Real‐time 3D MRI of contrast agents in whole living mice

A specific mouse whole body coil and a dedicated gradient system at 4.7 T were coupled with an ultra‐fast 3D gradient echo MRI and keyhole reconstruction technique to obtain 3D whole‐body dynamic T₁‐weighted or T₂*‐weighted imaging. The technique was used to visualize the real‐time distribution of non‐targeting T₁ and T₂* contrast agent (CA) in a glioma‐bearing mouse model. T₁ dynamic contrast‐enhancement imaging was performed with a fast imaging with steady‐state precession sequence [echo time/repetition time (TE/TR), 1.32/3.7 ms] before and after CA injection (Gd–DOTA and BSA–Gd–DOTA) for 21 min. The temporal resolution was 1 image/6.5 s. T₂* imaging (TE/TR, 4/8 ms) was performed before and after iron‐based (small and ultra‐small particles of iron oxide) CA injection for 45 min. The temporal resolution was 1 image/14 s. Signal‐to‐noise ratio curves were determined in various mouse organs. The whole‐body coil and gradient systems made it possible to acquire data with sufficient and homogeneous signal‐to‐noise ratio on the whole animal. The spatial resolution allowed adequate depiction of the major organs, blood vessels and brain glioma. The distribution and the time‐course of T₁ and T₂* contrasts upon contrast agent injection were also assessed. 3D whole‐body mouse MRI is feasible at high spatial resolution in movie mode and can be applied successfully to visualize real‐time contrast agent distribution. This method should be effective in future preclinical molecular imaging studies. Copyright © 2011 John Wiley & Sons, Ltd.     

A self‐calibrating PARACEST MRI contrast agent that detects esterase enzyme activity

The CEST effect of many PARACEST MRI contrast agents changes in response to a molecular biomarker. However, other molecular biomarkers or environmental factors can influence CEST, so that a change in CEST is not conclusive proof for detecting the biomarker. To overcome this problem, a second control CEST effect may be included in the same PARACEST agent, which is responsive to all factors that alter the first CEST effect except for the biomarker to be measured. To investigate this approach, a PARACEST MRI contrast agent was developed with one CEST effect that is responsive to esterase enzyme activity and a second control CEST effect. The ratio of the two CEST effects was independent of concentration and T₁ relaxation, so that this agent was self‐calibrating with respect to these factors. This ratiometric method was dependent on temperature and was influenced by MR coalescence as the chemical exchange rates approached the chemical shifts of the exchangable protons as temperature was increased. The two CEST effects also showed evidence of having different pH dependencies, so that this agent was not self‐calibrating with respect to pH. Therefore, a self‐calibrating PARACEST MRI contrast agent can more accurately detect a molecular biomarker such as esterase enzyme activity, as long as temperature and pH are within an acceptable physiological range and remain constant. Copyright © 2010 John Wiley & Sons, Ltd.     

Connexin 43‐targeted T1 contrast agent for MRI diagnosis of glioma

Glioblastoma multiforme is the most aggressive form of brain tumor. Early and accurate diagnosis of glioma and its borders is an important step for its successful treatment. One of the promising targets for selective visualization of glioma and its margins is connexin 43 (Cx43), which is highly expressed in reactive astrocytes and migrating glioma cells. The purpose of this study was to synthesize a Gd‐based contrast agent conjugated with specific antibodies to Cx43 for efficient visualization of glioma C6 in vivo. We have prepared stable nontoxic conjugates of monoclonal antibody to Cx43 and polylysine–DTPA ligands complexed with Gd(III), which are characterized by higher T₁ relaxivity (6.5 mM^?1 s^?1 at 7 T) than the commercial agent Magnevist® (3.4 mM^?1 s^?1). Cellular uptake of Cx43‐specific T₁ contrast agent in glioma C6 cells was more than four times higher than the nonspecific IgG‐contrast agent, as detected by flow cytometry and confocal analysis. MRI experiments showed that the obtained agents could markedly enhance visualization of glioma C6 in vivo after their intravenous administration. Significant accumulation of Cx43‐targeted contrast agents in glioma and the peritumoral zone led not only to enhanced contrast but also to improved detection of the tumor periphery. Fluorescence imaging confirmed notable accumulation of Cx43‐specific conjugates in the peritumoral zone compared with nonspecific IgG conjugates at 24 h after intravenous injection. All these features of Cx43‐targeted contrast agents might be useful for more precise diagnosis of glioma and its borders by MRI. Copyright © 2015 John Wiley & Sons, Ltd.     

Specific E‐selectin targeting with a superparamagnetic MRI contrast agent

Targeting of the endothelial inflammatory adhesion molecule E‐selectin by magnetic resonance imaging (MRI) was performed with a superparamagnetic contrast agent in the context of in vitro and in vivo models of inflammation. The specific contrast agent was obtained by grafting a synthetic mimetic of sialyl Lewis^x (sLe^x), a natural ligand of E‐selectin expressed on leukocytes, on the dextran coating of ultrasmall particles of iron oxide (USPIO). This new contrast agent, called USPIO‐g‐sLe^x, was tested, in vitro, on cultured human umbilical vein endothelial cells (HUVECs) stimulated to express inflammatory adhesion molecules, and in vivo, on a mouse model of hepatitis. In vitro, HUVECs were stimulated with the pro‐inflammatory cytokine tumor necrosis factor alpha (TNF‐α) and were then incubated with USPIO‐g‐sLe^x or ungrafted USPIO. In vivo, hepatitis was induced on NMRI mice by injection of concanavalin A (Con A). USPIO‐g‐sLe^x and ungrafted USPIO were injected intravenously. In vitro results showed an extensive retention of USPIO‐g‐sLe^x on TNF‐α stimulated HUVECs. Image intensity and R₂ measurements performed on T₂‐weighted MR images demonstrated a significantly higher binding of USPIO‐g‐sLe^x on stimulated HUVECs. In vivo, USPIO are known to pass through the fenestrae of the liver and to be captured by Kupffer cells, inducing a loss of signal intensity on T₂‐weighted MR images. Unexpectedly, when injected to Con A‐treated mice, USPIO‐g‐sLe^x induced a significantly lower attenuation of liver signal intensity than USPIO or USPIO‐g‐sLe^x injected to healthy mice, or USPIO injected to Con A‐treated mice, suggesting that the specific contrast media is retained extracellularly by an interaction with E‐selectin overexpressed on the vascular endothelium. Both in vitro and in vivo results therefore indicate that USPIO‐g‐sLe^x is recognizing endothelial E‐selectin. USPIO‐g‐sLe^x is thus well suited for the MRI diagnosis of inflammation and for the in vitro evaluation of endothelial cells activation. Copyright © 2006 John Wiley & Sons, Ltd.     

Main applications of hybrid PET‐MRI contrast agents: a review

In medical imaging, the continuous quest to improve diagnostic performance and optimize treatment strategies has led to the use of combined imaging modalities. Positron emission tomography (PET) and computed tomography (CT) is a hybrid imaging existing already for many years. The high spatial and contrast resolution of magnetic resonance imaging (MRI) and the high sensitivity and molecular information from PET imaging are leading to the development of this new hybrid imaging along with hybrid contrast agents. To create a hybrid contrast agent for PET‐MRI device, a PET radiotracer needs to be combined with an MRI contrast agent. The most common approach is to add a radioactive isotope to the surface of a small superparamagnetic iron oxide (SPIO) particle. The resulting agents offer a wide range of applications, such as pH variation monitoring, non‐invasive angiography and early imaging diagnosis of atherosclerosis. Oncology is the most promising field with the detection of sentinel lymph nodes and the targeting of tumor neoangiogenesis. Oncology and cardiovascular imaging are thus major areas of development for hybrid PET‐MRI imaging systems and hybrid contrast agents. The aim is to combine high spatial resolution, high sensitivity, morphological and functional information. Future prospects include the use of specific antibodies and hybrid multimodal PET‐MRI‐ultrasound‐fluorescence imaging with the potential to provide overall pre‐, intra‐ and postoperative patient care. Copyright © 2015 John Wiley & Sons, Ltd.     

New synthesis of a high molecular weight ligand derived from dota; thermodynamic stability of the MRI contrast agent formed with gadolinium

The new total synthesis in four steps of the compound P1041 is reported. This compound is a high molecular mass ligand (MW 6.32 kDa) derived from dota in which the four substituents are hydroxylated and contain amidic groups. The attribution of the nine protonation constants of P1041 is based on the comparison with the behaviour of the precursor ligands dota and tced, a tetracarboxylated derivative of dota. From these results, the studies of the systems P1041/Na⁺ and P1041/Gd³⁺ lead to the determination of the stability constants corresponding to the three species Na(P1041)H_h (h = 0, 2 or 4) and to the five complexes Gd(P1041)H_h (h = 0, 2, 3, 4 or 5). The complexing ability of P1041 towards Gd³⁺ is compared with those of dota and tced. At physiological pH = 7.4, the very stable species Gd(P1041)H (currently named P792 in the literature) of this rapid clearance blood pool agent is predominant. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis and characterization of a porphyrazine–Gd(III) MRI contrast agent and in vivo imaging of a breast cancer xenograft model

Porphyrazines (Pz), or tetraazaporphyrins, are being studied for their potential use in detection and treatment of cancer. Here, an amphiphilic Cu–Pz–Gd(III) conjugate has been prepared via azide–alkyne Huisgen cycloaddition or ‘click’ chemistry between an azide functionalized Pz and alkyne functionalized DOTA–Gd(III) analog for use as an MRI contrast agent. This agent, Cu–Pz–Gd(III), is synthesized in good yield and exhibits solution‐phase ionic relaxivity (r₁ = 11.5 mm ^?1 s^?1) that is approximately four times higher than that of a clinically used monomeric Gd(III) contrast agent, DOTA–Gd(III). Breast tumor cells (MDA‐MB‐231) associate with Cu–Pz–Gd(III) in vitro, where significant contrast enhancement (9.336 ± 0.335 contrast‐to‐noise ratio) is observed in phantom cell pellet MR images. This novel contrast agent was administered in vivo to an orthotopic breast tumor model in athymic nude mice and MR images were collected. The average T₁ of tumor regions in mice treated with 50 mg kg^?1 Cu–Pz–Gd(III) decreased relative to saline‐treated controls. Furthermore, the decrease in T₁ was persistent relative to mice treated with the monomeric Gd(III) contrast agent. An ex vivo biodistribution study confirmed that Cu–Pz–Gd(III) accumulates in the tumors and is rapidly cleared, primarily through the kidneys. Differential accumulation and T₁ enhancement by Cu–Pz–Gd(III) in the tumor's core relative to the periphery offer preliminary evidence that this agent would find application in the imaging of necrotic tissue. Copyright © 2014 John Wiley & Sons, Ltd.     

Multi‐modal magnetic resonance imaging and histology of vascular function in xenografts using macromolecular contrast agent hyperbranched polyglycerol (HPG‐GdF)

Macromolecular gadolinium (Gd)‐based contrast agents are in development as blood pool markers for MRI. HPG‐GdF is a 583 kDa hyperbranched polyglycerol doubly tagged with Gd and Alexa 647 nm dye, making it both MR and histologically visible. In this study we examined the location of HPG‐GdF in whole‐tumor xenograft sections matched to in vivo DCE‐MR images of both HPG‐GdF and Gadovist. Despite its large size, we have shown that HPG‐GdF extravasates from some tumor vessels and accumulates over time, but does not distribute beyond a few cell diameters from vessels. Fractional plasma volume (fPV) and apparent permeability–surface area product (aPS) parameters were derived from the MR concentration–time curves of HPG‐GdF. Non‐viable necrotic tumor tissue was excluded from the analysis by applying a novel bolus arrival time (BAT) algorithm to all voxels. aPS derived from HPG‐GdF was the only MR parameter to identify a difference in vascular function between HCT116 and HT29 colorectal tumors. This study is the first to relate low and high molecular weight contrast agents with matched whole‐tumor histological sections. These detailed comparisons identified tumor regions that appear distinct from each other using the HPG‐GdF biomarkers related to perfusion and vessel leakiness, while Gadovist‐imaged parameter measures in the same regions were unable to detect variation in vascular function. We have established HPG‐GdF as a biocompatible multi‐modal high molecular weight contrast agent with application for examining vascular function in both MR and histological modalities. Copyright © 2015 John Wiley & Sons, Ltd.     

Nano assembly and encapsulation; a versatile platform for slowing the rotation of polyanionic Gd3+‐based MRI contrast agents

Encapsulating discrete Gd³⁺ chelates in nano‐assembled capsules (NACs) is a simple and effective method of preparing an MRI contrast agent capable of delivering a large payload of high relaxivity imaging agent. The preparation of contrast agent containing NACs had previously focussed on preparations incorporating GdDOTP^5‐ into the internal aggregate. In this report we demonstrate that other Gd³⁺ chelates bearing overall charges as low as 2‐ can also be used to prepare NACs. This discovery opens up the possibility of using Gd³⁺ chelates that have inner‐sphere water molecules that could further increase the relaxivity enhancement associated with the long τ_R that arises from encapsulation. However, encapsulation of the q = 1 chelate GdDTPA^2‐ did not give rise to a significant increase in relaxivity relative to encapsulation of the outer‐sphere chelate GdTTHA^3‐. This leads us to the conclusion that in the NAC interior proton transport is not mediated by movement of whole water molecules and the enhanced relaxivity of Gd³⁺ chelate encapsulated within NACs arises primarily from second sphere effects. Copyright © 2015 John Wiley & Sons, Ltd.     

Characterization of MRI contrast agent‐loaded polymeric nanocapsules as versatile vehicle for targeted imaging

Various contrast agents (Magnevist®, Gadovist® and Multihance®) loaded into polymeric nanocapsules were synthesized by the inverse miniemulsion technique. The relaxivity of the resultant contrast agents was assessed at 1.5 T magnetic field strength. The ionic relaxivity of the contrast agents could at least be maintained after their encapsulation in different polymer capsules. The chemical composition of the nanocapsules was characterized by Fourier transform infrared spectroscopy. The distribution of the contrast agent in the nanocapsules could be identified by energy filtered transmission electron microscopy and energy dispersive X‐ray spectroscopy. The results indicate entrapment of the gadolinium complex into the inner shell of the polymeric nanocapsules. The payload of contrast agent per nanocapsule resulted in some 2.5 × 10⁶ Gd³⁺ complexes yielding a particle‐based relaxivity of 10.75 × 10⁶ mM ^?1 s^?1. Maintained or even slightly increased ionic relaxivity of the different contrast agents after encapsulation in combination with high payloads and the possibility of functionalization of the capsules' surface facilitate the application of the nanocapsules as promising targeted contrast agents for MRI. Copyright © 2010 John Wiley & Sons, Ltd.     

Novel Gd(III)‐based probes for MR molecular imaging of matrix metalloproteinases

Two novel Gd‐based contrast agents (CAs) for the molecular imaging of matrix metalloproteinases (MMPs) were synthetized and characterized in vitro and in vivo. These probes were based on the PLG*LWAR peptide sequence, known to be hydrolyzed between Gly and Leu by a broad panel of MMPs. A Gd–DOTA chelate was conjugated to the N‐terminal position through an amide bond, either directly to proline (compd Gd–K11) or through a hydrophilic spacer (compd Gd–K11N). Both CA were made strongly amphiphilic by conjugating an alkyl chain at the C‐terminus of the peptide sequence. Gd–K11 and Gd–K11N have a good affinity for β‐cyclodextrins (K_D 310 and 670 µ m respectively) and for serum albumin (K_D 350 and 90 µ m respectively), and can be efficiently cleaved in vitro at the expected site by MMP‐2 and MMP‐12. Upon MMP‐dependent cleavage, the CAs lose the C‐terminal tetrapeptide and the alkyl chain, thus undergoing to an amphiphilic‐to‐hydrophilic transformation that is expected to alter tissue pharmacokinetics. To prove this, Gd–K11 was systemically administered to mice bearing a subcutaneous B16.F10 melanoma, either pre‐treated or not with the broad spectrum MMP inhibitor GM6001 (Ilomastat). The washout of the Gd‐contrast enhancement in MR images was significantly faster for untreated subjects (displaying MMP activity) with respect to treated ones (MMP activity inhibited). The washout kinetics of Gd‐contrast enhancement from the tumor microenvironment could be then interpreted in terms of the local activity of MMPs. Copyright © 2012 John Wiley & Sons, Ltd.     

In‐vivo high‐resolution X‐ray microtomography for liver and spleen tumor assessment in mice

The present study sought to validate the use of glycery1‐2‐oley‐1,3‐bis‐[7‐(3‐amino‐2,4,6‐triiodophenyl)‐ heptanoate] (DHOG) contrast agent for mouse spleen tumor and liver metastasis imaging by high‐resolution X‐ray microtomography. Three groups of female nude mice were compared: controls (n = 5), and mice injected with 2.5 × 10⁶ STC1 tumor cells in the spleen, imaged at 15 days (group G15, n = 5) and at 30 days (group G30, n = 5, of which one died before imaging). Micro‐CT scans (X‐ray voltage, 50 kVp; anode current, 200 µA; exposure time, 632 ms; 180 rotational steps resulting in 35 µm isotropic spatial resolution) were acquired at 0, 0.75, 2 and 4 h after i.v. injection of DHOG. CT number (Hounsfield units: HU) and contrast‐to‐noise ratios (CNR) were determined in three organs. Statistical analysis was performed by Mann–Whitney U‐test. Contrast enhancement in normal spleen and liver increased, respectively to 1020 ± 159 and 351 ± 27 HU over baseline at 4 h, and 482 ± 3 and 203 ± 14 HU on day 6 after a single contrast injection. Automated three‐dimensional reconstruction and modeling of the spleen provided accurate and quantifiable images. Spleen tumor and liver metastases did not take up DHOG, making them detectable in contrast to the increased signal in normal tissue. The smallest liver metastasis detected measured 0.3 mm in diameter. High‐resolution X‐ray micro‐CT in living mice using DHOG contrast agent allowed visualization and volume quantification of normal spleen and of spleen tumor and its liver metastases. Copyright © 2007 John Wiley & Sons, Ltd.     

CT增强扫描中不同浓度碘对比剂所致不良反应观察及护理

目的对CT增强扫描中不同浓度碘对比剂所致不良反应观察及护理,从而为临床不同浓度碘对比所致的不良反应的预后提供依据。方法对本院需要进行CT增强扫描检查的1 328例患者进行分析,按照增强扫描所用的碘的浓度不同分为2组,A组660例采用碘海醇350mg I/m L进行常规扫描,B组668例采用碘克沙醇270 mg I/m L,观察2组患者在增强扫描中所出现的不良反应,以及针对所出现的不良反应进行针对性的护理措施。结果 A组有7例发生不同程度的不良反应,发生率为1.06%;B组有5例发生不同程度的不良反应,发生率为0.75%,2组不良反应发生率相比,差异有统计学意义(P0.05)。对本组研究中所出现的不同程度的过敏反应及对比剂的外渗现象按照本科室的抢救流程均获得成功救治,无死亡病例,且对比剂外渗现象都得到妥善处理。结论采用碘克沙醇270 mg I/m L作为对比剂在CT增强扫描中不良反应发生率较常规的碘海醇350 mg I/m L要低,且在发生不良反应时需要医务人员熟练掌握抢救技术,在不良反应发生时在最短的时间内进行处理,是提高成功救治率的关键,也是保证患者顺利完成检查的必要手段。     

Polyglycerol‐grafted superparamagnetic iron oxide nanoparticles: highly efficient MRI contrast agent for liver and kidney imaging and potential scaffold for cellular and molecular imaging

Polyglycerol as a water‐soluble and biocompatible hyperbranched polymer was covalently grafted on the surface of superparamagnetic iron oxide nanoparticles. With this aim, superparamagnetic magnetite nanoparticles were prepared by coprecipitation in aqueous media, then the surface of nanoparticles was modified to introduce the reactive groups on the surface of nanoparticles. After that, polyglycerol was grafted on the surface of nanoparticles by ring‐opening anionic polymerization of glycidol using n‐bulyllithium as initiator. The magnetometry, relaxometry and phantom MRI experiments of this highly stable ferrofluid showed its high potential as a negative MRI contrast agent. Calculated r₁ and r₂ relaxivities at different magnetic fields were higher than the values reported for commercially available iron oxide contrast agents. The in vivo MRI studies showed that, after intravenous injection into mice, the particles produced a strong negative contrast in liver and kidneys, which persisted for 80 min (in liver) to 110 min (in kidneys). The negative contrast of the liver and kidneys weakened over the time, suggesting that polyglycerol coating renders the nanoparticles stealth and possibly optimal for renal excretion. Copyright © 2012 John Wiley & Sons, Ltd.     

Evaluation of eXIA 160XL cardiac‐related enhancement in C57BL/6 and BALB/c mice using micro‐CT

Evaluation of cardiovascular function in mice using micro‐CT requires that a contrast agent be administered to differentiate the blood from the myocardium. eXIA 160XL, an aqueous colloidal poly‐disperse contrast agent with a high iodine concentration (160 mg I ml^?1), creates strong contrast between blood and tissue with a low injection volume. In this study, the blood‐pool enhancement time‐course of eXIA 160XL is monitored over a 48 h period to determine its optimal use during cardiac function studies in C57BL/6 and BALB/c mice. Eight‐second scans were performed (80 kV_p, 110 mA) using the GE Locus Ultra micro‐CT scanner. Six C57BL/6 and six BALB/c male mice (22–24 g) were injected via tail vein with 5 µl g^?1 body weight eXIA 160XL. A precontrast scan was performed; following injection, mice were scanned at 5, 15, 30, 45 and 60 min, and 2, 4, 8, 12, 24 and 48 h. Images were reconstructed, and enhancement–time curves were generated for each of the following tissues: left ventricle (LV), myocardium, liver, spleen, renal cortex, bladder and brown adipose tissue. The highest contrast in the LV occurred at 5 min in both strains (~670 HU above precontrast value). Uptake of the contrast agent by the myocardium was also observed: myocardial tissue showed increasing enhancement over a 4 h period in both strains, remaining even once the contrast was eliminated from the vasculature. In both C57BL/6 and BALB/c strains, eXIA 160XL provided high contrast between blood and myocardial tissue for a period of 30 min following injection. Notably, this contrast agent was also taken up by the myocardium and provided continued enhancement when it was eliminated from the blood, making LV wall motion studies possible. In conclusion, eXIA 160XL, with its high iodine concentration and targeted tissue uptake characteristics, is an ideal agent to use when evaluating cardiovascular function in mice. Copyright © 2012 John Wiley & Sons, Ltd.     

Design of ProCAs (Protein‐Based Gd3+ MRI Contrast Agents) with High Dose Efficiency and Capability for Molecular Imaging of Cancer Biomarkers

Magnetic resonance imaging (MRI) is the leading imaging technique for disease diagnostics, providing high resolution, three‐dimensional images noninvasively. MRI contrast agents are designed to improve the contrast and sensitivity of MRI. However, current clinically used MRI contrast agents have relaxivities far below the theoretical upper limit, which largely prevent advancing molecular imaging of biomarkers with desired sensitivity and specificity. This review describes current progress in the development of a new class of protein‐based MRI contrast agents (ProCAs) with high relaxivity using protein design to optimize the parameters that govern relaxivity. Further, engineering with targeting moiety allows these contrast agents to be applicable for molecular imaging of prostate cancer biomarkers by MRI. The developed protein‐based contrast agents also exhibit additional in vitro and in vivo advantages for molecular imaging of disease biomarkers, such as high metal‐binding stability and selectivity, reduced toxicity, proper blood circulation time, and higher permeability in tumor tissue in addition to improved relaxivities.     

Dual nano‐sized contrast agents in PET/MRI: a systematic review

Nowadays molecular imaging plays a vital role in achieving a successful targeted and personalized treatment. Hence, the approach of combining two or more medical imaging modalities was developed. The objective of this review is to systematically compare recent dual contrast agents in Positron Emission Tomography (PET)/Magnetic Resonance Imaging (MRI) and in some cases Single photon emission computed tomography (SPECT)/MRI in terms of some their characteristics, such as tumor uptake, and reticuloendothelial system uptake (especially liver) and their relaxivity rates for early detection of primary cancer tumor. To the best of our knowledge, this is the first systematic and integrated overview of this field. Two reviewers individually directed the systematic review search using PubMed, MEDLINE and Google Scholar. Two other reviewers directed quality assessment, using the criteria checklist from the CAMARADES (Collaborative Approach to Meta‐Analysis and Review of Animal Data from Experimental Studies) tool, and differences were resolved by consensus. After reviewing all 49 studies, we concluded that a size range of 20–200 nm can be used for molecular imaging, although it is better to try to achieve as small a size as it is possible. Also, small nanoparticles with a hydrophilic coating and positive charge are suitable as a T₂ contrast agent. According to our selected data, the most successful dual probes in terms of high targeting were with an average size of 40 nm, PEGylated using peptides as a biomarker and radiolabeled with copper 64 and gallium 68. Copyright © 2017 John Wiley & Sons, Ltd.     

Cellular uptake and imaging studies of gadolinium‐loaded single‐walled carbon nanotubes as MRI contrast agents

We quantify here, for the first time, the intracellular uptake (J774A.1 murine macrophage cells) of gadolinium‐loaded ultra‐short single‐walled carbon nanotubes (gadonanotubes or GNTs) in a 3 T MRI scanner using R₂ and R₂* mapping in vitro. GNT‐labeled cells exhibited high and linear changes in net transverse relaxations (ΔR₂ and ΔR) with increasing cell concentration. The measured ΔR₂* were about three to four times greater than the respective ΔR₂ for each cell concentration. The intracellular uptake of GNTs was validated with inductively coupled plasma optical emission spectrometry (ICP‐OES), indicating an average cellular uptake of 0.44 ± 0.09 pg Gd per cell or 1.69 × 10⁹ Gd³⁺ ions per cell. Cell proliferation MTS assays demonstrated that the cells were effectively labeled, without cytotoxicity, for GNTs concentrations ≤28 µM Gd. In vivo relaxometry of a subcutaneously‐injected GNT‐labeled cell pellet in a mouse was also demonstrated at 3 T. Finally, the pronounced R₂* effect of GNT‐labeled cells enabled successful in vitro visualization of labeled cells at 9.4 T. Copyright © 2010 John Wiley & Sons, Ltd.     

Anatomical and functional imaging of myocardial infarction in mice using micro‐CT and eXIA 160 contrast agent

Noninvasive small animal imaging techniques are essential for evaluation of cardiac disease and potential therapeutics. A novel preclinical iodinated contrast agent called eXIA 160 has recently been developed, which has been evaluated for micro‐CT cardiac imaging. eXIA 160 creates strong contrast between blood and tissue immediately after its injection and is subsequently taken up by the myocardium and other metabolically active tissues over time. We focus on these properties of eXIA and show its use in imaging myocardial infarction in mice. Five C57BL/6 mice were imaged ~2 weeks after left anterior descending coronary artery ligation. Six C57BL/6 mice were used as controls. Immediately after injection of eXIA 160, an enhancement difference between blood and myocardium of ~340 HU enabled cardiac function estimation via 4D micro‐CT scanning with retrospective gating. Four hours post‐injection, the healthy perfused myocardium had a contrast difference of ~140 HU relative to blood while the infarcted myocardium showed no enhancement. These differences allowed quantification of infarct size via dual‐energy micro‐CT. In vivo micro‐SPECT imaging and ex vivo triphenyl tetrazolium chloride (TTC) staining provided validation for the micro‐CT findings. Root mean squared error of infarct measurements was 2.7% between micro‐CT and SPECT, and 4.7% between micro‐CT and TTC. Thus, micro‐CT with eXIA 160 can be used to provide both morphological and functional data for preclinical studies evaluating myocardial infarction and potential therapies. Further studies are warranted to study the potential use of eXIA 160 as a CT molecular imaging tool for other metabolically active tissues in the mouse. Copyright © 2014 John Wiley & Sons, Ltd.