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Toxicodynamics of rigid polystyrene microparticles on pulmonary gas exchange in mice: implications for
1Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
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 (6-8 weeks) were intravenously administered 10, 25 and 45 μm diameter MPs. Oxygen hemoglobin saturation in the blood (SpO(2)) was measured non-invasively using a pulse oximeter while varying inhaled oxygen concentration (F(I)O(2)). The resulting data were fit to a physiologically based non-linear mathematical model that estimates 2 parameters: ventilation-perfusion ratio (V(A)/Q) and shunt (percentage of deoxygenated blood returning to systemic circulation). The number of MPs administered prior to a statistically significant reduction in normalized V(A)/Q was dependent on particle size. MP doses that resulted in a significant reduction in normalized V(A)/Q one day post-treatment were 4000, 40,000 and 550,000 MPs/g for 45, 25 and 10 μm MPs, respectively. The model estimated V(A)/Q and shunt returned to baseline levels 7 days post-treatment. Measuring SpO(2) alone was not sufficient to observe changes in gas exchange; however, when combined with model-derived V(A)/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.
Insights
Pulmonary microemboli from polystyrene particles showed size-dependent toxicity, with gas exchange effects reversible within seven days. Combining pulse oximetry with mathematical modeling is crucial for detecting early, reversible toxicity.
Area of Science:
- Pulmonary physiology
- Toxicology
- Biomaterials science
Background:
- Pulmonary microemboli (PMEs) can impact gas exchange.
- Polystyrene microparticles (MPs) are used in research and drug delivery.
- Understanding PME toxicity is vital for safe applications.
Purpose of the Study:
- To investigate the toxicodynamic relationship between PME characteristics and pulmonary gas exchange.
- To determine the dose-dependent effects of varying MP sizes on gas exchange.
- To assess the utility of pulse oximetry and mathematical modeling in detecting PME toxicity.
Main Methods:
- Intravenous administration of 10, 25, and 45 μm MPs to CD-1 male mice.
- Non-invasive measurement of blood oxygen saturation (SpO2) under varying inspired oxygen concentrations (FiO2).
- Application of a physiologically based mathematical model to estimate ventilation-perfusion ratio (V(A)/Q) and shunt.
Main Results:
- MP dose required for significant V(A)/Q reduction varied by size (4000, 40,000, 550,000 MPs/g for 45, 25, 10 μm MPs, respectively).
- V(A)/Q and shunt returned to baseline within 7 days post-treatment, indicating reversible toxicity.
- SpO2 alone was insufficient; model-derived V(A)/Q and shunt were necessary for early toxicity detection.
Conclusions:
- The number of MPs causing significant gas exchange impairment depends on particle size.
- Early, reversible pulmonary toxicity from MPs can be detected using combined SpO2 measurements and mathematical modeling.
- Microemboli-based pulmonary drug delivery appears potentially safe at doses below those causing significant gas exchange alteration.
