“Molecular” MR imaging at high fields

Magnetic resonance imaging (MRI) and spectroscopy (MRS) have contributed considerably to clinical radiology, and a variety of MR techniques have been developed to evaluate pathological processes as well as normal tissue biology at the cellular and molecular level. However, in comparison to nuclear imaging, MRI has relatively poor sensitivity for detecting true molecular changes or for detecting the presence of targeted contrast agents, though these remain under active development. In recent years very high field (7 T and above) MRI systems have been developed for human studies and these provide new opportunities and technical challenges for molecular imaging. We identify 5 types of intrinsic contrast mechanisms that do not require the use of exogenous agents but which can provide molecular and cellular information. We can derive information on tissue composition by (i) imaging different nuclei, especially sodium (ii) exploiting chemical shift differences as in MRS (iii) exploiting specific relaxation mechanisms (iv) exploiting tissue differences in the exchange rates of molecular species such as amides or hydroxyls and (v) differences in susceptibility. The increased signal strength at higher fields enables higher resolution images to be acquired, along with increased sensitivity to detecting subtle effects caused by molecular changes in tissues.     

Dynamic imaging with MRI contrast agents: quantitative considerations

Time-resolved MRI has had enormous impact in cognitive science and may become a significant tool in basic biological research with the application of new molecular imaging agents. In this paper, we examine the temporal characteristics of MRI contrast agents that could be used in dynamic studies. We consider "smart" T1 contrast agents, T2 agents based on reversible aggregation of superparamagnetic nanoparticles and sensors that produce changes in saturation transfer effects (chemical exchange saturation transfer, CEST). We discuss response properties of several agents with reference to available experimental data, and we develop a new theoretical model that predicts the response rates and relaxivity changes of aggregation-based sensors. We also perform calculations to define the extent to which constraints on temporal resolution are imposed by the imaging methods themselves. Our analysis confirms that some small T1 agents may be compatible with MRI temporal resolution on the order of 100 ms. Nanoparticle aggregation T2 sensors are applicable at much lower concentrations, but are likely to respond on a single second or slower timescale. CEST agents work at high concentrations and temporal resolutions of 1-10 s, limited by a requirement for long presaturation periods in the MRI pulse sequence.     

Synthetic and biogenic magnetite nanoparticles for tracking of stem cells and dendritic cells

Accurate delivery of cells to target organs is critical for success of cell-based therapies with stem cells or immune cells such as antigen-presenting dendritic cells (DC). Labeling with contrast agents before implantation provides a powerful means for monitoring cellular migration using magnetic resonance imaging (MRI). In this study, we investigated the uptake of fully synthesized or bacterial magnetic nanoparticles (MNPs) into hematopoietic Flt3⁺ stem cells and DC from mouse bone marrow. We show that (i) uptake of both synthetic and biogenic nanoparticles into cells endow magnetic activity and (ii) low numbers of MNP-loaded cells are readily detected by MRI.     

Comparison of fast field-cycling magnetic resonance imaging methods and future perspectives

ABSTRACT

Fast field-cycling (FFC) nuclear magnetic resonance relaxometry is a well-established method to determine the relaxation rates as a function of magnetic field strength. This so-called nuclear magnetic relaxation dispersion gives insight into the underlying molecular dynamics of a wide range of complex systems and has gained interest especially in the characterisation of biological tissues and diseases. The combination of FFC techniques with magnetic resonance imaging (MRI) offers a high potential for new types of image contrast more specific to pathological molecular dynamics. This article reviews the progress in FFC-MRI over the last decade and gives an overview of the hardware systems currently in operation. We discuss limitations and error correction strategies specific to FFC-MRI such as field stability and homogeneity, signal-to-noise ratio, eddy currents and acquisition time. We also report potential applications with impact in biology and medicine. Finally, we discuss the challenges and future applications in transferring the underlying molecular dynamics into novel types of image contrast by exploiting the dispersive properties of biological tissue or MRI contrast agents.     

Comparisons of EPR imaging and T1-weighted MRI for efficient imaging of nitroxyl contrast agents

The resolution and signal to noise ratio of EPR imaging and T(1)-weighted MRI were compared using an identical phantom. Several solutions of nitroxyl contrast agents with different EPR spectral shapes were tested. The feasibility of T(1)-weighted MRI to detect nitroxyl contrast agents was described. T(1)-weighted MRI can detect nitroxyl contrast agents with a complicated EPR spectrum easier and quicker; however, T(1)-weighted MRI has less quantitative ability especially for lipophilic nitroxyl contrast agents, because T(1)-relaxivity, i.e. accessibility to water, is affected by the hydrophilic/hydrophobic micro-environment of a nitroxyl contrast agent. The less quantitative ability of T(1)-weighted MRI may not be a disadvantage of redox imaging, which obtains reduction rate of a nitroxyl contrast. Therefore, T(1)-weighted MRI has a great advantage to check the pharmacokinetics of newly modified and/or designed nitroxyl contrast agents.     

Visualization of superior mesenteric lymph nodes by the combined oral and intravenous administration of the ultrasmall superparamagnetic iron oxide, AMI-227

Superior mesenteric lymph nodes which lie as a chain near the small intestine are difficult to visualize in the rat with MRI either with or without the use of contrast agents. We previously demonstrated that the oral administration of an ultrasmall superparamagnetic iron oxide (AMI-227) produces a brightening of the lumen of the GI tract with a T₁-weighted spin-echo pulse sequence. We have also shown that AMI-227 darkens abdominal lymph nodes. In the present study we show that the combined oral and intravenous administration of AMI-227 produces a brightening of the lumen of the GI tract and a darkening of the superior mesenteric lymph node chain. As a result of these combined and opposing effects on image signal intensity, a necessary contrast is established to reliably locate the superior mesenteric lymph nodes in vivo, which, to our knowledge, have been elusive by other techniques.     

Method for intracellular magnetic labeling of human mononuclear cells using approved iron contrast agents

A method for intracellular iron labeling of human mononuclear cells (lymphocytes and monocytes) for magnetic resonance imaging (MRI) using simple incubation of cells with approved MRI iron contrast agents is presented. Labeled cells can be detected by MRI in vitro, and this suggests the possibility that the technique could become a marker for in vivo lymphocyte and monocyte trafficking studies in acute inflammatory lesions such as those in Multiple Sclerosis.     

Magnetic resonance imaging of dissolved hyperpolarized Xe using a membrane-based continuous flow system

A technique for continuous production of solutions containing hyperpolarized ¹²⁹Xe is explored for MRI applications. The method is based on hollow fiber membranes which inhibit the formation of foams and bubbles. A systematic analysis of various carrier agents for hyperpolarized ¹²⁹Xe has been carried out, which are applicable as contrast agents for in vivo MRI. The image quality of different hyperpolarized Xe solutions is compared and MRI results obtained in a clinical as well as in a nonclinical MRI setting are provided. Moreover, we demonstrate the application of ¹²⁹Xe contrast agents produced with our dissolution method for lung MRI by imaging hyperpolarized ¹²⁹Xe that has been both dissolved in and outgassed from a carrier liquid in a lung phantom, illustrating its potential for the measurement of lung perfusion and ventilation.     

靶向肺癌干细胞的多肽Gd基T1型MRI探针的研究

用固相多肽合成技术制备了特异性靶向肺癌干细胞的T_1型多肽核磁共振成像(MRI)探针——Gd-DOTA-HCBP-1.在11.7 T静磁场条件下,其纵向弛豫效率(r1)为6.15 mmol~(-1)·L·s~(-1),是商用T1造影剂Dotarem的1.6倍.体外细胞成像表明,此探针的使用可显著提高肺癌干细胞克隆球的可观测性,单个克隆球(包含2 000~4 000个细胞)可被明显辨识.     

Magnetic and relaxometric properties of polyethylenimine-coated superparamagnetic MRI contrast agents

Novel systems to be employed as superparamagnetic contrast agents (CA) for magnetic resonance imaging (MRI) have been synthesized. These compounds are composed of an iron oxide magnetic core coated by polyethylenimine (PEI) or carboxylated polyethylenimine (PEI-COOH). The aim of the present work was to prepare and study new nanostructured systems (with better or at least comparable relaxivities, R₁ and R₂, with respect to the commercial ones) with controlled, almost monodisperse average dimensions and shape, as candidates for molecular targeting. By means of atomic force microscopy (AFM) measurements we determined the average diameter, of the order of 200 nm, and the shape of the particles. The superparamagnetic behavior was assessed by SQUID measurements. From X-ray data the estimated average diameters of the magnetic cores were found to be 5.8 nm for PEI-COOH60 and 20 nm for the compound named PEI25. By NMR-dispersion (NMRD), we found that PEI-COOH60 presents R₁ and R₂ relaxivities slightly lower than Endorem^®. The experimental results suggest that these novel compounds can be used as MRI CA.     

Molecular imaging contrast media for visualization of liver function

Background and Aims

Diagnosis of liver disease has improved because of progress in imaging technology. Among the imaging methods, magnetic resonance imaging (MRI) has the advantage of a lack of radiation exposure, but the basis of the method (imaging of hydrogen atoms in water molecules) makes it hard to detect changes in tissue or the location of the diseased tissue in the liver. The aims of this study are to develop new contrast media for visualization of functional changes in the liver and to check the effectiveness of the media.

Methods

We developed a new molecular imaging contrast media that targets the asialoglycoprotein receptor (ASGP-R), a membrane protein that is specific to hepatocytes. We first checked the contrast media diameter and the cytotoxicity. Next, we examined the interaction of the media with ASGP-R through observation of fluorescein isothiocyanate (FITC)-labeled molecular imaging contrast media bound to normal hepatocellular ASGP-R using confocal laser scanning microscopy. Finally, we used MRI to observe hepatocyte interactions with the molecular imaging contrast media.

Results

The contrast media forms a nanoparticle of about 30 nm diameter in aqueous solution and the cytotoxicity is low. In vitro, the media has high specificity for ASGP-R in normal rat hepatocyte RLN-8 cells and this interaction was blocked by lactose (which has a similar molecular structure to that of galactose) and by an anti-ASGP-R antibody. The contrast media markedly enhanced T1-weighted images in MRI of normal rat hepatocytes compared to the signal strength for rat liver cancer cells.

Conclusions

We have shown that our new contrast media for molecular imaging of hepatocytes by MRI is effective in vitro.     

Factors affecting nitroxide reduction in ascorbate solution and tissue homogenates

Because of their paramagnetic properties, nitroxides are potentially useful as contrast agents in magnetic resonance imaging (MRI). They are reduced in vivo to their corresponding hydroxylamines which are nonparamagnetic and have no contrast enhancing property. Nitroxides with high resistance to reduction would be advantageous as pharmaceutical contrast enhancing agents. We show that in the presence of ascorbic acid and in tissue homogenates, the reduction is faster for piperidine than for pyrrolidine nitroxides and for positively-charged than for negatively-charged derivatives. The data also suggest that nitroxide reduction in tissue homogenates is mainly due to sulfhydryl groups on proteins and that endogenous ascorbic acid plays a relatively minor role.     

Microbubbles containing gadolinium as contrast agents for both phase contrast and magnetic resonance imaging

Portal vein imaging is an important method for investigating portal venous disorders. However, the diagnostic requirements are not usually satisfied when using single imaging techniques. Diagnostic accuracy can be improved by combining different imaging techniques. Contrast agents that can be used for combined imaging modalities are needed. In this study, the feasibility of using microbubbles containing gadolinium (MCG) as contrast agents for both phase contrast imaging (PCI) and magnetic resonance imaging (MRI) are investigated. MCG were made by encapsulating sulfur hexafluoride (SF₆) gas with gadolinium and lyophilized powder. Absorption contrast imaging (ACI) and PCI of MCG were performed and compared in vitro. MCG were injected into the main portal trunk of living rats. PCI and MRI were performed at 2 min and 10 min after MCG injection, respectively. PCI exploited the differences in the refractive index and visibly showed the MCG, which were not detectable by ACI. PCI could facilitate clear revelation of the MCG‐infused portal veins. The diameter of the portal veins could be determined by the largest MCG in the same portal vein. The minimum diameter of clearly detected portal veins was about 300 µm by MRI. These results indicate that MCG could enhance both PCI and MRI for imaging portal veins. The detection sensitivity of PCI and MRI could compensate for each other when using MCG contrast agents for animals.     

Simultaneous PET–MRI in oncology: a solution looking for a problem?

With the recent development of integrated positron emission tomography–magnetic resonance imaging (PET–MRI) scanners, new possibilities for quantitative molecular imaging of cancer are realized. However, the practical advantages and potential clinical benefits of the ability to record PET and MRI data simultaneously must be balanced against the substantial costs and other requirements of such devices. In this review, we highlight several of the key areas where integrated PET–MRI measurements, obtained simultaneously, are anticipated to have a significant impact on clinical and/or research studies. These areas include the use of MR-based motion corrections and/or a priori anatomical information for improved reconstruction of PET data, improved arterial input function characterization for PET kinetic modeling, the use of dual-modality contrast agents, and patient comfort and practical convenience. For widespread acceptance, a compelling case could be made if the combination of quantitative MRI and specific PET biomarkers significantly improves our ability to assess tumor status and response to therapy, and some likely candidates are now emerging. We consider the relative advantages and disadvantages afforded by PET–MRI and summarize current opinions and evidence as to the likely value of PET–MRI in the management of cancer.     

Consistent Quantification of Complex Dynamics via a Novel Statistical Complexity Measure

Natural systems often show complex dynamics. The quantification of such complex dynamics is an important step in, e.g., characterization and classification of different systems or to investigate the effect of an external perturbation on the dynamics. Promising routes were followed in the past using concepts based on (Shannon’s) entropy. Here, we propose a new, conceptually sound measure that can be pragmatically computed, in contrast to pure theoretical concepts based on, e.g., Kolmogorov complexity. We illustrate the applicability using a toy example with a control parameter and go on to the molecular evolution of the HIV1 protease for which drug treatment can be regarded as an external perturbation that changes the complexity of its molecular evolutionary dynamics. In fact, our method identifies exactly those residues which are known to bind the drug molecules by their noticeable signal. We furthermore apply our method in a completely different domain, namely foreign exchange rates, and find convincing results as well.     

Encapsulation of gadobutrol in AVE-based liposomal carriers for MR detectability

Artificial virus-like envelopes (AVEs) are liposomal carriers that may be useful for target-site-specific delivery of contrast agents. We speculated that T(1) relaxation times of a suspension of Gadolinium-filled AVEs might be shortened after internalization and lysosomal breakdown. To test this hypothesis we evaluated the T(1) relaxation times of Gadobutrol-containing AVEs before and after degradation in vitro and after receptor-mediated cellular uptake. AVEs were filled with 1 M Gadobutrol (Gadovist; Schering AG, Berlin, Germany) yielding Gd-chelate-AVEs. T(1)-relaxation times were calculated using an inversion recovery technique for different concentrations of the liposomal suspension. AVEs were degraded in vitro to mimic the release of the encapsulated Gadolinium in cells and to determine a putative increase of the T(1)-effect. Finally, Gd-chelate-AVEs where equipped with integrin-binding RGD ligands and the T1 relaxation times of these Gd-chelate-RDG-AVEs were determined after cellular uptake into endothelial or melanoma cells. Gadobutrol could be encapsulated into AVEs at a high concentration of 1 M (Gd-chelate-AVEs). The Gd-chelate-AVEs could be visualized by MRI. Concentrations down to 1:4 x 10(3) showed a significant T(1)-shortening effect. The degradation of the liposomes with Triton X-100 resulted in a further reduction down to concentrations of 1:10 x 10(3). In addition, cellular uptakes of Gd-chelate-RGD-AVEs also lead to a significant T(1)-shortening. Our study shows that Gadolinium can be efficiently encapsulated into AVEs and that Gd-chelate-AVEs can be detected by MRI T(1)-weighted measurements. The MRI detectability is enhanced by degradation. Gd-chelate-RGD-AVEs can be used to enhance the Gd uptake in cells expressing the alpha(v)beta(3) receptor.     

Low‐Magnetization Magnetic Microcapsules: A Synergistic Theranostic Platform for Remote Cancer Cells Therapy and Imaging

Multifunctional magnetic microcapsules (MMCs) for the combined cancer cells hyperthermia and chemotherapy in addition to MR imaging are successfully developed. A classical layer‐by‐layer technique of oppositely charged polyelectrolytes (poly(allylamine hydrochloride) (PAH) and poly(4‐styrene sulfonate sodium) (PSS)) is used as it affords great controllability over the preparation together with enhanced loading of the chemotherapeutic drug (doxorubicin, DOX) in the microcapsules. Superparamagnetic iron oxide (SPIOs) nanoparticles are layered in the system to afford MMC1 (one SPIOs layer) and MMC2 (two SPIOs layers). Most interestingly, MMC1 and MMC2 show efficient hyperthermia cell death and controlled DOX release although their magnetic saturation value falls below 2.5 emu g^?1, which is lower than the 7–22 emu g^?1 reported to be the minimum value needed for biomedical applications. Moreover, MMCs are pH responsive where a pH 5.5 (often reported for cancer cells) combined with hyperthermia increases DOX release predictably. Both systems prove viable when used as T2 contrast agents for MR imaging in HeLa cells with high biocompatibility. Thus, MMCs hold a great promise to be used commercially as a theranostic platform as they are controllably prepared, reproducibly enhanced, and serve as drug delivery, hyperthermia, and MRI contrast agents at the same time.     

生物激活磁共振成像造影剂的研究进展

介绍了磁共振成像新一代造影剂--生物激活造影剂（亦称之为“酶激活”、“生物应答”或“智能型”造影剂）的研究进展.主要讲述了这类造影剂的设计原理、性能与作用. 它们主要分别对生物体内的酶、金属离子浓度、pH等敏感.     

Euterpe Olerácea (Açaí) as an alternative oral contrast agent in MRI of the gastrointestinal system: preliminary results

Using contrast agents is a common practice in medical imaging protocols. Paramagnetic properties of certain compounds present in contrast agents can affect magnetic resonance imaging (MRI) signals. For abdominal applications, they are usually injected, but may also be administered orally. However, their use as a routine technique is limited, mainly due to the lack of appropriate oral contrast agents. We herein present the preliminary characterization and results for implementation of Euterpe Olerácea (popularly named A?aí) as a possible clinical oral contrast agent for MRI of the gastrointestinal tract. The pulp of A?aí, a fruit from the Amazon area, presented an increase in T(1)-weighted MRI signal, equivalent to that of gadolinium-diethyltriamine pentaacetic acid, and a decrease in T(2)-weighted images. We looked for intrinsic properties that could be responsible for the T(1) signal enhancement and T(2) opacification. Atomic absorption spectra revealed the presence of Fe, Mn and Cu ions in A?ai. The presence of such ions contribute to the susceptometric value found of chi = -4.83 x 10(-6). This finding assents with the hypothesis that image contrast changes were due to the presence of paramagnetic material. The first measurements in vivo demonstrate a clear increase of contrast, in T(1)-weighted images, due to the presence of A?aí. Consistently, the opacification in a T(2)-weighted acquisition was evident, revealing a good contrast on bowel walls of gastric tissues.     

Tracking of transplanted mesenchymal stem cells labeled with fluorescent magnetic nanoparticle in liver cirrhosis rat model with 3-T MRI

In vivo visualization of transplanted stem cells with noninvasive technique is essential for the monitoring of cell implantation, homing and differentiation. At present, superparamagnetic iron oxide (SPIO) is most commonly used for cell labeling. However, stem cells lack phagocytic capacity and transfection agent is required for sufficient internalization of SPIO for cellular imaging. However, the potential hazards of transfection agents are not fully investigated. Instead of SPIO, we used commercially available new tagging material, fluorescent magnetic nanoparticle (MNP) containing rhodamine B isothiocyanate within a silica shell (Biterials, Seoul, Korea). This tagging material does not require transfection agents for the cell labeling. In addition to that, the core of this MNP is composed of ferrite and the inner portion of silica shell contains fluorescent materials, therefore, it has both magnetic and optical features. This study was designed to track intrasplenically injected bone marrow mesenchymal stem cells (MSCs) labeled with fluorescent MNP in liver cirrhosis rat model with 3-T magnetic resonance equipment. We compared magnetic resonance imaging (MRI) of livers in rats which were injected with non-labeled stem cells or labeled stem cells with MNP or SPIO. We found that the respective liver-to-muscle contrast-to-noise ratios at 3 and 5 h after MNP or SPIO-labeled stem cell injection was significantly lower than that of pre-injection and non-labeled group. There was no significant difference between MNP-labeled group and SPIO-labeled group. We can effectively detect intrasplenically injected MNP-labeled MSCs in an experimental rat model of liver cirrhosis with 3-T MRI.