Chemical Exchange Saturation Transfer (CEST) Agents: Quantum Chemistry and MRI

Diamagnetic chemical exchange saturation transfer (CEST) contrast agents offer an alternative to Gd³⁺‐based contrast agents for MRI. They are characterized by containing protons that can rapidly exchange with water and it is advantageous to have these protons resonate in a spectral window that is far removed from water. Herein, we report the first results of DFT calculations of the ¹H nuclear magnetic shieldings in 41 CEST agents, finding that the experimental shifts can be well predicted (R²=0.882). We tested a subset of compounds with the best MRI properties for toxicity and for activity as uncouplers, then obtained mice kidney CEST MRI images for three of the most promising leads finding 16 (2,4‐dihydroxybenzoic acid) to be one of the most promising CEST MRI contrast agents to date. Overall, the results are of interest since they show that ¹H NMR shifts for CEST agents—charged species—can be well predicted, and that several leads have low toxicity and yield good in vivo MR images.     

磁共振成像造影剂的一些进展

本文综述了近年来磁共振成像造影剂的一些研究进展,对70余种钆配合物作了分类讨论。     

磁共振成像造影剂的研究进展

磁共振成像技术已成为临床医学影像学检查的重要手段,30%以上的磁共振成像诊断需要使用造影剂,因此磁共振成像造影剂也成为一种重要的临床诊断药物.本文简单介绍磁共振成像造影剂的定义、原理和分类,并对当前的研究进展进行了的评述,认为开发具有靶向性、高弛豫效率、使用安全的造影剂是研究的主要方向.     

Osmotically Shrunken LIPOCEST Agents: An Innovative Class of Magnetic Resonance Imaging Contrast Media Based on Chemical Exchange Saturation Transfer

The peculiar properties of osmotically shrunken liposomes acting as magnetic resonance imaging–chemical exchange saturation transfer (MRI–CEST) contrast agents have been investigated. Attention has been primarily devoted to assessing the contribution arising from encapsulated and incorporated paramagnetic lanthanide(III)‐based shift reagents in determining the chemical shift of the intraliposomal water protons, which is a relevant factor for generating the CEST contrast. It is demonstrated that a highly shifted resonance for the encapsulated water can be attained by increasing the percentage of the amphiphilic shift reagent incorporated in the liposome bilayer. It is also demonstrated that the shift contribution arising from the bulk magnetic susceptibility can be optimized through the modulation of the osmotic shrinkage. In terms of sensitivity, it is shown that the saturation transfer efficiency can be significantly improved by increasing the size of the vesicle, thus allowing a high number of exchangeable protons to be saturated. In addition, the role played by the intensity of the saturating radiofrequency field has also been highlighted.     

Redox Properties and in Vivo Magnetic Resonance Imaging of Cyclodextrin-Polynitroxides Contrast Agents

This paper reports the synthesis, characterization and in vivo application of water-soluble supramolecular contrast agents (Mw: 5–5.6 kDa) for MRI obtained from β-cyclodextrin functionalized with different kinds of nitroxide radicals, both with piperidine structure ( CD2 and CD3 ) and with pyrrolidine structure ( CD4 and CD5 ). As to the stability of the radicals in presence of ascorbic acid, CD4 and CD5 have low second order kinetic constants (≤0.05 M⁻¹ s⁻¹) compared to CD2 (3.5 M⁻¹ s⁻¹) and CD3 (0.73 M⁻¹ s⁻¹). Relaxivity (r₁) measurements on compounds CD3 - CD5 were carried out at different magnetic field strength (0.7, 3, 7 and 9.4 T). At 0.7 T, r₁ values comprised between 1.5 mM⁻¹ s⁻¹ and 1.9 mM⁻¹ s⁻¹ were found while a significant reduction was observed at higher fields (r₁≈0.6-0.9 mM⁻¹ s⁻¹ at 9.4 T). Tests in vitro on HEK293 human embryonic kidney cells, L929 mouse fibroblasts and U87 glioblastoma cells indicated that all compounds were non-cytotoxic at concentrations below 1 μmol mL⁻¹. MRI in vivo was carried out at 9.4 T on glioma-bearing rats using the compounds CD3 - CD5 . The experiments showed a good lowering of T₁ relaxation in tumor with a retention of the contrast for at least 60 mins confirming improved stability also in vivo conditions.     

Mn2＋-NaY型分子筛作为口服胃肠道MRI造影剂的研究

用离子交换法制备了Mn^2＋交换的NaY分子筛MnNaY, 用红外光谱(IR)和X射线粉末衍射(XRD)等方法进行了表征. 研究了Mn^2＋含量为3.2%的样品在酸性水溶液中的稳定性和离子交换选择性. 弛豫时间测量和体内磁共振成像实验表明其弛豫效率变化范围为4.9～9.7 mmol•L•s^－1, 高于目前临床所用造影剂Gd-DTPA, 对胃部MRI信号具有良好的增强效果. 它是比较好的潜在口服胃肠道造影剂.     

pH响应的磁共振成像造影剂的研究进展

pH响应的磁共振成像(MRI)造影剂不仅能够对病变部位进行特异性增强成像,提高MRI检测疾病的灵敏度,而且可通过检测病变组织中的pH变化,为疾病的诊断提供依据。本文综述了pH响应的MRI造影剂的研究进展,介绍了其pH响应机理、种类与结构及应用,并对它的发展前景做了展望。     

Cleaved Iron Oxide Nanoparticles as T2 Contrast Agents for Magnetic Resonance Imaging

Iron oxide nanoparticles as contrast agents are reported to effectively improve magnetic resonance imaging of tissues and cells. In this work, cleaved iron oxide nanoparticles (CIONPs) were generated from hydrophobic FeO nanoparticles (HIONPs) by coating their surfaces with PEG‐phospholipids, oxidizing them under water, and slowly removing the residual FeO phase in phthalate buffer. The synthesized CIONPs showed good r₂ values of up to 258 s^?1 mM ^?1. Thus, the CIONPs can be employed as vectors for drug delivery due to their unique structure with an empty inner space, which enables their use in a wide range of applications.     

Studies on Hepatocyte-Targeting Magnetic Resonance Imaging Macromolecular Contrast Media

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Highly Loaded Semipermeable Nanocapsules for Magnetic Resonance Imaging

Magnetic resonance imaging has become an essential tool in medicine for the investigation of physiological processes. The key issues related to contrast agents, i.e., substances that are injected in the body for imaging, are the efficient enhancement of contrast, their low toxicity, and their defined biodistribution. Polyurea nanocapsules containing the gadolinium complex Gadobutrol as a contrast agent in high local concentration and high relaxivity up to 40 s⁻¹ mmol⁻¹ L are described. A high concentration of the contrast agent inside the nanocapsules can be ensured by increasing the crystallinity in the shell of the nanocapsules. Nanocapsules from aliphatic polyurea are found to display higher crystallinity and higher relaxivity at an initial Gadobutrol concentration of 0.1 m than aromatic polyurea nanocapsules. The nanocapsules and the contrast agent are clearly identified in cells. After injection, the nanocarriers containing the contrast agent are mostly found in the liver and in the spleen, which allow for a significant contrast enhancement in magnetic resonance imaging.     

One-pot Synthesis of PEGylated Gd-based Nanoparticles as High-performance and Biocompatibility Contrast Agents for T1-Weighted Magnetic Resonance Imaging In vivo

Polyethylene glycol modified(PEGylated) NaGdF4(PEG-NaGdF4) nanoparticles as a novel T1-weighted magnetic resonance imaging(MRI) contrast agent was successfully constructed by a one-pot hydrothermal synthesis method. Because of the functionalization of PEG, the nanoprobes had excellent dispersity, excellent stability and high biocompatibility. More importantly, the as-prepared PEG-NaGdF4 nanoprobes revealed the high longitudinal relaxivity value and prominent -weighted MRI contrast performance, which was superior to the commercial MRI contrast agents. With the facile synthesis, excellent dispersity, outstanding stability, remarkable contrast performance and high biocompatibility, the PEGylated NaGdF4 nanoparticles brought more opportunities to the new generation of nanoparticulate-based T1-weighted MRI contrast agents in clinic.     

温度和pH敏感高分子含钆核磁共振成像造影剂的合成及性能

以N-异丙基丙烯酰胺为温度敏感单体,以甲基丙烯酸为p H敏感单体,与三丙烯酸菲洛啉钆进行无皂乳液聚合,一步合成了具有温度和pH敏感的高分子含钆核磁共振成像(MRI)造影剂(TPRPP).动态光散射测试结果表明,TPRPP的粒径随温度或p H值的变化而发生较大的改变.体外MRI测试结果表明,TPRPP的横向弛豫时间(T_1)的加权弛豫率约为11.3 L/(mmol·s),为临床造影剂Magnevist~的2.6倍.体内MRI结果表明,TPRPP在肝和脾中具有明显的正增强效果.研究结果表明,TPRPP是一种优异的多功能MRI造影剂,具有极大的临床研究价值.     

Superfine Magnetic Resonance Imaging of the Cerebrovasculature Using Self‐Assembled Branched Polyethylene Glycol–Gd Contrast Agent

Magnetic resonance angiography is an attractive method for the visualization of the cerebrovasculature, but small‐sized vessels are hard to visualize with the current clinically approved agents. In this study, a polymeric contrast agent for the superfine imaging of the cerebrovasculature is presented. Eight‐arm polyethylene glycol with a molecular weight of ≈17 000 Da conjugated with a Gd chelate and fluorescein (F‐8‐arm PEG‐Gd) is used. The relaxivity rate is 9.3 × 10⁻³m ⁻¹ s⁻¹, which is threefold higher than that of free Gd chelate. Light scattering analysis reveals that F‐8‐arm PEG‐Gd is formed by self‐assembly. When the F‐8‐arm PEG‐Gd is intravenously injected, cerebrovasculature as small as 100 µm in diameter is clearly visualized. However, signals are not enhanced when Gd chelate and Gd chelate‐conjugated 8‐arm PEG are injected. Furthermore, small vasculature around infarct region in rat stroke model can be visualized. These results suggest that F‐8‐arm PEG‐Gd enhances the MR imaging of cerebrovasculature.     

Carbon Dots as a New Class of Diamagnetic Chemical Exchange Saturation Transfer (diaCEST) MRI Contrast Agents

While carbon dots (C‐dots) have been extensively investigated pertaining to their fluorescent, phosphorescent, electrochemiluminescent, optoelectronic, and catalytic features, their inherent chemical exchange saturation transfer magnetic resonance imaging (CEST MRI) properties are unknown. By virtue of their hydrophilicity and abundant exchangeable protons of hydroxyl, amine, and amide anchored on the surface, we report here that C‐dots can be adapted as effective diamagnetic CEST (diaCEST) MRI contrast agents. As a proof‐of‐concept demonstration, human glioma cells were labeled with liposomes with or without encapsulated C‐dots and implanted in mouse brain. In vivo CEST MRI was able to clearly differentiate labeled cells from non‐labeled cells. The present findings may encourage new applications of C‐dots for in vivo imaging in deep tissues, which is currently not possible using conventional fluorescent (near‐infrared) C‐dots.     

水溶性金属卟啉肿瘤靶向磁共振成像造影剂的研究

利用显微荧光－阿达玛变换三维图像分析研究了Ｃｕ－ＴＳＰＰ，Ｍｎ－ＴＳＰＰ，Ｃｕ－ＴＭＡＰ，Ｍｎ－ＴＭＡＰ４种水溶性金属卟啉人细胞间质进入肿瘤细胞内的富集过程，对金属卟啉的自旋－晶格驰豫性能（Ｒ１）的天空结果表明，Ｍｎ（Ⅱ）卟啉配合物的Ｒ１、值结Ｇｄ－ＤＴＰＡ提高１．５－２倍。     

以阿拉伯半乳聚糖为载体的磁共振成像造影剂的研究

合成了阿拉伯半乳聚糖修饰的DTPA钆配合物,用红外光谱、元素分析、ICP-AES等手段进行了表征,用竞争性方法研究了其在水溶液中的稳定性,测试了其在水中及BSA溶液中的弛豫性能,并进行了体内成像实验.结果表明,其弛豫效率是目前临床所用造影剂Gd-DTPA的1.5～2.0倍,对肝脏和肾脏MRI信号具有良好的增强效果,是比较好的潜在磁共振成像造影剂.     

Rapid Determination of Fast Protein Dynamics from NMR Chemical Exchange Saturation Transfer Data

Functional motions of ¹⁵N‐labeled proteins can be monitored by solution NMR spin relaxation experiments over a broad range of timescales. These experiments however typically take of the order of several days to a week per protein. Recently, NMR chemical exchange saturation transfer (CEST) experiments have emerged to probe slow millisecond motions complementing R_1ρ and CPMG‐type experiments. CEST also simultaneously reports on site‐specific R₁ and R₂ parameters. It is shown here how CEST‐derived R₁ and R₂ relaxation parameters can be measured within a few hours at an accuracy comparable to traditional relaxation experiments. Using a “lean” version of the model‐free approach S² order parameters can be determined that match those from the standard model‐free approach applied to ¹⁵N R₁, R₂, and {¹H}‐¹⁵N NOE data. The new methodology, which is demonstrated for ubiquitin and arginine kinase (42 kDa), should serve as an effective screening tool of protein dynamics from picosecond‐to‐millisecond timescales.