LATE-BREAKING ABSTRACT: Host defence peptide prodrugs are respirable when delivered by vibrating mesh nebuliser

Abstract

Background: Host defence peptides (HDPs) are short antimicrobial components of the innate immune system. In cystic fibrosis (CF), deficiencies in HDP activity rationalises exogenous application. A prodrug model previous addressed HDP cytotoxicity (1). The prodrug requires local lung delivery for activation, with stability and droplet diameter Methods: Post-nebulisation, the prodrug, pro-WMR, and active peptide AAG-WMR were analysed by HPLC, mass spectrometry, and for antibacterial activity against CF Pseudomonas aeruginosa isolates. The volumetric mean diameters, mass median aerodynamic diameters (MMAD), and % delivery to a model adult lung were determined. Results: Both peptides were unchanged after nebulisation and maintained their anti-pseudomonal activity. The droplet size distribution was compatible with lower lung delivery (MMAD of 3.59 ± 0.23μm and 3.14 ± 0.25μm for pro- and AAG-WMR respectively). A large % of the dose (42 ± 3.1% of pro-WMR, 47.6 ± 7.8% of AAG-WMR) was delivered in the lung model. Nebulisation time was less than 3min/ml. Conclusions: The vibrating mesh-type Aerogen Solo nebuliser was shown to generate a highly respirable aerosol, potentially capable of targeting delivery to the peripheral airways. Importantly, both peptides were shown to be stable and active post-nebulisation. This further advances the application of pro-HDPs in CF lung infections. 1. Forde et al. Antimicrob Agents Chemother. 2014 Feb; 58(2): 978–985.