Toxicodynamics of rigid polystyrene microparticles on pulmonary gas exchange in mice: Implications for microemboli-based drug delivery systems

Abstract

The toxicodynamic relationship between the number and size of pulmonary microemboli resulting from uniformly sized, rigid polystyrene microparticles (MPs) administered intravenously and their potential effects on pulmonary gas exchange were investigated. CD-1 male mice (6–8weeks) were intravenously administered 10, 25 and 45μm diameter MPs. Oxygen hemoglobin saturation in the blood (SpO2) was measured non-invasively using a pulse oximeter while varying inhaled oxygen concentration (FIO2). The resulting data were fit to a physiologically based non-linear mathematical model that estimates 2 parameters: ventilation–perfusion ratio (VA/Q) and shunt (percentage of deoxygenated blood returning to systemic circulation). The number of MPs administered prior to a statistically significant reduction in normalized VA/Q was dependent on particle size. MP doses that resulted in a significant reduction in normalized VA/Q one day post-treatment were 4000, 40,000 and 550,000MPs/g for 45, 25 and 10μm MPs, respectively. The model estimated VA/Q and shunt returned to baseline levels 7days post-treatment. Measuring SpO2 alone was not sufficient to observe changes in gas exchange; however, when combined with model-derived VA/Q and shunt early reversible toxicity from pulmonary microemboli was detected suggesting that the model and physical measurements are both required for assessing toxicity. Moreover, it appears that the MP load required to alter gas exchange in a mouse prior to lethality is significantly higher than the anticipated required MP dose for effective drug delivery. Overall, the current results indicate that the microemboli-based approach for targeted pulmonary drug delivery is potentially safe and should be further explored.