Vibrating Mesh Nebulisation of Pro-Antimicrobial Peptides for Use in Cystic Fibrosis

Abstract

Background: There has been considerable interest in the use of antimicrobial peptides (AMPs) as antimicrobial therapeutics in many conditions including cystic fibrosis (CF). The aim of this study is to determine if the prodrugs of AMPs (pro-AMPs) can be delivered to the lung by a vibrating mesh nebuliser (VMN) and whether the pro-AMP modification has any effect on delivery. Methods: Physical characteristics of the peptides (AMP and pro-AMP) and antimicrobial activity were compared before and after nebulisation. Droplet size distribution was determined by laser diffraction and cascade impaction. Delivery to a model lung was determined in models of spontaneously-breathing and mechanically-ventilated patients. Results: The physical characteristics and antimicrobial activities were unchanged after nebulisation. Mean droplet size diameters were below 5 μm in both determinations, with the fine particle fraction approximately 67% for both peptides. Approximately 25% of the nominal dose was delivered in the spontaneously-breathing model for both peptides, with higher deliveries observed in the mechanically-ventilated model. Delivery times were approximately 170 s per mL for both peptides and the residual volume in the nebuliser was below 10% in nearly all cases. Conclusions: These results demonstrate that the delivery of (pro-)AMPs to the lung using a VMN is feasible and that the prodrug modification is not detrimental. They support the further development of pro-AMPs as therapeutics in CF.

Future Trends in Nebulized Therapies for Pulmonary Disease

“…Some studies have also demonstrated that it is possible to generate a respirable aerosol of antimicrobial peptides (AMPs) or prodrug AMPs. The AMP prodrug and its active peptide component were both unchanged after VMN and maintained their levels of antimicrobial activity against the most common CF pathogen, P. aeruginosa [56].…”

“…Aerogen Ltd. VMN technologies are the dominant device platform for mechanical ventilation trials [1]. This platform has been shown to retain the bioactivity of antibiotics [51], gene vectors [54], inhaled vaccines [55], or proteins [56,57]. The clinical effectiveness of VMN has been demonstrated in outcomes such as shorter ICU stays compared to MDI and JN in mechanically ventilated asthmatic patients [58].…”

“…Kim et al (2016) showed MSCs retain engraftment potential after been nebulized [ 169 ], while McCarthy et al (2019) showed that VMN delivered MSC-derived conditioned media retain their antibacterial capacity [ 170 ], probably by maintenance of AMPs. Supporting this hypothesis, Forde et al showed that VMN delivery of AMPs does not affect their function [ 56 ], while Casciaro et al (2019) demonstrated that JN emitted esculentin-1a-derived antimicrobial peptides did not lose the therapeutic effect compared with the intra-tracheal installation [ 171 ]. There is some pioneering research supporting the idea of the maintenance of integrity and function of small bioactive molecules after nebulization, like those associated with the MSC secretome.…”

Developing inhaled protein therapeutics for lung diseases

“…On the other hand, mesh nebulisers appear to maintain protein integrity to a greater extent than other nebulisers [ 32 ]. Safe aerosolisation with mesh nebulisers has already been demonstrated in several studies of labile drugs including proteins and mAbs [ 33 – 38 ]. The detailed designs and comparisons of various types of nebulizers have been reviewed previously and we will not elaborate further here [ 25 , 30 – 32 , 39 ].…”

Advances in Pulmonary Drug Delivery

“…AMPs do not only have direct antimicrobial activity, but also modulate the immune system and wound repair, making them of interest in CF therapy. Forde and colleagues studied whether prodrugs of AMPs (pro-AMPs) can be delivered by VMN and whether modifications of pro-AMP had an effect on the delivery [ 13 ]. Nebulisation did not alter AMPs’ physical characteristics and antimicrobial activity.…”