Research Project
9776357
Project Summary: With delineation of the pathogenesis of lung diseases, significant advances are being achieved in the pharmaceutical development of therapeutic interventions. New putative drugs are continually being identified; however, their initial availability is often extremely limited, particularly for biologically-based, macromolecule agents (e.g. proteins, genes, RNA, and antibodies). Translation of these agents is particularly challenging if the delivery mode is inhalation. Existing rodent exposure systems are unsuitable for these compounds, as typically more than 99% of the drug is lost. While it is possible to administer a small volume of solution of the agent to rodent models with an endotracheal needle, this requires anesthesia and results in poor distribution in the lung. This project addresses the critical need of efficient inhalation delivery--first in rodents and then in larger animals and human patients. An efficient rodent inhalation exposure system is needed not only for testing putative therapies but also infectious agents, new vaccines and engineered nanomaterials. Our proposed approach is non-invasive and will not require anesthesia and thus is amenable for trauma-free, daily dosing. Aerosols will be generated with a small volume of liquid (e.g. 10 micro-liters) with essentially no liquid trapped in the device. Further, the particles will be produced close to the nares of the animal, which will minimize the dead volume and thereby the loss of the agent. Aerosols escaping lung deposition will be electrostatically deposited on a mass microbalance equipped for real-time readout. The benefits include: (1) aerosol exposure will be monitored in real time allowing immediate dosing adjustments, and (2) fluctuations in the mass deposition on the microbalance would reveal the breathing frequency and tidal volume of the animal. The proposed device is expected to have an inhalation efficiency of about 60%. We propose to construct a prototype exposure system utilizing ?mechanical rodents? designed to simulate the anatomy/physiology of a rodent?s respiratory system with adjustable respiratory minute volume as well as breathing frequency for application to either a mouse or a rat. Aerosols inhaled by the mechanical rodent will be collected on a filter to assess deposition. Further, we will validate the exposure system in-vivo with mice for the total pulmonary deposition as well as distribution of inhaled aerosol in the pulmonary tree using ?nanocapsules? of macromolecular drugs encapsulated in a ligand shell enabling targeted delivery to solid tumor cells and inflamed fibroblastic cells. Successful completion of this work would establish the feasibility of the proposed exposure system for highly efficient inhalation exposure. In Phase II, this device will be developed into a multiple animal exposure system and used for safety and efficacy studies of nanocapsules in treating lung cancer and chronic obstructive pulmonary disease.
