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WIREs Nanomed Nanobiotechnol
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The issues and tentative solutions for contrast‐enhanced magnetic resonance imaging at ultra‐high field strength

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Magnetic resonance imaging (MRI) performed at ultra‐high field strengths beyond 3 Tesla (T) has become increasingly prevalent in research and preclinical applications. As such, the inevitable clinical implementation of such systems lies on the horizon. The major benefit of ultra‐high field MRI is the markedly increased signal‐to‐noise ratios achievable, enabling acquisition of MR images with simultaneously greater spatial and temporal resolution. However, at field strengths higher than 3 T, the efficacy of Gd(III)‐based contrast agents is diminished due to decreased r1 relaxivity, somewhat limiting imaging of the vasculature and contrast‐enhanced imaging of tumors. There have been extensive efforts to design new contrast agents with high r1 relaxivities based on macromolecular compounds or nanoparticles; however, the efficacy of these agents at ultra‐high field strengths has not yet been proven. The aim of this review article is to provide an overview of the basic principles of MR contrast enhancement processes and to highlight the main factors influencing relaxivity. In addition, challenges and opportunities for contrast‐enhanced MRI at ultra‐high field strengths will be explored. Various approaches for the development of effective contrast agent molecules that are suitable for a broad spectrum of applied field strengths will be discussed in the context of the current literature. WIREs Nanomed Nanobiotechnol 2014, 6:559–573. doi: 10.1002/wnan.1291 This article is categorized under: Diagnostic Tools > Diagnostic Nanodevices Diagnostic Tools > In Vivo Nanodiagnostics and Imaging
Coronal T1‐weighted sequences acquired at the level of an experimental brain glioma in a rat study with the unenhanced scans displayed on the left side and the corresponding contrast‐enhanced scans on the right. Intra‐individual administration of three different Gd(III)‐based contrast agents was performed (Gd‐DOTA, P846, P792) with the contrast agent doses being adjusted to compensate for the different relaxivities. P846 (@0.025 mmol/kg body weight) shows comparable enhancement relative to Gd‐DOTA (@0.1 mmol/kg body weight). In distinction, P792 (@0.05 mmol/kg body weight) demonstrates considerably less enhancement, which can be explained by the larger molecular size of the compound and a smaller amount of extravascular extravasation. (Reprinted with permission from Ref. Copyright 2009 Lippincott Williams & Wilkins, Inc.)
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Molecular structures of three Gd(III)‐based contrast agents. Gd‐DOTA represents a low‐molecular chelate with an extracellular distribution. In the case of P846 and P792, three and four side arms are added, respectively, thus resulting in a greater molecular mass and a larger hydrodynamic diameter. (Reprinted with permission from Ref. Copyright 2009 Lippincott Williams & Wilkins, Inc.)
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The field dependency of the r1 relaxivities for different clinical and experimental Gd(III)‐based contrast agents. While r1 is fairly constant for the low‐molecular compounds for a broad spectrum of field strengths, macromolecular agents demonstrate a large decrease in r1 at higher field strengths.
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The variables influencing the physicochemical process of enhancement for a Gd(III)‐based contrast agent. Here, r and r′ represent the distance between the Gd(III)‐ion and the water molecules in the inner and second hydration spheres, respectively. τR represents the rotational correlation time of the contrast agent complex, reflecting the tumbling rate. 1/τm reflects the water exchange rate between the inner sphere and the surrounding bulk water with τm corresponding to the mean residence time of the water molecule in the inner sphere.
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A T1‐weighted axial image in a rat with a hepatic colorectal cancer metastasis (diameter approximately 8 mm, arrows) after administration of 0.1 mmol/kg body weight Gd‐DOTA (a) and 0.01 mmol/kg body weight AGuIX (b). Although the doses of Gd are equivalent, post‐contrast images with AGuIX better depict the mass relative to Gd‐DOTA as is evident from the greater contrast‐to‐noise ratio (CNR, c) between normal liver tissue and the metastasis. Despite its greater molecular mass and size, AGuIX demonstrates enhancement kinetics comparable to a low‐molecular contrast agent (d) with a strong, early peak enhancement followed by a continuous washout.
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Schematic structure of AGuIX, which is based on a polysiloxane core and 10 DOTA species in the periphery that can bind to Gd(III) or 111In. In addition, NIR fluorophore or targeting ligands can be added enabling multimodal applications in diagnostic imaging and therapy.
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