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J Control Release. 2018 Oct 10;287:1-11. doi: 10.1016/j.jconrel.2018.08.014. Epub 2018 Aug 9.

Macrophage-targeted drugamers with enzyme-cleavable linkers deliver high intracellular drug dosing and sustained drug pharmacokinetics against alveolar pulmonary infections.

Author information

1
Department of Bioengineering, University of Washington, Seattle, WA 98195, United States.
2
Division of Pulmonary and Critical Care Medicine, Harborview Medical Center, University of Washington, Seattle, WA 98104, United States.
3
Division of Pulmonary and Critical Care Medicine, Harborview Medical Center, University of Washington, Seattle, WA 98104, United States; Department of Global Health, University of Washington, Seattle, WA 98195, United States. Electronic address: tewest@uw.edu.
4
Department of Bioengineering, University of Washington, Seattle, WA 98195, United States. Electronic address: dratner@uw.edu.
5
Division of Pulmonary and Critical Care Medicine, Harborview Medical Center, University of Washington, Seattle, WA 98104, United States. Electronic address: shawn@uw.edu.
6
Department of Bioengineering, University of Washington, Seattle, WA 98195, United States. Electronic address: stayton@uw.edu.

Abstract

Intracellular bacterial infections localized to the lung alveolar macrophage (AM) remain one of the most challenging settings for antimicrobial therapy. Current systemic antibiotic treatment fails to deliver sustained doses to intracellular bacterial reservoirs, which necessitates prolonged treatment regimens. Herein, we demonstrate a new intracellular enzyme-cleavable polymeric prodrug with tailored ciprofloxacin release profiles in the lungs and AM. The targeted polymeric prodrug, termed "drugamers", incorporates (1) hydrophilic mannose residues to solubilize the antibiotic cargo and to target and enhance AM uptake and intracellular delivery, and (2) enzyme-cleavable linkage chemistry to provide high and sustained intracellular AM drug dosing. Prodrug monomers, derived from the antibiotic ciprofloxacin, were synthesized with either an intracellular protease cleavable dipeptide linker or a hydrolytic phenyl ester linker. RAFT polymerization was used to copolymerize the prodrug monomers and mannose monomer to synthesize well-defined drugamers without requiring a post-polymerization conjugation step. In addition to favorable in vivo safety profiles following intratracheal administration, a single dose of the drugamers sustained ciprofloxacin dosing in lungs and AMs above the minimum inhibitory concentration (MIC) over at least a 48 h period. The enzyme-cleavable therapeutic achieved a >10-fold increase in sustained ciprofloxacin in AM, and maintained a significantly higher whole lung PK as well. Ciprofloxacin dosed in identical fashion displayed rapid clearance with a half-life of approximately 30 min. Notably, inhalation of the mannose-targeted ciprofloxacin drugamers achieved full survival (100%) in a highly lethal mouse model of pneumonic tularemia, contrasted with 0% survival using free ciprofloxacin. These findings demonstrate the versatility of the drugamer platform for engineering the intracellular pharmacokinetic profiles and its strong therapeutic activity in treating pulmonary intracellular infections.

KEYWORDS:

Ciprofloxacin; Drug conjugate; Enzyme-cleavable linker; Francisella; Prodrug; Tularemia

PMID:
30099019
PMCID:
PMC6223132
[Available on 2019-10-10]
DOI:
10.1016/j.jconrel.2018.08.014

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