Glycan Targeted Polymeric Antibiotic Prodrugs for Alveolar Macrophage Infections
Abstract
Alveolar macrophages resident in the lung are prominent phagocytic effector cells of the pulmonary innate immune response, and paradoxically, are attractive harbors for pathogens. Consequently, facultative intracellular bacteria, such as Francisella tularensis, can cause severe systemic disease and sepsis, with high morbidity and mortality associated with pulmonary infection. Current clinical treatment, which involves exhaustive oral or intravenous antibiotic therapy, has limitations such as systemic toxicity and off-target effects. Pulmonary administration represents a promising alternative to systemic dosing for delivering antibiotics directly to the lung. Here, we present synthesized mannosylated ciprofloxacin polymeric prodrugs for efficient pulmonary delivery, targeting, and subsequent internalization by alveolar macrophages. We demonstrate significant improvement in efficacy against intracellular infections in an otherwise uniformly lethal airborne Francisella murine model (F. novicida). When administered to the lungs of mice in a prophylactic regimen, the mannosylated ciprofloxacin polymeric prodrugs led to 50% survival. In a treatment regimen that was concurrent with infection, the survival of mice increased to 87.5%. Free ciprofloxacin antibiotic was ineffective in both cases. This significant difference in antibacterial efficacy demonstrates the impact of this delivery platform based on improved physiochemical, pharmacokinetic, and pharmacodynamic properties of ciprofloxacin administered via our glycan polymeric prodrug. This modular platform provides a route for overcoming the limitations of free drug and increasing efficacy in treatment of intracellular infection.
Recommended Citation
J. Chen et al., "Glycan Targeted Polymeric Antibiotic Prodrugs for Alveolar Macrophage Infections," Biomaterials, vol. 195, pp. 38 - 50, Elsevier Ltd, Mar 2019.
The definitive version is available at https://doi.org/10.1016/j.biomaterials.2018.10.017
Department(s)
Materials Science and Engineering
Keywords and Phrases
Alveolar macrophage; Antibiotic prodrug; Glycopolymer; Intracellular infection; Mannose
International Standard Serial Number (ISSN)
0142-9612
Document Type
Article - Journal
Document Version
Citation
File Type
text
Language(s)
English
Rights
© 2019 Elsevier Ltd, All rights reserved.
Publication Date
01 Mar 2019
Comments
This work was supported by the Defense Threat Reduction Agency (Grant #HDTRA1-13-1-0047 ) and by the NIH ( R01AI134729 ).