Inhaled antibiotic treatment of cystic fibrosis-related bacterial biofilm infections is challenging due to the pathological environment of the lungs. Here, we present an "environment adaptive" nanoparticle composed of a solid poly lactic-co-glycolic acid (PLGA) core and a mucus-inert, enzymatically cleavable shell of D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) for site-specific delivery of antibiotics to bacterial biofilms via aerosol administration. The hybrid nanoparticles with ultrasmall size were self-assembled via a nanoprecipitation process by using a facile microfluidic method. The interactions of the nanoparticles with the biological barriers were comprehensively investigated by using cutting-edge techniques (e.g. quartz crystal microbalance with dissipation monitoring, total internal reflection fluorescence microscopy-based particle tracking, in vitro biofilm model cultured in a flow-chamber system, and quantitative imaging analysis). Our results suggest that the mucus-inert, enzymatically cleavable TPGS shell enables the nanoparticles to penetrate through the mucus, accumulate in the deeper layer of the biofilms, and serve as sustained release depot, thereby, improving the killing efficacy of azithromycin (a macrolide antibiotic) against biofilm-forming Pseudomonas aeruginosa. In conclusion, the ultra-small TPGS-PLGA hybrid nanoparticles represent an efficient delivery system to overcome the multiple barriers and release antibiotics with a sustained manner in the vicinity of the biofilm-forming bacteria.
- TPGS-PLGA hybrid nanoparticles
- aerosol administration
- cystic fibrosis
- Pseudomonas aeruginosa biofilm
- bio-nano interaction