(632b) Particle Surface Properties of Pulmonary Drug Delivery Vehicles Impact Their Distribution and Cellular Association

Through controlled design properties, engineered nano- and microparticle drug delivery vehicles have the potential to expand the breadth of pulmonary therapeutics through cell-specific targeted delivery.  However, in many applications, such as mucosal vaccines or controlled-release lung depots, optimal particle properties have not yet been identified.  Thus, we investigated the role of particle surface properties to increase residence times and alter the cellular fate of nano- and microparticles delivered to the lung. Using the nano-molding technique Particle Replication In Non-wetting Templates (PRINT), various sizes of hydrogel particles, including 80x320 nm rods and 1.5 and 6 µm donuts, were fabricated with a range of surface properties, including cationic, anionic, PEGylated, and antigen-loaded surfaces. These particles were instilled into the lungs of c57b/6 mice and assessed after 1, 7, and 28 days.  We harvested broncheoalveolar lavage fluid, whole lungs, and draining lymph nodes to evaluate inflammatory cytokines, histopathology, cellular populations, and particulate uptake through flow cytometry, ELISAs, and fluorescent imaging. Similar to intravenous delivery, PEGylation was found to increase lung residence times of all sizes of particles tested, with the largest increase in residence time observed for smaller 80x320 nm particles. No particle formulation resulted in long term inflammatory responses, despite increased residence time. Interestingly, unPEGylated cationic nanoparticles preferentially associated with two important lung DC populations while simultaneously avoiding prolific macrophage uptake. Formulations of unPEGylated particles also trafficked to the medistinal lymph node, suggesting application for pulmonary vaccine carriers. Thus, surface modification of engineered particles was found to significantly affect uptake kinetics by key cell populations in the lung.  These findings increase understanding of how particle properties, such as size, shape, and surface chemistry, can direct interactions with key lung cells to design more effective pulmonary drug delivery vehicles.