title: Mesoporous Silica Nanoparticles with pH-Sensitive Nanovalves for Delivery of Moxifloxacin Provide Improved Treatment of Lethal Pneumonic Tularemia.
abstract: We have optimized mesoporous silica nanoparticles (MSNs) functionalized with pH-sensitive nanovalves for the delivery of the broad spectrum fluoroquinolone moxifloxacin (MXF) and demonstrated its efficacy in treating Francisella tularensis infections both in vitro and in vivo. We compared two different nanovalve systems, positive and negative charge modifications of the mesopores, and different loading conditions-varying pH, cargo concentration, and duration of loading-and identified conditions that maximize both the uptake and release capacity of MXF by MSNs. We have demonstrated in macrophage cell culture that the MSN-MXF delivery platform is highly effective in killing F. tularensis in infected macrophages, and in a mouse model of lethal pneumonic tularemia, we have shown that the drug-loaded MSNs are much more effective in killing F. tularensis than an equivalent amount of free MXF.
authors.affiliation: Department of Materials Science and Engineering, ‡Division of Infectious Diseases, Department of Medicine, §Department of Chemistry & Biochemistry, and ∥California NanoSystems Institute, University of California , Los Angeles, California 90095, United States.
authors.forename: Zilu
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Materials Science and Engineering, ‡Division of Infectious Diseases, Department of Medicine, §Department of Chemistry & Biochemistry, and ∥California NanoSystems Institute, University of California , Los Angeles, California 90095, United States.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Clemens
authors.affiliation: Department of Materials Science and Engineering, ‡Division of Infectious Diseases, Department of Medicine, §Department of Chemistry & Biochemistry, and ∥California NanoSystems Institute, University of California , Los Angeles, California 90095, United States.
authors.forename: Bai-Yu
authors.initials: BY
authors.lastname: Lee
authors.affiliation: Department of Materials Science and Engineering, ‡Division of Infectious Diseases, Department of Medicine, §Department of Chemistry & Biochemistry, and ∥California NanoSystems Institute, University of California , Los Angeles, California 90095, United States.
authors.forename: Barbara Jane
authors.initials: BJ
authors.lastname: Dillon
authors.affiliation: Department of Materials Science and Engineering, ‡Division of Infectious Diseases, Department of Medicine, §Department of Chemistry & Biochemistry, and ∥California NanoSystems Institute, University of California , Los Angeles, California 90095, United States.
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Horwitz
authors.affiliation: Department of Materials Science and Engineering, ‡Division of Infectious Diseases, Department of Medicine, §Department of Chemistry & Biochemistry, and ∥California NanoSystems Institute, University of California , Los Angeles, California 90095, United States.
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Zink
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry; D016503:Drug Delivery Systems; D024841:Fluoroquinolones / Q000494:pharmacology / Q000627:therapeutic use*; D005604:Francisella tularensis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D050296:Microbial Viability / Q000187:drug effects; D000077266:Moxifloxacin; D053758:Nanoparticles / Q000737:chemistry*; D010757:Phosphorous Acids / Q000737:chemistry; D011014:Pneumonia / Q000150:complications* / Q000188:drug therapy; D016062:Porosity; D012822:Silicon Dioxide / Q000737:chemistry*; D016896:Treatment Outcome; D014406:Tularemia / Q000150:complications* / Q000188:drug therapy*
chemical_list: D001562:Benzimidazoles; D024841:Fluoroquinolones; D010757:Phosphorous Acids; C570063:phosphonic acid; D012822:Silicon Dioxide; C031000:benzimidazole; D000077266:Moxifloxacin
keywords: Francisella tularensis; efficacy; intracellular bacteria; mesoporous silica nanoparticle; optimization of uptake and release capacities; pH-sensitive nanovalve; tularemia