Determination of liver‐specific r₂* of a highly monodisperse USPIO by ⁵⁹Fe iron core‐labeling in mice at 3 T MRI

Abstract

Accurate determination of tissue concentration of ultrasmall superparamagnetic iron oxide nanoparticles (USPIO) using T2 * MR relaxometry is still challenging. We present a reliable quantification method for local USPIO amount with the estimation of the liver specific relaxivity r2 * using monodisperse (59) Fe-core-labeled USPIO ((59) FeUSPIO). Dynamic and relaxometric in vivo characteristics of unlabeled monodisperse USPIO were determined in MRI at 3 T. The in vivo MR studies were performed for liver tissue with (59) FeUSPIO using iron dosages of 9 (n = 3), 18 (n = 2) and 27 (n = 3) µmol Fe kg(-1) body weight. The R2 * of the liver before and after USPIO injection (∆R2 *) was measured and correlated with (59) Fe activity measurements of excised organs by a whole body radioactivity counter (HAMCO) to define the dependency of ∆R2 * and (59) FeUSPIO liver concentration and calculate the r2 * of (59) FeUSPIO for the liver. Ultrastructural analysis of liver uptake was performed by histology and transmission electron microscopy. ∆R2 * of the liver revealed a dosage-dependent accumulation of (59) FeUSPIO with a percentage uptake of 70-88% of the injection dose. Hepatic ∆R2 * showed a dose-dependent linear correlation to (59) FeUSPIO activity measurements (r = 0.92) and an r2 * in the liver of 481 ± 74.9 mm(-1) s(-1) in comparison to an in vitro r2 * of 60.5 ± 3.3 mm(-1) s(-1) . Our results indicate that core-labeled (59) FeUSPIO can be used to quantify the local amount of USPIO and to estimate the liver-specific relaxivity r2 *.

Quantitative Activity Measurements of Brown Adipose Tissue at 7 T Magnetic Resonance Imaging After Application of Triglyceride-Rich Lipoprotein 59Fe-Superparamagnetic Iron Oxide Nanoparticle

“…10,25 An additional problem for quantifying iron concentrations in tissue is the high endogenous iron pool, which cannot be differentiated from exogenously applied iron (eg, SPIO) using typical laboratory methods (eg, atomic absorption spectrometry). By using 59 Fe-SPIOs, we were able to avoid this problem and observe a causal relationship between ΔR2* and radioactive 59 Fe measurements in accordance with the results of Raabe et al 8 As multiecho ΔR2* relaxometry technique is used for quantification of MRI signal, for example, to asses tumor vascularization changes in response to an antiangiogenic treatment, 26 the core labeling of SPIOs with 59 Fe is a powerful tool for preclinical and potential clinical quantification of SPIOs. The generation of a linear calibration curve provides a tool to noninvasively conclude from ΔR2* the 59 Fe-SPIO concentration in the targeted tissue, which is of particular interest in all studies that focus on quantifying SPIO contrast agents, for example, for the estimation of receptor densities on cell surfaces, which may vary in different types of tumor or even change during disease progression and in response to therapy.…”

“…Quantitative T2* and R2* mapping enables noninvasive estimations of cellular iron uptake [6][7][8] but is still challenging. 9 As the correlation of MR relaxivities with local particle concentration is difficult to determine due to particle agglomeration, increase in hydrodynamic diameters caused by opsonization 10 ("particle corona"), and due to the valuable genuine iron background that is present in most tissues, the SPIOs were labeled radioactively with 59 Fe to correlate MR relaxivity with radioactive measurements.…”

In vivo delivery, pharmacokinetics, biodistribution and toxicity of iron oxide nanoparticles

“…59 Fe 312, 335 , 111 In 336 , 51 Cr 337 or 69 Ge 309 ) or near infrared fluorescent molecules ( e.g. Cy5.5, 56, 86, 338 SBD/SDA 339 or VivoTag 800 275 fluorophores) have also been used for quantification of the IONPs in the tissues.…”

Magnetic Particle / Magnetic Resonance Imaging: In-Vitro MPI-Guided Real Time Catheter Tracking and 4D Angioplasty Using a Road Map and Blood Pool Tracer Approach

“…Magnetic labeling of endovascular instruments but no SPIO application was needed to perform intervention. This approach avoids SPIO accumulation in the reticuloendothelial system (RES) of liver and spleen [ 22 ], allowing theoretically unlimited repetitions of interventions. In an in-vivo setting in humans the MPI/MRI image fusion might be difficult to realize, e.g.…”