Synthesis, characterization, and in vivo efficacy of shell cross-linked nanoparticle formulations carrying silver antimicrobials as aerosolized therapeutics. Academic Article uri icon

abstract

  • The use of nebulizable, nanoparticle-based antimicrobial delivery systems can improve efficacy and reduce toxicity for treatment of multi-drug-resistant bacteria in the chronically infected lungs of cystic fibrosis patients. Nanoparticle vehicles are particularly useful for applying broad-spectrum silver-based antimicrobials, for instance, to improve the residence time of small-molecule silver carbene complexes (SCCs) within the lung. Therefore, we have synthesized multifunctional, shell cross-linked knedel-like polymeric nanoparticles (SCK NPs) and capitalized on the ability to independently load the shell and core with silver-based antimicrobial agents. We formulated three silver-loaded variants of SCK NPs: shell-loaded with silver cations, core-loaded with SCC10, and combined loading of shell silver cations and core SCC10. All three formulations provided a sustained delivery of silver over the course of at least 2-4 days. The two SCK NP formulations with SCC10 loaded in the core each exhibited excellent antimicrobial activity and efficacy in vivo in a mouse model of Pseudomonas aeruginosa pneumonia. SCK NPs with shell silver cation-load only, while efficacious in vitro, failed to demonstrate efficacy in vivo. However, a single dose of core SCC10-loaded SCK NPs (0.74 0.16 mg Ag) provided a 28% survival advantage over sham treatment, and administration of two doses (0.88 mg Ag) improved survival to 60%. In contrast, a total of 14.5 mg of Ag(+) delivered over 5 doses at 12 h intervals was necessary to achieve a 60% survival advantage with a free-drug (SCC1) formulation. Thus, SCK NPs show promise for clinical impact by greatly reducing antimicrobial dosage and dosing frequency, which could minimize toxicity and improve patient adherence.

published proceedings

  • ACS Nano

altmetric score

  • 10

author list (cited authors)

  • Shah, P. N., Lin, L. Y., Smolen, J. A., Tagaev, J. A., Gunsten, S. P., Han, D. S., ... Cannon, C. L.

citation count

  • 41

complete list of authors

  • Shah, Parth N||Lin, Lily Yun||Smolen, Justin A||Tagaev, Jasur A||Gunsten, Sean P||Han, Daniel S||Heo, Gyu Seong||Li, Yali||Zhang, Fuwu||Zhang, Shiyi||Wright, Brian D||Panzner, Matthew J||Youngs, Wiley J||Brody, Steven L||Wooley, Karen L||Cannon, Carolyn L

publication date

  • June 2013