(9f) Treating Cystic Fibrosis Lung Infections with Bacteria-Inspired Nanoscale Drug Delivery Systems

A cardinal feature of Cystic Fibrosis (CF) lung disease is bacterial colonization with multidrug resistant pathogens such as Pseudomonas aeruginosa (PA). Combinations of synergistic antimicrobials can help overcome resistant infections. However, controlling dosing and delivery of multiple drugs can prove challenging. Additionally, CF lung mucus barriers create significant obstacles to effective antibiotic delivery. To address these critical needs, we are developing antimicrobial-loaded Bacteria-Inspired Nanoscale Drug Delivery Systems (BINDDS), inspired by bacterial properties of mucus penetration and bacterial adherence. By permeating throughout the mucus, adhering to bacteria, and delivering combinations of synergistic antimicrobials as well as mucolytic agents, BINDDS will facilitate antimicrobial activity against CF pathogens at lower doses than antibiotic alone. BINDDS are functionalized using layer-by-layer (LbL) electrostatic assembly. LbL assembly was used to load tobramycin (Tob) and antimicrobial silver nanoparticles (AgNP) onto BINDDS with high loading efficiencies. AgTob-BINDDSs demonstrated synergistic antimicrobial activity against PA bacterial strains. AgTob-BINDDS are being delivered in CF mouse models of PA lung infection, and bacterial load and mouse survival will be analyzed to evaluate therapeutic efficacy. BINDDS are further functionalized with mucolytic agents such as DNAse (Pulmozyme), and we are studying how the shape, size, and charge of BINDDS influence their permeation into mucus barriers and subsequent mucolytic activity in order to improve therapeutic efficacy. Taken together, these studies are providing immense insight into methods for overcoming delivery barriers to treat CF lung infections, and will initiate the development of a translatable material to improve CF patient outcomes and quality of care.