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Updated: Jan 31, 2026
Alveolar Macrophage Phagocytosis and Bacteria Clearance in Mice
Published on: March 2, 2019
Glycan targeted polymeric antibiotic prodrugs for alveolar macrophage infections
Jasmin Chen1, Fang-Yi Su1, Debobrato Das1
1Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
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.
Insights
Mannosylated ciprofloxacin polymeric prodrugs enhance pulmonary delivery for intracellular lung infections. This novel approach significantly improves survival rates in a lethal Francisella murine model compared to free antibiotics.
Area of Science:
- Infectious Diseases
- Nanotechnology
- Pharmacology
Background:
- Alveolar macrophages are key in pulmonary immunity but can harbor intracellular pathogens like Francisella tularensis.
- Current systemic antibiotic treatments for severe pulmonary infections have limitations including toxicity and off-target effects.
- Pulmonary drug delivery offers a targeted approach to directly treat lung infections, minimizing systemic exposure.
Purpose of the Study:
- To develop and evaluate mannosylated ciprofloxacin polymeric prodrugs for targeted alveolar macrophage delivery and enhanced efficacy against intracellular pulmonary infections.
- To assess the therapeutic potential of this novel pulmonary delivery platform in a lethal airborne Francisella murine model.
Main Methods:
- Synthesis of mannosylated ciprofloxacin polymeric prodrugs.
- Evaluation of pulmonary delivery, alveolar macrophage targeting, and internalization efficiency.
- Assessment of *in vivo* efficacy in a *Francisella novicida* airborne infection mouse model under prophylactic and treatment regimens.
Main Results:
- Mannosylated ciprofloxacin polymeric prodrugs demonstrated improved pulmonary delivery and alveolar macrophage targeting.
- Prophylactic administration resulted in 50% survival in the lethal *F. novicida* model.
- Concurrent treatment with the prodrugs increased survival to 87.5%, while free ciprofloxacin was ineffective.
- The prodrug platform showed improved physiochemical, pharmacokinetic, and pharmacodynamic properties.
Conclusions:
- Mannosylated ciprofloxacin polymeric prodrugs represent a promising strategy for overcoming limitations of conventional antibiotic therapy for intracellular pulmonary infections.
- This targeted pulmonary delivery platform significantly enhances antibacterial efficacy, offering a potential new treatment route for severe lung infections.
- The modular nature of this glycan polymeric prodrug platform allows for broad applicability in treating various intracellular infections.
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