Hyaluronic Acid-Based Nanogels Produced by Microfluidics-Facilitated Self-Assembly Improves the Safety Profile of the Cationic Host Defense Peptide Novicidin.

Abstract

Cationic host defence peptides constitute a promising class of therapeutic drug leads with a wide range of therapeutic applications, including anticancer therapy, immunomodulation, and antimicrobial activity. Although potent and efficacious, systemic toxicity and low chemical stability have hamperedtheir commercial development. To overcome these challenges a novel nanogel-based drug delivery system was designed. The peptide novicidin was self-assembled with an octenyl succinic anhydride-modified analogue of hyaluronic acid, and this formulation was optimized using a microfluidics-based quality-by-design approach. By applying design-of-experiment it was demonstrated that the encapsulation efficiency of novicidin (15% to 71%) and the zeta potential (-24 to -57mV) of the nanogels could be tailored by changing the preparation process parameters, with a maximum peptide loading of 36 ± 4%. The nanogels exhibited good colloidal stability under different ionic strength conditions andallowed complete release of the peptide over 14days. Furthermore, self-assembly of novicidin with hyaluronic acid into nanogels significantly improved the safety profile at least five-fold and six-fold when tested in HUVECs and NIH3T3 cells, respectively, whilst showing no loss of antimicrobial activity against Escherichia coli and Staphylococcus aureus. Formulation in nanogels could be a viable approach to improve the safety profile of host defence peptides.