title: Redox-Triggered Release of Moxifloxacin from Mesoporous Silica Nanoparticles Functionalized with Disulfide Snap-Tops Enhances Efficacy Against Pneumonic Tularemia in Mice.
abstract: Effective and rapid treatment of tularemia is needed to reduce morbidity and mortality of this potentially fatal infectious disease. The etiologic agent, Francisella tularensis, is a facultative intracellular bacterial pathogen which infects and multiplies to high numbers in macrophages. Nanotherapeutics are particularly promising for treatment of infectious diseases caused by intracellular pathogens, whose primary host cells are macrophages, because nanoparticles preferentially target and are avidly internalized by macrophages. A mesoporous silica nanoparticle (MSN) has been developed functionalized with disulfide snap-tops that has high drug loading and selectively releases drug intracellularly in response to the redox potential. These nanoparticles, when loaded with Hoechst fluorescent dye, release their cargo exclusively intracellularly and stain the nuclei of macrophages. The MSNs loaded with moxifloxacin kill F. tularensis in macrophages in a dose-dependent fashion. In a mouse model of lethal pneumonic tularemia, MSNs loaded with moxifloxacin prevent weight loss, illness, and death, markedly reduce the burden of F. tularensis in the lung, liver, and spleen, and are significantly more efficacious than an equivalent amount of free drug. An important proof-of-principle for the potential therapeutic use of a novel nanoparticle drug delivery platform for the treatment of infectious diseases is provided.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of California, CHS 37-121, 10833 Le Conte Ave, Los Angeles, CA, 90095-1688, USA.
authors.forename: Bai-Yu
authors.initials: BY
authors.lastname: Lee
authors.affiliation: Department of Chemistry and Biochemistry, University of California, 3013 Young Dr. East, Los Angeles, CA, 90095-1569, USA.|Department of Materials Science and Engineering, University of California, Los Angeles, CA, 90095, USA.
authors.forename: Zilu
authors.initials: Z
authors.lastname: Li
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of California, CHS 37-121, 10833 Le Conte Ave, Los Angeles, CA, 90095-1688, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Clemens
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of California, CHS 37-121, 10833 Le Conte Ave, Los Angeles, CA, 90095-1688, USA.
authors.forename: Barbara Jane
authors.initials: BJ
authors.lastname: Dillon
authors.affiliation: Department of Chemistry and Biochemistry, University of California, 3013 Young Dr. East, Los Angeles, CA, 90095-1569, USA.
authors.forename: Angela A
authors.initials: AA
authors.lastname: Hwang
authors.affiliation: Department of Chemistry and Biochemistry, University of California, 3013 Young Dr. East, Los Angeles, CA, 90095-1569, USA.|California NanoSystems Institute, University of California, Los Angeles, CA, 90095-8352, USA.
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Zink
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of California, CHS 37-121, 10833 Le Conte Ave, Los Angeles, CA, 90095-1688, USA.
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Horwitz
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D024841:Fluoroquinolones / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D000077266:Moxifloxacin; D053758:Nanoparticles / Q000737:chemistry*; D012822:Silicon Dioxide / Q000737:chemistry*; D014406:Tularemia / Q000188:drug therapy*
chemical_list: D024841:Fluoroquinolones; D012822:Silicon Dioxide; D000077266:Moxifloxacin
keywords: disulfide snap-top; francisella tularensis; intracellular delivery; mesoporous silica nanoparticle; redox potential