and 3T showed higher T1 and T2 relaxivity values of free extracellular ferumoxtran-10 as opposed to intra- cellularly compartmentalized feru- moxtran-10, under ...
Eur Radiol DOI 10.1007/s00330-005-0031-2
Gerhard H. Simon Jan Bauer Olaf Saborovski Yanjun Fu Claire Corot Michael F. Wendland Heike E. Daldrup-Link
Received: 24 June 2005 Revised: 18 August 2005 Accepted: 13 September 2005 # Springer-Verlag 2005 This work was supported by a seed grant from the Department of Radiology, University of California of San Francisco. G. H. Simon . J. Bauer . O. Saborovski . Y. Fu . M. F. Wendland . H. E. Daldrup-Link Department of Radiology, UCSF Medical Center, University of California San Francisco, San Francisco, California, USA C. Corot Guerbet Group, Aulnay-sous-Bois, France G. H. Simon (*) UCSF Medical Center, Contrast Agent Research Group, Center for Functional and Molecular Imaging, 505 Parnassus Ave, San Francisco, CA 94143, USA e-mail: gerhard.simon@radiology. ucsf.edu Tel.: +1-415-4765592 Fax: +1-415-4760616
CONTRAST MEDIA
T1 and T2 relaxivity of intracellular and extracellular USPIO at 1.5T and 3T clinical MR scanning
Abstract In this study we evaluated the effects of intracellular compartmentalization of the ultrasmall superparamagnetic iron oxide (USPIO) ferumoxtran-10 on its proton T1 and T2 relaxivities at 1.5 and 3T. Monocytes were labeled with ferumoxtran10 by simple incubation. Decreasing quantities of ferumoxtran-10-labeled cells (2.5×107-0.3×107 cells/ml) and decreasing concentrations of free ferumoxtran-10 (without cells) in Ficoll solution were evaluated with 1.5 and 3T clinical magnetic resonance (MR) scanners. Pulse sequences comprised axial spin echo (SE) sequences with multiple TRs and fixed TE and SE sequences with fixed TR and increasing TEs. Signal intensity measurements were used to calculate T1 and T2 relaxation times of all samples, assuming a monoexponential signal decay. The iron content in all samples was determined by inductively coupled plasma atomic emission spectrometry and used for calculating relaxivities. Measurements at 1.5T
Introduction Superparamagnetic iron oxide nanoparticles have been introduced as contrast agents for magnetic resonance (MR) imaging because of their strong T2 relaxivity, which leads to a strong decrease in signal intensity (negative enhancement) of various target organs on T2-weighted images [1, 2]. In addition, these particles, especially the ultrasmall superparamagnetic iron oxides (USPIO), also have a high T1 relaxivity, which results in an additional increase in signal intensity (positive enhancement) on T1-weighted images [3–5]. The MR imaging characteristics and pharmacokinetics of these agents are far more complex than
and 3T showed higher T1 and T2 relaxivity values of free extracellular ferumoxtran-10 as opposed to intracellularly compartmentalized ferumoxtran-10, under the evaluated conditions of homogeneously dispersed contrast agents/cells in Ficoll solution and a cell density of up to 2.5×107 cells/ml. At 3T, differences in T1-relaxivities between intra- and extracellular USPIO were smaller, while differences in USPIO T2relaxivities were similar compared with 1.5T. In conclusion, cellular compartmentalization of ferumoxtran10 changes proton relaxivity. Keywords Monocytes . Cell labeling . Iron oxide particles . MR imaging
those of the standard extracellular contrast agents such as gadopentetate. The relaxation effects of iron oxide contrast agents are influenced by their local concentration as well as the applied field strength and the environment in which these agents interact with surrounding protons [1, 6–8]. The nanoparticulate contrast agents do not only distribute in the intravascular extracellular space, but they show a subsequent specific cellular uptake into macrophages [9]. This intracellular uptake of iron oxide contrast agents has recently been recognized as an important characteristic of phagocyte-associated pathologic processes. Besides the use of USPIO for metastatic lymph node imaging, applications of iron oxide contrast agents all focus
on the intracellular compartmentalization of these particles; a specific targeting of phagocyte-associated processes with iron oxides has been reported in arthritis [10, 11], multiple sclerosis-related autoimmune processes [12, 13], atherosclerotic plaques [14–16], and ischemic stroke lesions [17– 19]. Other, newer applications include the use of iron oxides for ex vivo labeling of progenitor and stem cells, which can be subsequently tracked in vivo with MR imaging after local or systemic administration. For example, the homing of iron-oxide-labeled stem cells in brain infarcts or myocardial infarcts can be visualized with this method [20, 21]. Other applications comprise tracking of intravenously injected iron-oxide-labeled cytotoxic natural killer cells to tumors or depiction of the accumulation of iron-oxide-labeled leukocytes in inflammations [22–24]. All of these new applications warrant the diagnosis of specific intracellular particle uptake versus nonspecific extracellular, intravascular, or interstitial accumulation and require an understanding of the T2 and T1 relaxivities of intracellular compartmentalized iron oxides. This becomes even more complex with the introduction of new, high-field 3T MR scanners, which are known to provide different proton relaxivities compared with standard 1.5T MR scanners. The relaxation effects of iron oxide particles in liver and spleen have been previously studied [25]. The effects of a noncommercial anionic magnetic nanoparticle compartmentalization in cells on relaxivity have been evaluated by Billotey and colleagues [26]. However, the direct effects of a clinically applicable iron oxide and the effects of different field strengths on cellular compartmentalization have not yet been studied. Thus, the purpose of this study was to evaluate differences in T1 and T2 relaxivities of a prototype USPIO, ferumoxtran-10, with respect to its intraor extracellular compartmentalization and the applied field strength in a controlled experimental setup.
Materials and methods Contrast agent Iron-oxide-based MR contrast agents are nanoparticles composed of a crystalline iron oxide core (Fe2O3 and Fe3O4) and a stabilizing (carboxy)dextran, starch, or citrate coat [26, 27]. The coating includes water molecules that are associated with the coating surface. The total size of the particles is expressed as the hydrated particle diameter. USPIO contain a single iron oxide crystal core and are covered by a coating with a diameter of
