Ratner, Daniel MChen, Jasmin2017-08-112017-08-112017-06Chen_washington_0250E_17207.pdfhttp://hdl.handle.net/1773/39946Thesis (Ph.D.)--University of Washington, 2017-06Intracellular pathogens are a major cause of global morbidity and mortality due to their complex and intricate ability to replicate within host cells while evading the innate immune defense system. Many intracellular pathogens, such as F. tularensis and B. pseudomallei, are highly infectious and can cause severe and fatal diseases. They are designated as Tier 1 select agents by the Centers for Disease Control and Prevention due to their high infectivity and mortality, transmission by pulmonary route of infection, and potential development as a bioweapon. Current antibiotics are limited by poor pharmacokinetic properties, and consequently require high frequency dosing at high concentrations to show promising clinical success. The physicochemical properties may also limit the route of administration of drugs – a critical factor to consider when select target tissues are of importance. To date, intravenous administration followed by oral tablets are the common routes of administration to deliver drugs; however, in a mass casualty setting, intravenous injections may not be practical. Therefore, new strategies are needed to improve the effectiveness of antibiotics in treating intracellular pulmonary infections. This work utilizes RAFT polymerization techniques to explore synthetic multivalent glycopolymer prodrug systems. Prodrugs are inactive forms of the drug, but when administered undergo hydrolysis to release the pharmacologically active drug. We hypothesized that engineering mannose glycopolymer prodrugs to target the macrophage mannose receptor on alveolar macrophage cells would eradicate or minimize bacterial replication and allow for better protection against intracellular infections. We demonstrated that mannose polymeric prodrug systems provided significantly improved protection against intracellular F. novicida infection in mice challenge models compared to free antibiotic. When intratracheally administered to the lungs of mice in a prophylactic setting, poly(Man-co-CTM) improved survival in 50% of the mice and in a post-infection treatment setting, the survival of mice increased to 87.5%. In both studies, mice treated with free antibiotics remained ineffective. We also show that these results are due to the improved pharmacokinetic and pharmacodynamic properties of ciprofloxacin, in which targeted mannose polymer prodrugs had more than double elimination half-life time in the lungs compared to non-specific polymer prodrugs. We are excited about the promising results of the work presented here, but even more so at the modularity of the prodrug system such that it can be expanded and fine-tuned to be utilized for other diseases and applications.application/pdfen-USnoneBiomedical engineeringBioengineeringThesis