(542g) Polymerizable Prodrug Monomers for the Treatment of Serious Intracellular Bacterial Infections

Polymeric prodrugs consist of a therapeutic agent that has been covalently conjugated to a macromolecular scaffold via a hydrolytic or enzymatically degradable linkage. This strategy has been shown to substantially increase the solubility and stability of the parent drug while also enhancing drug circulation half-lives and reducing immunogenicity. An attractive route for the synthesis of polymeric prodrugs is the direct reversible deactivation radical polymerization (RDRP) of therapeutic agents that have been reversibly modified with suitable vinyl functionality. This versatile approach allows for one or more drug moieties to be incorporated into the final polymer at predetermined ratios without the need for additional conjugation and purification steps. In this talk we will discuss the synthesis and subsequent polymerization of prodrug monomers derived from the antibiotic ciprofloxacin with phenolic or aliphatic esters linking the drug to a polymerizable methacrylate group. In aerosolized and completely lethal F.t. novicida mouse challenge models, the fast-releasing phenyl ester linked ciprofloxacin macromolecular prodrug provided high cure efficiencies (75% survival rate under therapeutic treatment vs. 0 % survival for free ciprofloxacin), 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.