Novel lipids with three C18-fatty acid chains and an amino acid head group for pH-responsive and sustained antibiotic delivery

Abstract

The acidic environment at bacterial infection sites is a potential external stimulus for targeted antibiotic delivery. This paper reports new biocompatible pH-sensitive lipids (PSLs) with three hydrocarbon tails, and a head group with a secondary amine and carboxylate function for site-specific nano delivery of vancomycin (VCM). PSLs formed stable liposomes with mean vesicle diameters and polydispersity indices between 99.38 ± 6.59 nm to 105.60 ± 5.38 nm and 0.161 ± 0.003 to 0.219 ± 0.05 respectively. The zeta potential values were negative at physiological pH (7.4) and shifted towards positivity with a decrease in pH. The encapsulation efficiency and loading capacity were in the range of 29–45% and 2.8–4.5% respectively. The VCM release increased and was more sustained at acidic pH than at the physiological pH. The molecular modeling studies revealed that structural changes in lipids at acidic pH could have caused the deformation of liposome structure and subsequent fast release. In vitro antibacterial activity revealed that the minimum inhibitory concentrations (MICs) of prepared liposomes at pH 6.5 were lower than the MICs at pH 7.4 against Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) respectively. In addition, in vivo antibacterial activity study performed on two of the most active formulations showed that log10 CFU/mL of MRSA recovered from TOAPA-VCM-Lipo and the TLAPA-VCM-Lipo treated mice were 1.5- and 1.8-fold lower than that found in bare VCM treated ones respectively.