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The relationship between microparticle (MP) size and lung targeting efficiency, intra-lung distribution and retention time was systematically studied after intravenous administration of rigid fluorescent polystyrene MPs of various sizes (2, 3, 6 and 10 μm) to Sprague Dawley rats. Total fluorescence was assessed and it was found that 2 μm and 3 μm MPs readily passed through the lung to the liver and spleen while 10 μm MPs were completely entrapped in the lung for the one-week duration of the study. Approximately 84% of 6 μm MPs that were initially entrapped in the lung were cleared over the next 2 days and 15% were cleared over the remaining 5 days. A Caliper IVIS® 100 small animal imaging system confirmed that 3 μm MPs were not retained in the lung but that 6 μm and 10 μm MPs were widely distributed throughout the lung. Moreover, histologic examination showed MP entrapment in capillaries but not arterioles. These studies suggest that for rigid MPs the optimal size range required to achieve transient but highly efficiently targeting to pulmonary capillaries after IV injection is >6 μm but <10 μm in rats and that systemic administration of optimally sized MPs may be an efficient alternative to currently used inhalation-based delivery to the lung.Passive entrapment due to size of microparticles was determined after IV injection to rats. Size plays a critical role in microparticle biodistribution, suggesting a possible pulmonary targeting route besides inhalation.