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Synthetic Macromolecular Antibiotic Platform for Inhalable Therapy against Aerosolized Intracellular Alveolar
Debobrato Das1, Jasmin Chen1, Selvi Srinivasan1
1Department of Bioengineering, University of Washington , Seattle, Washington 98195, United States.
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.
Insights
A new macromolecular prodrug platform delivers ciprofloxacin effectively to the lungs, offering sustained treatment for challenging intracellular bacterial infections like tularemia.
Area of Science:
- Nanomedicine
- Pharmacology
- Infectious Diseases
Background:
- Lung-based intracellular bacterial infections, such as tularemia, are difficult to treat due to poor pulmonary antibiotic bioavailability.
- Current antibiotic treatments for Francisella tularensis pneumonia (tularemia) have limitations in achieving sustained lung drug levels.
- There is an unmet need for effective, sustained antibiotic delivery to alveolar intracellular pathogens.
Purpose of the Study:
- To develop a macromolecular therapeutic platform for sustained local delivery of ciprofloxacin.
- To create nanotherapeutics with controlled dosing profiles for alveolar intracellular infections.
- To evaluate the efficacy of a novel ciprofloxacin macromolecular prodrug against Francisella tularensis.
Main Methods:
- Synthesis of macromolecular prodrugs using RAFT polymerization with high drug loading (16-17 wt%).
- Tuning hydrolysis kinetics via drug linkage chemistry (alkyllic vs. phenolic esters) to control release rates.
- In vivo evaluation in aerosolized, lethal F.t. novicida mouse models, including pharmacokinetic and biodistribution studies.
Main Results:
- The fast-releasing ciprofloxacin macromolecular prodrug achieved 75% survival in lethal F.t. novicida mouse models.
- Release kinetics were critical, as a slow-releasing version of the prodrug was inactive.
- Pharmacokinetics confirmed lung drug levels remained above the minimum inhibitory concentration (MIC) for 48 hours.
Conclusions:
- The developed macromolecular prodrug platform shows potential for treating alveolar intracellular infections like tularemia.
- Tailored antibiotic pharmacokinetic and release profiles are crucial for positive patient outcomes in treating F. tularensis.
- This nanotherapeutic platform offers a promising strategy for sustained local antibiotic delivery to the lungs.