title: Synthetic Macromolecular Antibiotic Platform for Inhalable Therapy against Aerosolized Intracellular Alveolar Infections.
abstract: Lung-based intracellular bacterial infections remain one of the most challenging infectious disease settings. For example, the current standard for treating Franciscella tularensis pneumonia (tularemia) relies on administration of oral or intravenous antibiotics that poorly achieve and sustain pulmonary drug bioavailability. Inhalable antibiotic formulations are approved and in clinical development for upper respiratory infections, but sustained drug dosing from inhaled antibiotics against alveolar intracellular infections remains a current unmet need. To provide an extended therapy against alveolar intracellular infections, we have developed a macromolecular therapeutic platform that provides sustained local delivery of ciprofloxacin with controlled dosing profiles. Synthesized using RAFT polymerization, these macromolecular prodrugs characteristically have high drug loading (16-17 wt % drug), tunable hydrolysis kinetics mediated by drug linkage chemistry (slow-releasing alkyllic vs fast-releasing phenolic esters), and, in general, represent new fully synthetic nanotherapeutics with streamlined manufacturing profiles. In aerosolized and completely lethal F.t. novicida mouse challenge models, the fast-releasing ciprofloxacin macromolecular prodrug provided high cure efficiencies (75% survival rate under therapeutic treatment), and the importance of release kinetics was demonstrated by the inactivity of the similar but slow-releasing prodrug system. Pharmacokinetics and biodistribution studies further demonstrated that the efficacious fast-releasing prodrug retained drug dosing in the lung above the MIC over a 48 h period with corresponding Cmax/MIC and AUC0-24h/MIC ratios being greater than 10 and 125, respectively; the thresholds for optimal bactericidal efficacy. These findings identify the macromolecular prodrug platform as a potential therapeutic system to better treat alveolar intracellular infections such as F. tularensis, where positive patient outcomes require tailored antibiotic pharmacokinetic and treatment profiles.
authors.affiliation: Department of Bioengineering, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Debobrato
authors.initials: D
authors.lastname: Das
authors.affiliation: Department of Bioengineering, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Bioengineering, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Selvi
authors.initials: S
authors.lastname: Srinivasan
authors.affiliation: Department of Bioengineering, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Abby M
authors.initials: AM
authors.lastname: Kelly
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Harborview Medical Center, University of Washington , Seattle, Washington 98104, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Lee
authors.affiliation: Department of Bioengineering, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Hye-Nam
authors.initials: HN
authors.lastname: Son
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Harborview Medical Center, University of Washington , Seattle, Washington 98104, United States.
authors.forename: Frank
authors.initials: F
authors.lastname: Radella
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Harborview Medical Center, University of Washington , Seattle, Washington 98104, United States.|Department of Global Health, University of Washington , Seattle, Washington 98195, United States.
authors.forename: T Eoin
authors.initials: TE
authors.lastname: West
authors.affiliation: Department of Bioengineering, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Ratner
authors.affiliation: Department of Bioengineering, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Convertine
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Harborview Medical Center, University of Washington , Seattle, Washington 98104, United States.
authors.forename: Shawn J
authors.initials: SJ
authors.lastname: Skerrett
authors.affiliation: Department of Bioengineering, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Patrick S
authors.identifier: 0000-0001-6939-6371
authors.initials: PS
authors.lastname: Stayton
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002939:Ciprofloxacin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D005604:Francisella tularensis / Q000187:drug effects / Q000472:pathogenicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D014018:Tissue Distribution
chemical_list: D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin
keywords: Francisella tularensis; bacterial infection; ciprofloxacin; infectious disease; pulmonary drug delivery