthenium(II) Polypyridyl Complexes as Photosensitizers for Antibacterial Photodynamic Therapy: A Structure–Activity Study on Clinical Bacterial Strains

“…For instance, amphiphiles like arsonium‐containing cationic lipids, silver complexes, phthalocyanine complexes, porphycene derivatives, or metal oxide (e.g., MgO, TiO 2 , or ZnO) nanoparticles have been reported as potent antibacterial reagents. Compared with antibiotics, they can show the noticeable advantage of being less subjected to loss of activity . Combination of such compounds can further decrease the risk of developing resistant mutants.…”

“…Compared with antibiotics, they can show the noticeable advantage of being less subjected to loss of activity. [13] Combination of such compounds can further decrease the risk of developing resistant mutants. Integration of chemical and physical approaches may also be relevant for reachingt he same objective.…”

Bis‐Thioether‐Containing Lipid Chains in Cationic Amphiphiles: Physicochemical Properties and Applications in Gene Delivery

“…coaservates [6] ), the design of nano-reactors, [7] the production of vesicles, [8] the production of carriers of nucleic acids delivery [9] ; others were designed for their own pharmaceutical properties (e.g. bactericidal agents, [10] modulation of ion channels activities, [11] anticancer properties [12] ). Whatever the application, the physicochemical properties of the amphiphiles must be finely tune to optimize their potential.…”