PEGylated mucus-penetrating nanocrystals for lung delivery of a new FtsZ inhibitor against Burkholderia cenocepacia infection

C109 is a potent but poorly soluble FtsZ inhibitor displaying promising activity against Burkholderia cenocepacia, a high-risk pathogen for cystic fibrosis (CF) sufferers. To harness C109 for inhalation, we developed nanocrystal-embedded dry powders for inhalation suspension consisting in C109 nanocrystals stabilized with D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) embedded in hydroxypropyl-β-cyclodextrin (CD). The powders could be safely re-dispersed in water for in vitro aerosolization. Owing to the presence of a PEG shell, the rod shape and the peculiar aspect ratio, C109 nanocrystals were able to diffuse through artificial CF mucus. The promising technological features were completed by encouraging in vitro/in vivo effects. The formulations displayed no toxicity towards human bronchial epithelial cells and were active against planktonic and sessile B. cenocepacia strains. The efficacy of C109 nanosuspensions in combination with piperacillin was confirmed in a Galleria mellonella infection model, strengthening their potential for combined therapy of B. cenocepacia lung infections. Dry powders for inhalation suspension embedding TPGS-stabilized nanocrystals of the new anti-burkholderia agent C109 were successfully developed. The PEG shell and the peculiar aspect ratio of the nanocrystals concurred to drug diffusion through artificial mucus. The developed C109 nanocrystal-embedded dry powders: i) maintain a broad-spectrum antimicrobial activity; ii) improve the inhibition ability of C109 against B. cenocepacia biofilm; ii) are safe at microbiologically active concentrations towards human bronchial epithelial cells; iii) exert in vivo a synergistic activity with piperacillin, a conventional antibiotic for treatment of B. cenocepacia lung infections. [Display omitted]