Encapsulation in Polymer Nanoparticles of a Quorum Sensing-Based Therapy for the Treatment of Pseudomonas aeruginosa Infection

Abstract

Pseudomonas aeruginosa is responsible for 51,000 infections annually in the U.S. It readily infects the lung, and is a major cause of mortality among cystic fibrosis patients. This infection is typically treated with a variety of antibiotics, but conventional treatments are complicated by antibiotic resistance and biofilm formation. Quorum sensing-based drugs could potentially circumvent these problems. Such drugs target bacterial communication, thereby repressing the expression of virulence traits such as toxins and secretion systems, and disrupting biofilm formation and maintenance processes. However, the usefulness of these therapeutic compounds can be limited by the mucus of the lungs, which acts as a physiological barrier, preventing therapeutically relevant concentrations of drug from reaching sites of infection. Flash nanoprecipitation is a process by which drug-loaded polymer nanoparticles that can penetrate mucus barriers can be formed. Encapsulation of quorum sensing-based therapies in polymer nanoparticles via this process may permit their delivery through mucus, allowing these drugs to be used clinically. The development of nanoparticles that modulate P. aeruginosa cell-cell communication through quorum sensing signaling is described. Biocompatible nanoparticles containing a quorum sensing-active therapeutic (V-06-018) were successfully produced, and formulations were optimized for nanoparticle stability and controlled drug release in open systems. Nanoparticles containing therapeutic inhibited the production of the toxin pyocyanin, a virulence trait, at the same concentration as bulk dissolved drug without requiring organic solvents for delivery. These nanoparticles also inhibited biofilm formation in a microfluidic channel. This work suggests that encapsulation in polymer nanoparticles may permit the delivery of quorum sensing therapeutics, which could be used in conjunction with and in place of antibiotics for the treatment of pernicious bacterial infections. Such treatments have the potential to curtail the spread of drug-resistant infections.