Redox-Triggered Release of Moxifloxacin from Mesoporous Silica Nanoparticles Functionalized with Disulfide Snap-Tops Enhances Efficacy Against Pneumonic Tularemia in Mice

• Published in: Small (Weinheim an der Bergstrasse, Germany) Germany), 2016-07, Vol.12 (27), p.3690-3702
• Main Authors: Lee, Bai-Yu, Li, Zilu, Clemens, Daniel L., Dillon, Barbara Jane, Hwang, Angela A., Zink, Jeffrey I., Horwitz, Marcus A.
• Format: Article
• Language: English
• Subjects: Animals; Bacteria; disulfide snap-top; Disulfides; Drug Delivery Systems - methods; Drugs; Female; Fluoroquinolones - administration & dosage; Fluoroquinolones - chemistry; Fluoroquinolones - therapeutic use; francisella tularensis; Infectious diseases; intracellular delivery; Macrophages; Medical services; mesoporous silica nanoparticle; Mice; Mice, Inbred BALB C; Mortality; Nanoparticles; Nanoparticles - chemistry; Nanotechnology; redox potential; Rodents; Silicon dioxide; Silicon Dioxide - chemistry; Tularemia; Tularemia - drug therapy
• ISSN: 1613-6810; 1613-6829
• DOI: 10.1002/smll.201600892

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. The drug trapping and intracellular release mechanism of redox‐responsive disulfide snap‐top mesoporous silica nanoparticles (MSN‐SS‐MXF) leading to the killing of intracellular bacteria is depicted. MSN‐SS‐MXF are mesoporous silica nanoparticles functionalized with disulfide snap‐tops that carry a large quantity of the broad spectrum antibiotic moxifloxacin within its pores. MSN‐SS‐MXF naturally targets macrophages, releases the antibiotic in response to the intracellular redox potential, and kills intracellular bacterial pathogens, such as Francisella tularensis, in vitro and in vivo.