Ring Opening Metathesis Polymerization of a ciprofloxacin-conjugated copolymer for pulmonary intracellular antibiotic delivery

Nina Warner, Maryann Zhao, Daniel M. Ratner, Daniel J. O'Leary

The utility of Ring Opening Metathesis Polymerization (ROMP) is explored in the context of aerosolized pulmonary drug delivery. A poly(oxanorbornene) random copolymer loaded with the fluoroquinolone antibiotic, Ciprofloxacin, and sulfobetaine pendant groups (P1) is synthesized to target intracellular Burkholderia pseudo-mallei, the causative agent of respiratory meliodosis and an attractive candidate for bioterrorism. This system is compared to a previoulsy reported Reversible Addition-Fragmentation Chain-Transfer Polymerization (RAFT) synthesized poly(methacrylate) random copolymer loaded with Ciprofloxacin and PEG pendant groups (P2). In both cases, Ciprofloxacin is conjugated to the polymer via a labile phenolic ester linkage. However, we expect the enhanced hydration of the hydrophillic poly(oxanorbornene) backbone of P1 to encourage hydrolytic cleavage of the drug to a greater extent than the hydrophobic P2 poly(methacrylate) backbone. Substitution of the P2 PEG moiety with a sulfobetaine pendant is predicted to enhance intracellular targeting due to the betaine’s affinity for the plasma membrane. Control over the antibiotic release rate and target will allow for more precise, effective treatment of respiratory meliodosis and other pulmonary infections caused by intracellular bacterial pathogens. Additionally, this work will inform future design of aerosolized polymers for pulmonary drug delivery by elucidating distinct advantages/disadvantages associated with the polymerization approach (ROMP v. RAFT), pendant group chemistry (PEG v. betaines) and backbone properties (poly(oxanorbornene) v. poly(methacrylate)) of aerosolized systems.

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