Honors College Thesis


Mycobacterium tuberculosis Selective Adenosine Kinase Nucleoside Polymers for Inhalation Therapy Public Deposited

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  • Respiratory illnesses caused by both viral and bacterial infection are serious issues for global healthcare providers. With the emergence of new, drug-resistant forms of these diseases, innovative drugs and treatment therapies are needed. M tuberculosis is an infection that affects a large portion of the world’s population each year. Aerosol inhalation therapy has been shown to be effective in the treatment and possible prevention of diseases of the lung and nucleoside and nucleotide analogs have been shown to be therapeutically effective in the treatment of viral lung infections. This study set the pathway to develop an alternative inhalation therapy approach to treating M. tuberculosis using two nucleoside analog polymers 2-fluoroadenosine and 2-methyladenosine. In vitro experiments were designed to compare the permeability of the monomer and polymer form of 2-fluoroadenosine and 2-methyladenosine in Calu-3 lung carcinoma cells as well as establish the basic pharmacokinetic properties of the pro-drugs using a surrogate marker, 5-fluorodeoxyuridine monophosphate. An inhalation apparatus was designed, constructed and validated through flow rate and particle size analysis. The data from the permeability experiments are still under analysis and have yet to be evaluated. Drug uptake experiments did not show an uptake of 5-FdUMP into the cells in culture. The inhalation apparatus was designed to theoretically provide efficient concentrations of inhaled pro-drug to the lung through eight directed-flow nose-only delivery cones. The flow rate of the inhalation apparatus was analyzed through non-linear regression and demonstrated that the rate followed a predictable decrease as the number of open cones increased. The size of the water particles produced by the inhalation apparatus was found to have an average size of 5 μm, which falls within the ideal range for inhalation therapy. A theoretical synthesis method for a 10-subunit polymer of 2-fluoroadenosine was proposed. The results of this study demonstrate that the inhalation apparatus produces particles of appropriate size for inhalation therapy with predictable rates of administration for use in future in vivo testing models. The proposed synthesis scheme for a 10-subunit polymer of 2-fluoroadenosine is ready for evaluation and analysis. The results of this study thus far suggest that inhalation therapy using polymer forms of 2-methyladenosine and 2-fluoroadenosine may be a novel and efficient method for the treatment of Mycobacterium tuberculosis.
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