Biopolymer nanogels improve antibacterial activity and safety profile of a novel lysine-based alpha-peptide/beta-peptoid peptidomimetic

Infections caused by Pseudomonas aeruginosa are associated with high morbidity and mortality, especially in immunocompromised patients. These bacteria frequently grow within a biofilm matrix, rendering therapy with conventional antibiotics inefficient; a fact that emphasizes the need for new treatment strategies. Antimicrobial peptidomimetics constitute potential alternatives to traditional antimicrobial agents. However, their application remains limited due to the lack of efficient delivery to their target site in vivo and the risk of high systemic toxicity. Nanogels composed of cross-linked networks of amphiphilic polymers with a therapeutic drug molecule embedded constitute attractive drug delivery systems, as they have been shown to display unique properties such as biocompatibility and biodegrability, as well as confer improved drug stability and reduced drug-mediated cytotoxicity. Here, we report on the first formulation of biopolymer nanogels incorporating a potent antibacterial peptidomimetic. A lysine-based alpha-peptide/beta-peptoid hybrid with potent activity against P. aeruginosa was designed and formulated into a nanogel together with octenyl succinic anhydride-modified hyaluronic acid in order to improve its cell selectivity. Twelve nanogel formulations were prepared by using a design of experiments setup in order to identify the parameters yielding the highest drug loading and the smallest particle size. Encapsulation of the peptidomimetic into nanogels significantly decreased the cytotoxicity of the peptidomimetic to eukaryotes. The most promising formulation with high encapsulation efficiency (88%) of the peptidomimetic demonstrated a three-fold reduction in cytotoxicity towards hepatocytes along with improved bacterial killing kinetics.