Acute respiratory distress syndrome (ARDS) afflicts tens of thousands of individuals annually in the United States and is associated with significant mortality. Presently, there is no effective treatment and little optimism exists for prospective therapies currently under investigation. A unique antiinflammatory agent (protein) that reduces neutrophil reactive oxygen species (ROS)-mediated injury in an animal model of lung inflammation has been identified and represents a potentially viable therapy for ARDS. Therefore, the broad, long-term objectives of this research and drug development program are to develop a unique, localized (lung-targeted) therapy that will be effective in reducing the mortality associated with ARDS. The purpose of this phase I application is to prove the principle of this strategy in man by developing a drug formulation that will sustain the nebulization process and distribute adequately into the human respiratory tract. To this end, the specific aims of this project are to: 1) formulate the agent to make it suitable for local pulmonary delivery via nebulization while retaining activity. Optimal formulation will be derived by the addition of varying concentrations of surfactant. The formulation activities will include an assessment of protein stability, aerodynamic particle size, and biological function. Protein stability will be measured by total protein recovery and structural integrity. Particle size will be determine using a cascade impactor and biological activity will be quantified by the ability of the agent to inhibit neutrophil ROS production; 2) characterize the respiratory deposition of a nebulized formulation of the agent in a human lung replica model.
This aim i s designed to generate additional supportive evidence to prove the principle of the formulation in man. To accomplish this aim, each viable formulation, as determined by the feasibility criteria of specific aim #1, will be nebulized into a human lung replica. A high-fidelity human lung replica reproduced from a master cast made from a human cadaver which includes five to nine generations of bronchi will be utilized. Deposition in the small airways and alveoli regions of the cast is simulated by material that passes through the upstream airways and is collected on foam filters. The results of the work performed in both specific aims will determine the feasibility of the nebulized formulation of this new and novel agent as well as serve as the basis for a phase II application and the subsequent commercialization of the product
| Lin, Swan; Racz, Jennifer; Tai, Melissa F et al. (2016) A Role for Low Density Lipoprotein Receptor-Related Protein 1 in the Cellular Uptake of Tissue Plasminogen Activator in the Lungs. Pharm Res 33:72-82 |
| Lackowski, Nicholas P; Pitzer, Josh E; Tobias, Meghan et al. (2010) Safety of prolonged, repeated administration of a pulmonary formulation of tissue plasminogen activator in mice. Pulm Pharmacol Ther 23:107-14 |
| Dunn, John S; Nayar, Rajiv; Campos, Jackie et al. (2005) Feasibility of tissue plasminogen activator formulated for pulmonary delivery. Pharm Res 22:1700-7 |
