Novel Therapies for Enhancing Clearance of Inhaled Radioactive Particles

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DESCRIPTION (provided by applicant): In this application, we propose a research and development project with the goal of advancing a therapeutic countermeasure for radiological material inhalation exposure through the product development process. As discussed below, the greatest risk to the lungs following a radiological attack, such as a dirty bomb, results from the inhalation and retention of insoluble radioactive particles. As a result of radioactive particle retention, the cumulative exposure to the lung is significantly increased, ultimately resulting in pulmonary fibrosis/pneumonitis and death. Insoluble particles cannot be systemically cleared by chelating agents as they are not in solution. To date, the physical removal of particulate matter through bronchoalveolar lavage is the only therapeutic regimen shown to be effective at mitigating radiation-induced lung disease. In this application, we will test the ability of novel compounds to accelerate the removal of insoluble particles in the lung by enhancing hydration of pulmonary surfaces. Pharmacologically induced increases in pulmonary surface hydration increase both (1) mechanical clearance of particles from airway surfaces and (2) increases in alveolar macrophage clearance. In essence, our compounds via the aerosol route produce a 'non-invasive lavage' of the lung which can be used in concert with other available therapeutic strategies as a means to decrease the cumulative radiation exposure and therefore, mitigate lung disease. The advantages of our approach are several-fold. First, our strategy is not isotope selective and will facilitate clearance of any insoluble particles from the lungs. Importantly, we have successfully completed proof-of-concept studies in animals and humans which demonstrate that our compounds efficaciously facilitate radioactive particle clearance by increasing mucociliary clearance (MCC) greater than 10-fold. Second, we have extensive safety and toxicology data for our compounds that will promote rapid availability of this therapeutic. Our lead compound, 552-02, has been in six human clinical trials without any serious adverse events. Furthermore, we have made substantial progress towards 552-02 development with respect to large scale synthesis, stability, formulation, and delivery. In this application, we propose to test our compounds as both a stand alone therapy and in combination with bronchoalveolar lavage, the only treatment presently shown to effectively remove insoluble radionuclides from the lungs. Our goal is to identify the most effective therapeutic countermeasure against radiological-induced lung disease following inhalation exposure.