Aerosolized Nanomedicine for Lung Infections
Cystic fibrosis (CF) is a genetic disease with a life expectancy of only 44 years, with 85% of the mortality due to complications from lung disease. Owing to the buildup of mucus in the lungs, which is a hallmark of CF, patients suffer chronic bacterial infections of a variety of Gram-positive and Gram-negative species, most notably Pseudomonas aeruginosa and Staphylococcus aureus. These are complicated further by the formation of bacterial biofilms within CF sputum and by the emergence of multi-drug resistant organism (MDRO) strains. The antibiotic dosages needed for eradication of biofilm infections may be 10-1,000 times greater than the minimum inhibitory concentration (MIC) for planktonic bacteria and can therefore lead to serious adverse side effects.
Antibiotics that would normally be effective against P. aeruginosa infections are not efficacious in the CF setting, where the buildup of mucus and development of bacterial biofilms prevent delivery of antibiotic at the levels needed for eradication. There is no approved drug delivery technology that addresses the simultaneous need for lung-specific delivery and the challenge of penetrating a lung environment rich with mucus and colonized with chronic bacterial biofilms. A key aspect of our proposed research is to utilize the thermodynamic relationship between the detergency and hydrophile:lipophile balance (HLB) of surfactants to develop a novel, biomaterial-based polyelectrolyte surfactant with improved detergent activity against CF mucus in order to achieve substantially improved antimicrobial activity against P.aeruginosa biofilm CF lung infections.
Our laboratory has developed amphiphilic graft anionic polyelectrolyte surfactants (PSs) with “smart” surface-active chemistry that facilitates self-assembly with cationic biomolecular cargoes into nanovectors that promote passage across the multiple physiological barriers that limit drug distribution and efficacy. We have found that these surface-active polyelectrolytes can be tuned to self-assemble with both cationic peptides (CAPs) and aminoglycosides (which are cationic at physiological pH) to form stable PS-CAP and PS-tobramycin nanoparticles that can subsequently be aerosolized using a nebulizer with droplet sizes suitable for distribution to the lungs. Furthermore, we hypothesize that these aerosolized nanoparticles can provide improved penetration into the mucus hydrogel-like environment of the lungs of CF patients, enable controlled release, and exert improved activity against biofilms of P. aeruginosa and other strains common to CF patients.