Antimicrobial nanotherapies for respiratory infection in cystic fibrosis

This thesis presents the design, development and efficacy of antimicrobial nanotherapies, to overcome the challenges faced by conventional antimicrobial delivery for the treatment of Pseudomonas aeruginosa respiratory infections in cystic fibrosis (CF). In the CF lungs, mucus and biofilms pre.sent complex barriers to the optimal delivery of antimicrobial therapy, leading to low antimicrobial exposure to resident bacteria and inadequate eradication. Respiratory disease, associated with chronic respiratory infection, is ultimately the main cause of morbidity and mortality in CF patients. There is a need to develop improved antimicrobial and anti-biofilm therapies in this patient group. Firstly, alginate/chitosan polymeric nanoparticle (NP) delivery vehicles for the antimicrobial tobramycin were formulated. Tobramycin NPs demonstrated antimicrobial efficacy against laboratory and clinically isolated strains of P. aeruginosa in vitro and in vivo against infected Galleria mellonella. Next, functionalisation of the mucolytic DNase to tobramycin NPs was investigated with the aim to improve penetration of the mucus and biofilm barriers, to increase the accessibility of tobramycin to the difficult-to-reach sites of infection. Functional activity of both drugs was established against DNA, P. aeruginosa strains and in CF sputum. DNase functionalisation was found to improve the sputum penetration of NPs and these DNase tobramycin NPs possessed anti microbia! activity in sputum samples from CF patients. Finally, the antimicrobial activity of the developed nanotherapies against P. aeruginosa biofilms was studied. DNase tobramycin NPs have the potential to target both the biofilm matrix and bacterial cells through the combined DNA degradation and bactericidal actions of DNase and tobramycin. Against established P. aeruginosa biofilms, both tobramycin NPs and DNase tobramycin NPs were found to be effective antimicrobial agents. The developed antimicrobial nanotherapies represent a promising therapeutic strategy for improving tobramycin delivery to mucus-embedded, biofilm-associated respiratory infections in CF.