Nanogel encapsulation improves pharmacokinetics and biodistribution of antimicrobial peptide LL37 upon lung deposition: In vivo evaluation by SPECT/CT

Antimicrobial peptides (AMPs) constitute the first line of defense in the human body and exogenous application of AMPs is a desirable therapeutic strategy to combat bacterial infections. However, the antibacterial properties of AMPs are often time limited due to fast degradation by host and bacterial proteases, and administration of the needed high doses may result in local inflammation, as well as nephro- and hepatotoxicity. In this study, we assessed the possibility of using nanogels composed of hyaluronic acid modified with octenyl succinic anhydride (HA-OSA) as a drug delivery system to improve the pharmacokinetics and safety profile of LL37, a naturally occurring AMP, when administered to the mucosal surface of the lungs. The peptide LL37 and the polymer HA-OSA were radiolabeled with ⁶⁷gallium and ¹¹¹indium, respectively, allowing for non-invasive tracking over time in mice following intratracheal administration. When non-formulated LL37 was administered, approximately 85 % of the peptide dose was cleared from the lungs over 48 h, whereas encapsulation of LL37 in HA-OSA nanogels increased peptide retention in the lungs by 36 %. Additionally, the amount of peptide in excretory organs was reduced, decreasing potential liver and kidney toxicity known to be associated with AMP-based therapies. The findings in this study indicate that encapsulation of LL37 in nanogels provides beneficial pharmacokinetic effects.