Recent advances in iron oxide nanocrystal technology for medical imaging☆
Introduction
For several years now, research in the field of magnetic resonance imaging (MRI) contrast agents has been directed towards the study and development of superparamagnetic nanoparticles, consisting of iron oxides, magnetite (Fe3O4), maghemite (γFe2O3) or other ferrites, which are insoluble in water [1], [2]. Unlike ferromagnetic substances and because of their size, superparamagnetic agents have no magnetic properties outside an external magnetic field [1]. Superparamagnetic nanoparticles are coated nanocrystals of iron oxides, characterized by a large magnetic moment in the presence of a static external magnetic field [4], [5]. Superparamagnetic nanoparticles are mostly used because of their negative enhancement effect on T2- and T2⁎-weighted sequences. This predominant effect on the T2 relaxation time does not prevent the use of the properties of these agents on the T1 relaxation time when appropriate imaging sequences are chosen [6], [7].
These nanoparticles have in common their specific uptake by the monocyte–macrophage system, explaining why, if they are not entirely captured by the liver and spleen, they are widely evaluated as MRI markers for the diagnosis of inflammatory and degenerative disorders associated with high macrophage phagocytic activity [8].
Two distinct classes of superparamagnetic nanoparticles are currently used for clinical imaging depending on hydrodynamic particle size: superparamagnetic iron oxide (SPIO) particles with a mean particle diameter of more than 50 nm and ultrasmall superparamagnetic iron oxide (USPIO) particles with a smaller hydrodynamic diameter [9].
Two compounds in the SPIO family are commercialized for intravenous use: Ferumoxides (Endorem® – Europe, Feridex® in the USA and Japan) and Ferucarbotran (Resovist® – Europe and Japan). In both cases, the clinical targets are liver tumours. These nanoparticles are medium-sized and coated with dextran (ferumoxides) or carboxydextran (ferucarbotran) [10].
Several USPIO have been investigated in humans for several imaging applications, such as ferumoxtran-10 (dextran) [11], [12], VSOP (citrate) [13], feruglose (pegylated starch) [14] or SHU555C (carboxydextran) [15].
Multiple components determine the efficacy of these agents such as the size of the iron oxide crystals, the charge, the nature of the coating, the hydrodynamic size of the coated particle, etc. These physicochemical characteristics not only affect the efficacy of the superparamagnetic particles in MRI, but also their stability, biodistribution, opsonization and metabolism as well as their clearance from the vascular system.
The chemical coating of these nanoparticles may also allow them to be linked to molecules capable of specifically targeting a specific area such as an organ, a disease or a particular biological system [16], [17]. Furthermore, ex vivo labelling using iron oxide nanoparticles of progenitor and stem cells which can be subsequently tracked in vivo with MRI is a major research subject [18], [19]. These two approaches are under investigation and further developments are needed for large-scale clinical applications.
Section snippets
Chemical composition
Iron oxide nanoparticles are ferrites composed of maghemite and magnetite (Fe2O3, Fe3O4); metal ions in the ferrite crystal occupy two different crystallographic latices in a spinel structure. This crystal structuration results in a net spontaneous magnetization of the iron nanoparticule. Ferrites are characterized by their saturation magnetization at 300 K (92 emug− 1 for magnetite and 78 emug− 1 for maghemite [20].
Numerous chemical methods can be used to synthesize magnetic nanoparticles for
Superparamagnetism
Bulk ferromagnetic materials are composed of fully magnetized domains the size of a micron. In the absence of an external magnetic field, a ferromagnetic material is not magnetized, as magnetization of these ferromagnetic domains is oriented in several directions. Superparamagnetism occurs when the size of the crystals is smaller than ferromagnetic domains (approximately 30 nm) and, consequently, they do not show any magnetic remanence (i.e. restoration of the induced magnetization to zero upon
Iron oxide nanoparticle imaging
Several clinical applications are possible according to the iron oxide nanoparticle composition and size, which influence their biodistribution (Table 2):
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SPIO with intense macrophage uptake are used for liver imaging: the healthy liver tissue, which is rich in Kupffer cells (macrophages) phagocytes the SPIO producing a dark signal with a T2/T2⁎ sequence, while no modification of contrast is observed in liver tumours due to the absence of Kupffer cells.
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USPIO with minor macrophage uptake and
Molecular imaging
Molecular medicine will open up new treatment paradigms for currently untreatable diseases by generating new targets more closely related to pathophysiology. Molecular medicine will also allow more personalized medicine with treatments tailored to the needs of the individual patient.
To fully exploit the new possibilities of molecular medicine, new diagnostic procedures have to be developed, in particular molecular diagnostic compounds and new imaging technologies, such as high-field MRI.
Cellular labelling imaging
Recent progress in the field of stem cells and progenitor cells suggests that these cells could be used, in the near future, to correct or replace defective cell populations. Clinical applications are numerous and promising, both for CNS-related diseases (spinal cord injury, Parkinson's disease, myelin disorders, Huntington's disease, etc) and regeneration of the myocardium. Renal and hepatic diseases may also benefit from progress in cell therapies. The development of these new stem cell-based
Conclusions
Iron oxides now have a variety of applications in molecular and cellular imaging. Most of the recent research has concerned cellular imaging with imaging of in vivo macrophage activity. Stem cell migration and immune cell trafficking, as well as targeted iron oxide nanoparticles for molecular imaging studies, are at the stage of proof of concept, mainly in animal models.
The physicochemical characteristics not only determine the efficacy of the superparamagnetic particles in MRI, but also their
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Particulate Nanomedicines”, Vol. 58/14, 2006.