Overcoming barriers in Pseudomonas aeruginosa lung infections: Engineered nanoparticles for local delivery of a cationic antimicrobial peptide.
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.
Di.S.T.A.Bi.F., Second University of Naples, 81100 Caserta, Italy.
Ivana
I
d'Angelo
Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy.
Bruno
B
Casciaro
Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy.
Agnese
A
Miro
Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy.
Fabiana
F
Quaglia
Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy.
Maria Luisa
ML
Mangoni
Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy. Electronic address: ungaro@unina.it.
Francesca
F
Ungaro
D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D002412:Cations; D003550:Cystic Fibrosis / Q000150:complications; D004337:Drug Carriers; D006801:Humans; D053758:Nanoparticles; D010455:Peptides / Q000008:administration & dosage*; D011552:Pseudomonas Infections / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity*; D012141:Respiratory Tract Infections / Q000188:drug therapy* / Q000209:etiology / Q000382:microbiology
D000900:Anti-Bacterial Agents; D002412:Cations; D004337:Drug Carriers; D010455:Peptides
Antimicrobial peptide; Biofilm; Cystic fibrosis; Nanoparticles; PLGA; Pseudomonas aeruginosa; Pulmonary delivery