Degradation, Metabolism and Relaxation Properties of Iron Oxide Particles for Magnetic Resonance Imaging

Sammanfattning: Whereas the effect of size and coating material on the pharmacokinetics and biodistribution of iron oxide based contrast agents are well documented, the effect of these parameters on liver metabolism has never been investigated. The primary purpose of this work was to evaluate the effect of iron oxide particle size and coating on the rate of liver clearance and particle degradation using a rat model. The magnetic and relaxation properties of five different iron oxide contrast agents were determined prior to the onset of the animal studies. The R2' values and the T1-enhancing efficacy of the agents were also evaluated in blood using phantom models. The results of these studies indicated that the efficacy of these agents was matrix and frequency dependent. Correlations between the R2' values and the magnetic properties of the agents were established and a new parameter, Msat/r1, was created to enable better estimations of contrast agent T1-enhancing efficacy in blood. The bio-distribution of one of the agents was also evaluated to assess the importance of sub-cellular particle distribution, using an isolated rat liver cell model. Phantom models were also used to verify that materials with magnetic properties similar to the particle breakdown products (ferritin/hemosiderin) may induce signal reduction when compartmentalized in a liver cell suspension. The results revealed that the cellular distribution of the agent did not influence the rate of particle degradation. This finding conflicted with current theory. Additionally, the study indicated that the compartmentalization of magnetic materials similar to ferritin may induce significant signal loss.Methods enabling the accurate determination of contrast agent concentration in the liver were developed and validated using one of the agents. From these measurements the liver half-life of the agent was estimated and compared to the rate of liver clearance, as determined from the evolution of the effective transverse relaxation rate (R2') in rat liver. The results indicate that the liver R2' enhancement persisted at time points when the concentration of contrast agent present in the liver was below method detection limits. The prolonged R2' enhancement was believed to be a result of the compartmentalisation of the particle breakdown products within the liver cells. Finally, the liver clearance and degradation rates of the five different iron oxide particles in rat liver were evaluated. The results revealed that for materials with similar iron oxide cores and particle sizes, the rate of liver clearance was affected by the coating material present. Materials with similar coating, but different sizes, exhibited similar rates of liver clearance.In conclusion, the results of this work strongly suggest that coating material of the iron oxide particles may contribute significantly to the rate of iron oxide particle clearance and degradation in rat liver cells.