SBIR-STTR Award

With delineation of the pathogenesis of lung diseasessignificant advances are being achieved in the pharmaceutical development of therapeutic interventionsNew putative drugs are continually being identifiedhowevertheir initial availability is often extremely limitedparticularly for biologically basedmacromolecule agentse gproteinsgenesRNAand antibodiesTranslation of these agents is particularly challenging if the delivery mode is inhalationExisting rodent exposure systems are unsuitable for these compoundsas typically more thanof the drug is lostWhile it is possible to administer a small volume of solution of the agent to rodent models with an endotracheal needlethis requires anesthesia and results in poor distribution in the lungThis project addresses the critical need of efficient inhalation deliveryfirst in rodents and then in larger animals and human patientsAn efficient rodent inhalation exposure system is needed not only for testing putative therapies but also infectious agentsnew vaccines and engineered nanomaterialsOur proposed approach is non invasive and will not require anesthesia and thus is amenable for trauma freedaily dosingAerosols will be generated with a small volume of liquide gmicro literswith essentially no liquid trapped in the deviceFurtherthe particles will be produced close to the nares of the animalwhich will minimize the dead volume and thereby the loss of the agentAerosols escaping lung deposition will be electrostatically deposited on a mass microbalance equipped for real time readoutThe benefits includeaerosol exposure will be monitored in real time allowing immediate dosing adjustmentsandfluctuations in the mass deposition on the microbalance would reveal the breathing frequency and tidal volume of the animalThe proposed device is expected to have an inhalation efficiency of aboutWe propose to construct a prototype exposure system utilizingmechanical rodentsdesigned 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 ratAerosols inhaled by the mechanical rodent will be collected on a filter to assess depositionFurtherwe 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 usingnanocapsulesof macromolecular drugs encapsulated in a ligand shell enabling targeted delivery to solid tumor cells and inflamed fibroblastic cellsSuccessful completion of this work would establish the feasibility of the proposed exposure system for highly efficient inhalation exposureIn Phase IIthis 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 PROJECT NARRATIVE New compounds for inhalation delivery are often tested with rodents through invasive endotracheal access under anesthesiaas non invasive aerosol delivery is too wasteful to be practicalWe propose development of a new highly efficient non invasive aerosol delivery system for rodentswith the additional benefits of real time monitoring and plethysmographyThrough advancement of rodent inhalation exposure equipmentthis project promises to shorten the time from discovery to regulatory approval for new inhalation drugsThe advanced exposure system would also significantly improve the outcome of preclinical studies on infectious agentsinhalation vaccines and airborne nanomaterials