Overcoming barriers in Pseudomonas aeruginosa lung infections: Engineered nanoparticles for local delivery of a cationic antimicrobial peptide

• Published in: Colloids and surfaces, B, Biointerfaces B, Biointerfaces, 2015-11, Vol.135, p.717-725
• Main Authors: d’Angelo, Ivana, Casciaro, Bruno, Miro, Agnese, Quaglia, Fabiana, Mangoni, Maria Luisa, Ungaro, Francesca
• Format: Article
• Language: English
• Subjects: Airways; Anti-Bacterial Agents - administration & dosage; Antiinfectives and antibacterials; Antimicrobial peptide; Bacteria; Biofilm; Biofilms; Carriers; Cations; Cystic fibrosis; Cystic Fibrosis - complications; Drug Carriers; Humans; Lungs; Mathematical models; Mucus; Nanoparticles; Peptides - administration & dosage; PLGA; Pseudomonas aeruginosa; Pseudomonas aeruginosa - pathogenicity; Pseudomonas Infections - drug therapy; Pulmonary delivery; Respiratory Tract Infections - drug therapy; Respiratory Tract Infections - etiology; Respiratory Tract Infections - microbiology
• ISSN: 0927-7765; 1873-4367
• DOI: 10.1016/j.colsurfb.2015.08.027

[Display omitted] •A method to engineer PLGA nanoparticles for lung delivery of cationic antimicrobial peptides is described.•Engineered nanoparticles afforded efficient entrapment and prolonged release of a model cationic antimicrobial peptide, colistin.•Surface-engineering of nanoparticles with polyvinyl alcohol or chitosan promoted colistin diffusion through artificial mucus.•Nanoparticles penetrated P. aeruginosa biofilm and extended the in vitro anti-biofilm activity of colistin.•Embedding nanoparticles in lactose microparticles resulted in dry powders with promising aerosolization properties for inhalation. Cationic antimicrobial peptides (CAMPs) are very promising in the treatment of multi-drug resistant Pseudomonas aeruginosa lung infections experienced by cystic fibrosis (CF) patients. Nevertheless, there is an urgent need of inhalable formulations able to deliver the intact CAMP in conductive airways and to shield its interactions with airway mucus/bacterial biofilm, thus enhancing CAMP/bacteria interactions. Along these lines, the aim of this work was the design and development of nano-embedded microparticles (NEM) for sustained delivery of CAMPs in the lung. To this purpose, nanoparticles (NPs) made of poly(lactide-co-glycolide) (PLGA) containing a model CAMP, colistin (Col), were produced by emulsion/solvent diffusion technique. Engineering NPs with chitosan (CS) and poly(vinyl alcohol) (PVA) allowed to modulate surface properties and, in so doing, to improve NP transport through artificial CF mucus. In order to achieve a long-term stable dosage form useful for NP inhalation, NPs were spray-dried in different carriers (lactose or mannitol), thus producing NEM. The most promising NEM formulations were selected on the basis of bulk and flow properties, distribution of NPs in the carrier and aerosolization performance upon delivery through a breath-actuated dry powder inhaler. Of note, selected Col-loaded NEM were found to kill P. aeruginosa biofilm and to display a prolonged efficacy in biofilm eradication compared to the free Col. This effect was likely ascribable to the ability of NPs to penetrate into bacterial biofilm, as demonstrated by confocal analysis, and to sustain Col release inside it. Taken all together, our results indicate that adequate engineering of PLGA NPs represents an enticing technological approach to harness novel antimicrobials for P. aeruginosa lung infection, such as CAMPs, especially in CF.