Synthesis of α,ε-,'-Di-stearoyl Lysine-Derived Amide Lipids and Their Application to Liposome Formulation: Incorporation of Lipid A-Ligand for Bacterial Targeting and Sialic Acid for Phagocytosis Resistance.

As part of an antimicrobial resistance (AMR) strategy, we have prepared α,ε-,'-di-stearoyl lysine-based amide lipids to improve the chemical and biological stabilities of nanoparticles. Those amide lipids incorporated a variety of head groups, including lipid A-binding ligand (polymyxin B nonapeptide, PMBN) for bacterial targeting and sialic acid as an alternative to PEGylation for phagocytosis resistance. The study demonstrated that the PMBN-liposome specifically targeted lipid A-containing Gram-negative bacteria, but not Gram-positive . However, such interaction was interrupted by the adsorption of serum proteins onto liposomes, demonstrating the complexity and challenge of targeted delivery. As expected, slower uptake of sialic acid-liposomes by human leukemia monocytic THP-1 cells was observed, suggesting their resistance to phagocytosis. Additionally, in a mouse model, the sialic acid-containing liposomes showed more favorable biodistribution and longer retention time than the comparable phospholipid-only liposomes. We observed that both sialic acid-incorporated and PEGylated liposomes distributed over the whole mouse bodies and remained for over 48 h. In contrast, the phospholipid-only liposomes rapidly migrated to the liver (5-15 min). In conclusion, although this study did not achieve bacteria-targeted liposome delivery, it provided evidence that the sialic acid-amide lipid can serve as an alternative to PEGylation in future nanomedicine.