Structural Modifications of DPPC Bilayers upon Inclusion of an Antibacterial Cationic Bolaamphiphile

The emergence of antibiotic-resistant bacterial strains has fostered fundamental research to develop alternative antimicrobial strategies. Among the several systems proposed so far, the association complexes (nanoplexes) formed by transcription factor decoys (TFDs), i.e., short oligonucleotides targeting a crucial bacterial transcription factor, and a bolaform cationic amphiphile, 10,10'-(dodecane-1,12-diyl)-bis-(9-amino-1,2,3,4-tetrahydroacridinium) chloride (12-bis-THA), have demonstrated their potential in vitro and in vivo. The application of these nanoplexes is hampered by a scarce colloidal stability, which can be addressed by including the bolaamphiphile in a liposomal carrier, which is then associated to the TFD. The present study reports an investigation on the effects of 12-bis-THA on the structure of synthetic lipid bilayers to assess the morphology of the mixed assemblies, gain insight into the location of the host within the bilayer, and determine the loading capacity of the carrier. Our results demonstrate that 12-bis-THA promptly inserts within 1,2-dipalmitoyl- sn-glycero-3-phosphocholine (DPPC) bilayers, bending its C-12 spacer chain to adopt a conelike shape and shifting the gel-liquid crystalline transition of the chains to lower temperatures. The host liposomal structure is retained for a bolaamphiphile concentration of up to 3.2% mol to DPPC, whereas higher concentrations lead to the destabilization by means of a detergency-like mechanism, with the simultaneous existence of different lamellar-based structures, such as liposomes, bicelles, and rafts, in which DPPC and 12-bis-THA could be present in different molar ratios. Overall, these results shed light on the interaction of the bolaamphiphile with a lipid bilayer and provide valuable insight to better formulate the antimicrobial amphiphile in liposomal carriers to circumvent the colloidal instability of nanoplexes.