title: Synthesis, characterization, and in vivo efficacy of shell cross-linked nanoparticle formulations carrying silver antimicrobials as aerosolized therapeutics.
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.
authors.affiliation: Department of Pediatrics, Division of Pulmonary and Vascular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Parth N
authors.initials: PN
authors.lastname: Shah
authors.forename: Lily Yun
authors.initials: LY
authors.lastname: Lin
authors.forename: Justin A
authors.initials: JA
authors.lastname: Smolen
authors.forename: Jasur A
authors.initials: JA
authors.lastname: Tagaev
authors.forename: Sean P
authors.initials: SP
authors.lastname: Gunsten
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Han
authors.forename: Gyu Seong
authors.initials: GS
authors.lastname: Heo
authors.forename: Yali
authors.initials: Y
authors.lastname: Li
authors.forename: Fuwu
authors.initials: F
authors.lastname: Zhang
authors.forename: Shiyi
authors.initials: S
authors.lastname: Zhang
authors.forename: Brian D
authors.initials: BD
authors.lastname: Wright
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Panzner
authors.forename: Wiley J
authors.initials: WJ
authors.lastname: Youngs
authors.forename: Steven L
authors.initials: SL
authors.lastname: Brody
authors.forename: Karen L
authors.initials: KL
authors.lastname: Wooley
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Cannon
mesh_terms: D000336:Aerosols; D000818:Animals; D000890:Anti-Infective Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D007249:Inflammation / Q000139:chemically induced; D008168:Lung / Q000187:drug effects; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D053758:Nanoparticles / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D012834:Silver / Q000737:chemistry*
chemical_list: D000336:Aerosols; D000890:Anti-Infective Agents; D011108:Polymers; D012834:Silver