Princeton University Library Catalog

Encapsulation of Positively Charged Prodrugs and Antibiotics in Polymeric Nanoparticles via Flash NanoPrecipitation

Suarez, Sofia Elena [Browse]
Senior thesis
Prud'homme, Robert K. [Browse]
Princeton University. Department of Chemical and Biological Engineering [Browse]
Class year:
89 pages
Summary note:
Antibiotic resistance is a pressing global problem, augmenting to $20 billion per year in excess health care costs in the United States alone. Among patients with cystic fibrosis, there is currently no cure for pulmonary infections, and antibiotics are the principal effective treatment that can manage the disease. The spread of antibiotic resistance will endanger and essentially eliminate any method of managing pulmonary infections among individuals with cystic fibrosis. In addition, patients with cystic fibrosis have excessively thick pulmonary mucus that prevents effective drug delivery in the lung. The development of an economical and scalable antibiotic nanoparticle encapsulation processes to deliver drugs through cystic fibrosis mucus will greatly help manage infections in this population. Particles can enable sustained delivery of therapeutics to improve medical outcomes. Flash NanoPrecipitation (FNP) is a scalable and economical process that can produce large quantities of nanoparticles coated in mucus-penetrating polymers. Traditionally FNP relies on the encapsulation of a hydrophobic compound. We here work to develop a new form of FNP that can encapsulate hydrophilic antibiotics into mucus-penetrating coatings. In our work we utilized cationic condensation based FNP which takes advantage of the electrostatic interactions between a positively charged active and a negatively charged polymer to formulate nanoparticles. We successfully applied cationic condensation and FNP to encapsulate nitric oxide prodrugs in polymeric nanoparticles. The nanoparticle core was also covalently crosslinked, which provided the nanoparticle stability in high ionic strength water based solvents. In addition, three antibiotics used to treat bacteria that are found in pulmonary infections were successfully encapsulated: tobramycin, polymyxin and nisin. To encapsulate these antibiotics cationic condensation was again applied to FNP. For the polymyxin single layer nanoparticles drug to polymer charge ratio had a linear dependence with NP size. The single layer nanoparticles also demonstrated high antimicrobial activity against S. aureus and P. aeruginosa. However, single-layer PEG coated nanoparticles demonstrated relatively rapid release. Thus, we developed a bilayer nanoparticle where antibiotics were coated with a hydrophobic interior layer, and a PEG outer layer. These formulations exhibited sustained release, promising for therapeutic purposes. This work is the first example of the formation of positively charged antibiotic loaded nanoparticles that exhibit controlled release formed via FNP. Our work has the potential to produce drug-loaded nanoparticles in a scalable, economical process which can mitigate antibiotic resistance and provide better drug delivery in the lung for cystic fibrosis patients.