(4ah) Fabrication of Engineered, Monodisperse Particles for Respiratory Drug Delivery

Drug delivery via the lung holds great promise for the local and systemic delivery of a wide variety of materials; however, current respiratory drug delivery systems are surprisingly inefficient, making delivery of expensive materials, such as biologicals, impractical. Using the top-down, micro-molding technique referred to as PRINT (Particle Replication In Non-wetting Templates), powders have been fabricated with predetermined individual particle properties which can improve dispersion, control deposition and tailor therapeutic responses.  These aerosols have been characterized with geometric standard deviations well below 1.2 when nebulized, indicating a monodisperse aerosol. Shape factors have been characterized for all non-spherical geometries by correcting for the drag of shaped particles in the flow conditions of an aerodynamic particle size (APS) spectrometer.  Dry powder PRINT aerosols have been sized from numerous aerosol devices, yielding high emitted doses and tailored deposition as a function of particle geometry.  Particle shape was found to also be critical in downstream cellular interactions in the lung; particle uptake by alveolar macrophages was observed to differ by over two-fold between particles of similar aerodynamic diameters but different shapes, implying the potential to tailor avoidance of macrophage clearance in the lung.  When dosed to mice airways via intratracheal administration, cargo-free PRINT particles were observed to remain immunologically inert in the lung for seven days, with minimal clearance, airway remodeling, or triggering of host immunity by either pro-inflammatory cytokine production or cellular recruitment.  In total, these data suggest that PRINT aerosols hold promise for localized and sustained pulmonary therapeutics through designed particle characteristics which modulate dispersion, deposition, cellular interactions and therapeutic responses.