肝胆特异性磁共振对比剂Gd-EOB-DTPA的应用现状及展望

Gd-EOB-DTPA是一种新型对比剂,同时具有非特异性细胞外对比剂和肝胆特异性对比剂的特性,可用以在相对较短的时间窗内进行肝脏血管成像、胆管成像、检出与定性诊断肝脏局灶性病变、评价肝功能,实现"一站式"检查。本文对该对比剂的基本特性、扫描参数、应用现状及前景进行综述。     

Acute infarct selective MRI contrast agent

To determine the infarct affinity of a low molecular weight contrast agent, Gd(ABE-DTTA), during the subacute phase of myocardial infarct (MI). Dogs (n = 7) were examined, using a closed-chest, reperfused MI model. MI was generated by occluding for 180 min the Left Anterior Descending (LAD) coronary artery with an angioplasty balloon. DE-MRI images with Gd(ABE-DTTA) were obtained on days 4, 14, and 28 after MI. Control DE-MRI by Gd(DTPA) was carried out on day 27. T2-TSE images were acquired on day 3, 13 and 27. Triphenyltetrazolium chloride (TTC) histomorphometry validated postmortem the existence of infarct. Gd(ABE-DTTA) highlighted the infarct on day 4, but not at all on day 14 or on day 28, following MI. On day 4, the mean ± SD signal intensity (SI) of infarcted myocardium in the presence of Gd(ABE-DTTA) significantly differed from that of healthy myocardium (45 ± 6.0 vs. 10 ± 5.0, P < 0.05), but it did not on day 14 (11 ± 9.4 vs. 10 ± 5.7, P = NS), nor on day 28 (7 ± 1.5 vs. 7 ± 2.4, P = NS). The mean ± SD signal intensity enhancement (SIE) induced by Gd(ABE-DTTA) was 386 ± 165% on day 4, significantly different from mean SIE on day 14 (9 ± 20%), and from mean SIE on day 28 (12 ± 18%), following MI (P < 0.05). The last two mean values did not differ significantly (P = NS) from each other. As control, Gd(DTPA) was used and it did highlight the infarct on day 27, inducing a mean SIE value of 312 ± 40%. The mean SIE on day 3, 13, or 27 did not vary significantly (P = NS) on the T2-TSE images (114 ± 41%, 123 ± 41%, and 150 ± 79%, respectively). Post mortem, the existence of infarcts was confirmed by TTC staining. The infarct affinity of Gd(ABE-DTTA) vanishes in the subacute phase of scar healing, allowing its use for infarct age differentiation early on, immediately following the acute phase.     

A polymeric micelle MRI contrast agent with changeable relaxivity.

Polymeric micelles were formed from cationic polymers (polyallylamine or protamine) and anionic block copolymers (poly(ethylene glycol)-b-poly(aspartic acid) derivative) that bound Gd ions providing high contrasts in Magnetic Resonance Imaging (MRI) by shortening the T(1) longitudinal relaxation time of protons of water. The Gd-binding block copolymer alone showed high relaxivity (T(1)-shortening ability) values from 10 to 11 mol(-1) s(-1), while the polymeric micelles exhibited low relaxivity values from 2.1 to 3.6 mol(-1) s(-1). These findings point to the feasibility of a novel MRI contrast agent that selectively provides high contrasts at solid tumor sites owing to a dissociation of the micelle structures, while selective delivery to the tumor sites is achieved in the polymeric micelle form.     

生物响应MRI对比剂的研究进展

不同组织和疾病都存在特异性的生物信号。开发能对这些生物信号响应的磁共振成像（MRI）对比剂,不仅有望增加MRI检测疾病的灵敏度,而且能够对病变产生的信号进行分子成像,提高疾病诊断的准确度。该文详细综述了白蛋白、pH、金属离子、酶、氧化还原以及其他生物分子等响应对比剂的最新进展,对未来的研究方向做了展望。     

A review of responsive MRI contrast agents: 2005–2014

This review focuses on MRI contrast agents that are responsive to a change in a physiological biomarker. The response mechanisms are dependent on six physicochemical characteristics, including the accessibility of water to the agent, tumbling time, proton exchange rate, electron spin state, MR frequency or superparamagnetism of the agent. These characteristics can be affected by changes in concentrations or activities of enzymes, proteins, nucleic acids, metabolites, or metal ions, or changes in redox state, pH, temperature, or light. A total of 117 examples are presented, including ones that employ nuclei other than ¹H, which attests to the creativity of multidisciplinary research efforts to develop responsive MRI contrast agents. Copyright © 2014 John Wiley & Sons, Ltd.     

MR contrast agent at high-field MRI (3 Tesla)

Tumor-to-brain contrast after gadolinium administration using MP-RAGE and T1-SE scans in patients with primary and secondary brain tumors was significantly higher at 3 T than at 1.5 T. The subjective assessment of cumulative triple-dose 3 Tesla images obtained the best results in the detection of brain metastases compared with other sequences followed by 1.5 T cumulative triple-dose enhanced images. In macroadenomas of the hypophysis, contrast-enhanced 3 T MRI was superior to standard MRI in the diagnosis of cavernous sinus infiltration and in visualization of cranial nerves within the cavernous sinus. Due to higher spatial resolution, contrast-enhanced MR venography at 3 T showed more details in and around tumors than at 1.5 T, additionally enhanced by stronger susceptibility weighting and higher signal-to-noise ratio at 3 T. In summary, administration of gadolinium-based contrast agent produces higher contrast between tumor and normal brain at 3 T than at 1.5 T, helps to detect more cerebral metastases at 3 T versus 1.5 T in single and cumulative triple dose, improves the evaluation of macroadenomas of the hypophysis, and makes MR venography at 3 T clinically attractive with increase in spatial resolution within the same measurement time, thus providing more detailed information.     

Improved pH measurements with a single PARACEST MRI contrast agent

The measurement of extracellular pH has potential utility for assessing the therapeutic effects of pH‐dependent and pH‐altering therapies. A PARAmagnetic chemical exchange saturation transfer (PARACEST) MRI contrast agent, Yb–DO3A–oAA, has two CEST effects that are dependent on pH. A ratio derived from these CEST effects was linearly correlated with pH throughout the physiological pH range. The pH can be measured with a precision of 0.21 pH units and an accuracy of 0.09 pH units. The pH measurement is independent of concentration and T₁ relaxation times, but is dependent on temperature. Although MR coalescence affects the CEST measurements, especially at high pH, the ratiometric analysis of the CEST effects can account for incomplete saturation of the agent's amide and amine that results from MR coalescence. Provided that an empirical calibration is determined with saturation conditions, magnetic field strength and temperature that can be used for subsequent studies, these results demonstrate that this single PARACEST MRI contrast agent can accurately measure pH. Copyright © 2012 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.     

磁共振扫描发生对比剂渗漏致静脉炎的护理

目的探讨磁共振扫描发生对比剂渗漏致静脉炎护理措施及效果。方法选取以往50例磁共振扫描发生对比剂渗漏致静脉炎患者回顾性分析。随机将25例行常规护理的静脉炎患者分为对照组,另25例静脉炎患者采用有效护理措施分为试验组。观察对比两组患者护理满意度、护理效果。结果试验组患者护理总满意率高于对照组,差异有统计学意义（23% vs 19%, P<0.05）;试验组患者护理总有效率高于对照组,差异具有统计学意义（25% vs 22%,P<0.05）。结论有效的护理措施对磁共振扫描发生对比剂渗漏致静脉炎患者作用突出,能改善患者病情,提高治疗效果,提高护理满意度,可推广使用。     

Kinetic analysis of hyaluronidase activity using a bioactive MRI contrast agent

One of the attractions of molecular imaging using ‘smart’ bioactive contrast agents is the ability to provide non‐invasive data on the spatial and temporal changes in the distribution and expression patterns of specific enzymes. The tools developed for that aim could potentially also be developed for functional imaging of enzyme activity itself, through quantitative analysis of the rapid dynamics of enzymatic conversion of these contrast agents. High molecular weight hyaluronan, the natural substrate of hyaluronidase, is a major antiangiogenic constituent of the extracellular matrix. Degradation by hyaluronidase yields low molecular weight fragments, which are proangiogenic. A novel contrast material, HA‐GdDTPA‐beads, was designed to provide a substrate analog of hyaluronidase in which relaxivity changes are induced by enzymatic degradation. We show here a first‐order kinetic analysis of the time‐dependent increase in R₂ as a result of hyaluronidase activity. The changes in R₂ and the measured relaxivity of intact HA‐GdDTPA‐beads (r_2B) and HA‐GdDTPA fragments (r_2D) were utilized for derivation of the temporal drop in concentration of GdDTPA in HA‐GdDTPA‐beads as the consequence of the release of HA‐GdDTPA fragments. The rate of dissociation of HA‐GdDTPA from the beads showed typical bell‐shaped temperature dependence between 7 and 36 °C with peak activity at 25 °C. The tools developed here for quantitative dynamic analysis of hyaluronidase activity by MRI would allow the use of activation of HA‐GdDTPA‐beads for the determination of the role of hyaluronidase in altering the angiogenic microenvironment of tumor micro metastases. Copyright © 2006 John Wiley & Sons, Ltd.     

A contrast agent recognizing activated platelets reveals murine cerebral malaria pathology undetectable by conventional MRI

Human and murine cerebral malaria are associated with elevated levels of cytokines in the brain and adherence of platelets to the microvasculature. Here we demonstrated that the accumulation of platelets in the brain microvasculature can be detected with MRI, using what we believe to be a novel contrast agent, at a time when the pathology is undetectable by conventional MRI. Ligand-induced binding sites (LIBS) on activated platelet glycoprotein IIb/IIIa receptors were detected in the brains of malaria-infected mice 6 days after inoculation with Plasmodium berghei using microparticles of iron oxide (MPIOs) conjugated to a single-chain antibody specific for the LIBS (LIBS-MPIO). No binding of the LIBS-MPIO contrast agent was detected in uninfected animals. A combination of LIBS-MPIO MRI, confocal microscopy, and transmission electron microscopy revealed that the proinflammatory cytokine TNF-alpha, but not IL-1beta or lymphotoxin-alpha (LT-alpha), induced adherence of platelets to cerebrovascular endothelium. Peak platelet adhesion was found 12 h after TNF-alpha injection and was readily detected with LIBS-MPIO contrast-enhanced MRI. Temporal studies revealed that the level of MPIO-induced contrast was proportional to the number of platelets bound. Thus, the LIBS-MPIO contrast agent enabled noninvasive detection of otherwise undetectable cerebral pathology by in vivo MRI before the appearance of clinical disease, highlighting the potential of targeted contrast agents for diagnostic, mechanistic, and therapeutic studies.     

小动物脑功能磁共振成像研究进展

本文主要介绍血氧水平依赖的小动物脑功能磁共振成像的研究条件、范围和研究方法,并简述小动物在发展非血氧水平依赖功能磁共振技术中所起的作用。尽管小动物脑磁共振成像研究受到麻醉等条件的限制,这项研究已经在神经科学及神经药理学范围作出了诸多贡献,并受到越来越多的重视。     

Radial correlation contrast--a functional connectivity MRI contrast to map changes in local neuronal communication

A functional connectivity MRI method that groups neighboring voxels in relation to their degree of temporal cross-correlation between their time courses is presented. This grouping generates a vector field, which is assumed to provide insights into the local organization of neuronal activity. Application with high spatial resolution fMRI rat data subjected to electric forepaw sensory stimulation (156 . 156 . 1000 micron1) shows a significant localized increase of the vector field amplitude in cortical layers 4 and 2/3 of the primary sensory cortex and in layer 2/3 of the primary motor cortex, suggesting a strong correlation with local neuronal communication. Vector field phases exhibit a transition with neuronal activation from random-like orientations during rest to clusters of common orientations. Cluster size is shown to be weakly dependent on the radii of the vector field calculation, and shuffling voxel position within clusters generates a random-like vector orientation instead. This suggests that changes in vector orientations upon activation represent changes in the internal correlation between voxels that is interpreted as a change in the internal neuronal communication.     

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.     

A semi-parametric analysis for identifying Scleroderma patients responsive to an anti-fibrotic agent

In a recently concluded multi-center two-armed clinical trial for Scleroderma patients, results from a variety of analyses based on parametric models showed that late phase patients benefited from the bovine collagen treatment at 15 months and the placebo group did not. However, the cutoff time for defining early or late phase patients was somewhat arbitrary and sample size for late phase patients was small in the two groups. We apply a combination of semi-parametric and parametric approaches to further ascertain treatment efficacy and address modeling issues related to the choice of the cutoff and the scientific hypothesis of interest. We compare results with those obtained from parametric models and demonstrate how semi-parametric methods can help to better identify Scleroderma patients responsive to an anti-fibrotic agent.     

纳米级超声造影剂的研究现状与展望

随着纳米生物学技术和超声造影剂的迅速发展,造影剂粒径步入纳米时代。不同核心成分和包膜材料的纳米级超声造影剂分别表现出不同的特性。在实际应用中,纳米级超声造影剂在肿瘤显像和治疗方面有其独特的优势。本文就纳米超声造影剂的研究背景、现状及应用发展前景等方面做一综述。     

MRI造影剂钆喷酸葡胺对弥散加权成像的影响

目的评价钆喷酸葡胺(Gd-DTPA)在体外对弥散加权成像(DWI)信号及表观弥散系数(ADC)值的影响。方法先后以T2map、化学位移选择饱和脉冲(CHESS)、压脂化学位移选择饱和脉冲(CHESS-FAT)及短时间反转恢复(STIR)序列对不同浓度Gd-DTPA溶液水模进行扫描。高浓度组Gd-DTPA浓度分别为0、0.05、0.075、0.1、0.15、0.2 mmol/L,低浓度组Gd-DTPA浓度为0、0.005、0.01、0.025、0.05 mmol/L。定性观察图像伪影,测量及计算各水模的T2值及3种DWI序列下的ADC值、信噪比(SNR)。应用线性回归方法评价T2值、ADC值、SNR、浓度的相关关系。结果低浓度组与高浓度组水模T2值随Gd-DTPA浓度升高依次下降,与造影剂浓度呈负相关。低浓度组水模在CHESS、CHESS-FAT和STIR组中,不同浓度水模SNR随Gd-DTPA浓度上升无明显变化,图像伪影轻微,ADC值未见明显变化。高浓度组在CHESS和CHESS-FAT组中,信号随Gd-DTPA浓度升高依次下降,SNR与浓度呈负相关,与T2值呈正相关,图像伪影轻微,ADC值未见明显变化;但STIR组水模可见明显伪影,SNR明显下降,但与浓度、T2值无明显相关。伪影最重的水模ADC值下降,余无明显变化。结论 Gd-DTPA造影剂在低浓度水平下,对CHESS、CHESS-FAT和STIR序列的DWI图像信号及ADC值无明显影响;但应用高浓度或强T2缩短效应的造影剂可能会影响DWI图像质量和ADC值。     

Design and characterization of a polymeric MRI contrast agent based on PVA for in vivo living‐cell tracking

A novel water‐soluble MRI contrast agent for in vivo living cell tracking was developed. Unlike the conventional in vivo cell tracking system based on superparamagnetic iron oxide beads, the newly developed contrast agent is eliminated from the body when the contrast agent exits the cells upon cell death, which makes living cell tracking possible. The contrast agent is composed of gadolinium chelates (Gd–DOTA) and a water‐soluble carrier, poly(vinyl alcohol) (PVA), which is known to interact with cells and tissues very weakly. Since the Gd–PVA was not taken up by cells spontaneously, the electroporation method was used for cell labeling. The delivered Gd–PVA was localized only in the cytosolic compartment of growing cells with low cytotoxicity and did not leak out of the living cells for long periods of time. This stability may be due to the weak cell‐membrane affinity of Gd–PVA, and did not affect cell proliferation at all. After cell labeling, signal enhancement of cells was observed in vitro and in vivo. These results indicate that Gd–PVA can visualize only the living cells in vivo for a long period of time, even in areas deep within large animal bodies. Copyright © 2010 John Wiley & Sons, Ltd.     

磁共振成像及对比剂在细胞移植中的研究进展

随着细胞移植研究的不断深入,细胞移植在临床治疗中的应用逐渐增多.但不论是在科研工作还是临床治疗中进行细胞移植,都需要监测移植后细胞的命运.磁共振成像技术具有无创伤性、时间连续性等优点,是在活体上对移植细胞进行连续多时间点监测的理想方法之一.应用磁共振对比剂在体外标记细胞后将细胞移植入动物体内,可通过磁共振成像追踪移植细...