靶向血栓MR分子探针的构建及初步鉴定

目的构建一种靶向血栓MR分子探针并对其相关特性进行鉴定。方法采用双乳化法,以端羧基聚乳酸/羟基乙酸(PLGA-COOH)为载体包裹MR对比剂钆喷酸葡胺(Gd-DTPA)制备Gd-PLGA微球,再采用碳二亚胺法共价结合血小板膜上GPⅡb/Ⅲa受体拮抗剂精氨酸-甘氨酸-天冬氨酸-丝氨酸(Arg-Gly-Asp-Ser,RGDS)短肽片段,构建靶向血栓MR分子探针。观察其理化性质、体外靶向特异性,于1.5 T MRI测量并计算MR纵向弛豫率。结果采用本方法成功构建了靶向血栓MR分子探针,其形态规则,大小较均一,平均粒径为2.04μm,RGDS携带率达89.69%,Gd-DTPA包封率为39.53%;体外寻靶实验显示其对离体血栓具有较强的靶向性及稳定性;在1.5 TMR成像仪上能实现显像,同时随着Gd-DTPA浓度的增加,纵向弛豫率增加。结论成功构建靶向血栓MR分子探针,有望为分子水平诊断血栓提供新技术、新方法。     

卵巢癌的MR分子成像研究进展

卵巢癌在女性恶性肿瘤中死亡率高,早期诊断困难,提高卵巢癌早期诊断准确率至关重要。近年来MR分子成像技术的开发及应用,为卵巢癌的早期诊断及后续的靶向治疗提供了可能。就卵巢癌分子成像的靶点选择及MR特异性对比剂的研究进展进行论述,并进一步对MR分子成像应用于卵巢癌靶向治疗及其疗效检测做出展望。     

适于MR分子成像的钆基靶向纳米粒研究进展

影像技术与纳米技术的结合促进了MR分子靶向成像的发展,基于各种材料的纳米粒在构建分子靶向对比剂中的地位愈来愈突出。利用纳米粒作为载体,可增加Gd3＋的荷载量、增强弛豫效果、减少对比剂的用量,实现主动靶向成像,并因此弥补了MRI在分子成像中低敏感性的缺陷。就含钆纳米粒的优缺点、合成材料与方法、弛豫效果、安全性进行综述。     

适于MR分子成像的钆基靶向纳米粒研究进展

影像技术与纳米技术的结合促进了MR分子靶向成像的发展,基于各种材料的纳米粒在构建分子靶向对比剂中的地位愈来愈突出。利用纳米粒作为载体,可增加Gd3+的荷载量、增强弛豫效果、减少对比剂的用量,实现主动靶向成像,并因此弥补了MRI在分子成像中低敏感性的缺陷。就含钆纳米粒的优缺点、合成材料与方法、弛豫效果、安全性进行综述。     

肿瘤靶向性MR分子探针的标记及研究进展

使用MR分子成像技术对肿瘤细胞进行标记、显像的关键在于MR分子探针的运用。运用不同的分子识别系统合成靶向性探针,从肿瘤的基因、分子水平特异性地诊断肿瘤的发生是肿瘤成像的基础。针对肿瘤细胞的各种MR靶向分子探针标记方法进行综述。     

肿瘤靶向性MR分子探针的标记及研究进展

使用MR分子成像技术对肿瘤细胞进行标记、显像的关键在于MR分子探针的运用。运用不同的分子识别系统合成靶向性探针,从肿瘤的基因、分子水平特异性地诊断肿瘤的发生是肿瘤成像的基础。针对肿瘤细胞的各种MR靶向分子探针标记方法进行综述。     

RSNA2012分子影像学进展

RSNA2012报道的分子影像学研究进展主要包括以下几个方面:①靶向特异性分子探针及多功能分子探针的研发:如靶向特异性磁性纳米对比剂、超声微泡对比剂及放射性示踪剂等,应用于肿瘤靶向显像、动脉粥样硬化斑块易损性评价、老年痴呆Aβ斑块显像及感染分期和预后评估等。②多模态分子显像技术的发展:包括MRI、PET、光学成像及超声分子成像。③干细胞示踪及成像。     

肿瘤微环境靶点及相关磁共振超顺磁氧化铁分子探针研究进展

影响肿瘤生物学行为的新生血管内皮细胞、肿瘤细胞及肿瘤间质细胞上的特异性受体的显像研究是肿瘤磁共振(magnetic resonance,MR)分子影像学的重要内容。针对上述特异性靶点,合成MR特异性分子探针的研究近年来得到了广泛的关注。本文就目前已知的肿瘤细胞及其微环境中主要的生物靶点阐述其相关MR超顺磁氧化铁分子探针的研究进展。     

靶向血管生成的分子探针构建及体外细胞MR成像的初步研究

目的 探讨体外细胞MR成像的可行性.方法 通过GoldMagTM-CS纳米金磁微粒与抗整合素αvβ3抗体非共价键偶联方法 构建特异性分子探针.培养ECV304细胞,利用激光共聚焦显微镜及流式细胞术,观察该探针与αvβ3整合素结合的特异性.建立MR扫描序列,将已构建的MR探针标记ECV304细胞,进行MR成像.结果 成功构建了靶向血管生成的特异性MR分子探针;构建的MR分子探针能与ECV304细胞特异性地结合;并可特异性显著降低T2*序列信号,而非特异抗体偶联的探针对细胞MR信号无显著影响.结论 应用纳米金磁微粒及抗整合素αvβ3抗体构建的MR分子探针,能与ECV304细胞特异结合,并显著影响其T2*序列MR信号,提示该探针有望应用于活体的肿瘤新生血管的特异性显像.     

RSNA2015分子影像学

RSNA2015报道的分子影像学研究进展主要包括以下几个方面:①靶向特异性分子探针及复合分子探针的研发和应用:如靶向特异性超顺磁氧化铁纳米探针,放射性核素示踪剂免疫,复合超声微泡对比剂及光学对比剂等,应用于肿瘤血管靶向显像,肿瘤诊断、治疗疗效评估及肿瘤淋巴结转移等.③新型的放射学分子成像方法:如磁性粒子成像,磁共振波谱成像及化学交换饱和转移成像等.③多模态或多参数分子显像:MRI、PET、SPECT、超声及光学分子成像技术中两种或多种技术的结合.④干细胞追踪及显像.     

Extracellular biodegradable macromolecular gadolinium(III) complexes for MRI.

The clinical application of macromolecular gadolinium (Gd) complexes as MRI contrast agents is limited by the slow excretion of Gd(III) complexes and consequent long-term tissue accumulation of toxic Gd ions. To alleviate the problem of slow excretion, biodegradable polydisulfide-based macromolecular Gd(III) complexes were designed and prepared based on the disulfide-thiol exchange to allow degradation of the macromolecules by endogenous thiols and to facilitate excretion of Gd(III) complexes after the MRI examination. The in vitro degradation study showed that the polydisulfide agent was readily degraded by cysteine at plasma thiol concentrations. No cross-reaction was observed between the cysteine-34 on human serum albumin (HSA) with the agent. Concentration-dependent blood pool contrast enhancement was observed for the polydisulfide agents. The agents of both high molecular weight (35,000 Da) and low molecular weight (17,700 Da) produced significant contrast enhancement in the heart and aorta in rats at relatively high doses. Except for the bladder, the signal intensities gradually decreased over time. Significant blood pool contrast enhancement was also observed for the high molecular weight agent at a low dose (0.03 mmol-Gd/kg), but not for the agent with a lower molecular weight. The contrast enhancement in the urinary bladder increased over time for the polydisulfide agents and Gd(III)-(DTPA-BMA). Degradation products were identified by mass spectrometry in the urine samples from the rats administered with both polydisulfide agents, which confirmed that the polydisulfide agents were degraded in vivo and excreted through renal filtration. The preliminary results demonstrated the in vitro and in vivo degradability, superior blood pool contrast enhancement, and rapid clearance through renal filtration of the novel biodegradable macromolecular agent. This agent has a great potential for further preclinical and clinical development with application in contrast-enhanced blood pool and cancer MR imaging.     

Kinetics of avidin‐induced clearance of biotinylated bimodal liposomes for improved MR molecular imaging

Dual labeled liposomes, carrying both paramagnetic and fluorescent lipids, were recently proposed as potent contrast agents for MR molecular imaging. These nanoparticles are coated with poly(ethylene glycol) (PEG) to increase their blood circulation half‐life, which should allow extensive accumulation at the targeted site. To eliminate nonspecific blood pool signal from the MR images, the circulating liposomes should ideally be cleared from the circulation when sufficient target‐specific contrast enhancement is obtained. To that aim, we designed an avidin chase that allowed controlled and rapid clearance of paramagnetic biotinylated liposomes from the blood circulation in C57BL/6 mice. Avidin‐induced alterations in blood clearance kinetics and tissue distribution were studied quantitatively by determination of the Gd content in blood and tissue samples ex vivo. Intrinsic liposomal blood clearance showed bi‐exponential behavior with half‐lives t_1/2α = 2.1 ± 1.1 and t_1/2β = 15.1 ± 5.4 hours, respectively. In contrast, the contrast agent was cleared from the blood by the avidin infusion to <1% of the initial dose within 4 hours. Avidin‐induced liposomal blood clearance was also demonstrated in vivo by dynamic T₁‐weighted MRI. The ability to rapidly clear circulating contrast agents opens up exciting possibilities to study targeting kinetics, to increase the specificity of molecular MRI and to optimize nanoparticulate contrast agent formulations. Magn Reson Med 60:1444–1456, 2008. © 2008 Wiley‐Liss, Inc.     

Gadolinium-DTPA-dextran: a macromolecular MR blood pool contrast agent

RATIONALE AND OBJECTIVES: Magnetic resonance (MR) imaging blood pool agents offer numerous advantages for vascular and tumor imaging. The purpose of this study was to test gadolinium-diethylenetriaminepentaacetate-dextran ([Gd]DTPA-dextran) as a new water soluble macromolecular blood pool agent for MR imaging. MATERIALS AND METHODS: [Gd]DTPA-dextran (187 gadolinium atoms per dextran, molecular weight 165 kD, diameter 17.6 nm) was synthesized. Fifteen anesthetized New Zealand White rabbits with thigh VX2 tumors were scanned in a knee coil at 1.5T. Coronal 3D MR angiographic sequences were obtained before and at several time points up to 72 hours after the intravenous bolus injection of [Gd]DTPA-dextran providing gadolinium at either 0.05 (n = 4) or 0.1 mmol/kg (n = 8) or [Gd]DTPA-bismethylamide (BMA) providing gadolinium at 0.1 mmol/kg (n = 3). Time enhancement curves for aorta, cava, and tumor rim were compared by univariate General Linear Model. RESULTS: Contrast enhancement of cava and aorta relative to a water phantom were significantly greater at all time points after either dose of [Gd]DTPA-dextran than after [Gd]DTPA-BMA (P < 0.01). Tumor rim enhancement was less intense for either dose of [Gd]DTPA-dextran at peak than for [Gd]DTPA-BMA (P < 0.05). Tumor rim enhancement with both doses of [Gd]DTPA-dextran became equivalent to that of [Gd]DTPA-BMA at one hour and was greater at 24 hours (P < 0.05). CONCLUSION: [Gd]DTPA-dextran is a new macromolecular MR contrast agent that can be synthesized to carry a high density of gadolinium atoms without intra-molecular cross-linking. It provides significantly greater vascular residence time than a conventional gadolinium chelate and shows promise for MR blood pool imaging.     

MR techniques for in vivo molecular and cellular imaging

MR-based molecular imaging is a science in infancy. Current clinical contrast agents are often geared toward the assessment of gross physiologic function, rather than targeting specific biochemical pathways. The development of specific targeted smart contrast agents for Food and Drug Administration approval or clinical trials has only begun. The fact that MR imaging can obtain images of extremely high resolution, coupled with its ability to simultaneously assess structure and function through the use of targeted contrast agents indicates that MR will play a pivotal role in clinical molecular imaging of the future. Many of the challenges that face MR imaging and spectroscopy are inherent to all modalities in the rapidly growing field of molecular imaging. The development of smart contrast agents to report on receptor function, and to monitor gene expression or the results of gene therapy in humans is paramount. These compounds need to undergo rigorous testing to be approved for clinical use: the assessment of acute toxicity, pharmacokinetics, long-term accumulation, and subsequent chronic effects. For receptor-targeted contrast agents, the degree of receptor occupancy and the intrinsic agonist or antagonist properties of the probe that may affect normal cellular function need to be determined to avoid undesired side effects. The particular problems that face MR imaging, those of sensitivity and target specificity, need to be overcome. Signal amplification achieved through high relaxivity contrast agents containing multiple paramagnetic centers, or of larger superparamagnetic particles, is the first step in this direction. The modulation of relaxivity through oligomerization, or other modifications that cause restriction of rotational motions, shows great promise for improving the discriminative powers of MR imaging, and may permit multiple targets to be assessed simultaneously. Moreover, the introduction of smart indicators that lead to changes in spectroscopic properties will allow further discrimination to be achieved through the implementation of chemical shift or spectroscopic imaging. The growing number of MR imaging applications in this rapidly expanding field point to a bright future for MR imaging in molecular imaging.     

Targeted nanoparticles for quantitative imaging of sparse molecular epitopes with MRI.

Before molecular imaging with MRI can be applied clinically, certain problems, such as the potential sparseness of molecular epitopes on targeted cell surfaces, and the relative weakness of conventional targeted MR contrast agents, must be overcome. Accordingly, the conditions for diagnostic conspicuity that apply to any paramagnetic MRI contrast agent with known intrinsic relaxivity were examined in this study. A highly potent paramagnetic liquid perfluorocarbon nanoparticle contrast agent ( approximately 250 nm diameter, >90,000 Gd3+/particle) was imaged at 1.5 T and used to successfully predict a range of sparse concentrations in experimental phantoms with the use of standard MR signal models. Additionally, we cultured and targeted the smooth muscle cell (SMC) monolayers that express "tissue factor," a glycoprotein of crucial significance to hemostasis and response to vascular injury, by conjugating an anti-tissue factor antibody fragment to the nanoparticles to effect specific binding. Quantification of the signal from cell monolayers imaged at 1.5 T demonstrated, as predicted via modeling, that only picomolar concentrations of paramagnetic perfluorocarbon nanoparticles were required for the detection and quantification of tissue factor at clinical field strengths. Thus, for targeted paramagnetic agents carrying high payloads of gadolinium, it is possible to quantify molecular epitopes present in picomolar concentrations in single cells with routine MRI.     

A dendrimer-based nanosized contrast agent dual-labeled for magnetic resonance and optical fluorescence imaging to localize the sentinel lymph node in mice

PURPOSE: To preoperatively and intraoperatively localize the sentinel lymph node (SLN), a single hybrid probe for MR and near infrared (NIR) optical imaging was synthesized and tested. MATERIALS AND METHODS: A macromolecular MR/NIR optical contrast agent was synthesized based on a approximately 191 gadolinium-labeled contrast agent using generation-6 polyamidoamine dendrimer (G6), which is also labeled with 2 Cy5.5, an NIR fluorophore. After establishing the optimal dose, the agent was injected into mammary glands of 10 normal mice to examine the lymphatic drainage from the breast using a 3T clinical scanner. Immediately after the MRI scan, NIR optical imaging and image-guided surgery were performed to compare the two imaging modalities. RESULTS: To consistently identify the SLNs, we needed to inject 25 microL of 30 mM [Gd] G6-Cy5.5. All SLNs could be easily identified and resected under NIR optical imaging-guided surgery. Although external NIR optical imaging failed to identify SLNs close to the injection site due to shinethrough, MR lymphography (MRL) consistently identified all SLNs regardless of their location. CONCLUSION: We have successfully synthesized and tested a dual labeled MR/NIR optical hybrid contrast agent, G6-Cy5.5 for reoperative and intraoperative localization of SLNs.     

Gadolinium cryptelates as MR contrast agents

Gadolinium cryptelates are complexes of a lanthanide metal ion with amino acids of macrocyclic polyamines. These compounds are water soluble and possess reduced relaxation properties similar to Gd diethylene triamine pentaacetic acid (DTPA). Three Gd cryptelates (Gd NOTA, DOTA, TETA) were evaluated. Gadolinium DOTA is the most stable Gd complex with a dissociation constant of 10(-28) and appears to have a greater serum stability than Gd DTPA. Gadolinium NOTA and Gd TETA have lower dissociation constants than Gd DTPA at 10(-17) and 10(-19). Gadolinium DOTA has tissue distribution properties similar to Gd DTPA, is rapidly excreted by the kidneys, and provides a high degree of contrast enhancement on magnetic resonance (MR) images, both systemically and within the CNS. Hence, Gd DOTA is an alternative water-soluble MR contrast agent to Gd DTPA.     

Dynamic coronary MR angiography and first-pass perfusion with intracoronary administration of contrast agent

PURPOSE: To evaluate whether dynamic imaging of the coronary arteries can be performed with intracoronary infusion of low-dose gadolinium (Gd)-based contrast agent and assess the effect of long duration and multiple infusions on the image signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR). MATERIALS AND METHODS: Dynamic coronary magnetic resonance (MR) imaging (130 msec/image) and contrast agent first pass myocardial perfusion studies were performed with intracoronary infusions of low-dose Gd-based MR contrast agent on dogs (N = 4) using a fast multislice gradient recalled echo (GRE) sequence. RESULTS: Contrast-enhanced coronary arteries were clearly imaged during infusion periods as long as 2.3 minutes. The SNR and CNR of the contrast-enhanced coronary arteries remained essentially unchanged over multiple consecutive angiographic sessions. In addition, we demonstrated that first pass studies performed with intracoronary injection of MR contrast agent can be used as a means of assessing regional myocardial perfusion. CONCLUSION: These studies demonstrated that, using intracoronary infusion of Gd, coronary magnetic resonance angiography (MRA) can be performed with high temporal resolution, and multiple low-dose slow infusions of Gd-based MR contrast agent can be performed without compromise of the vessel SNR and CNR.     

MRA contrast bolus timing with ultrasound bubbles.

The purpose of this study was to determine the feasibility of using an ultrasound contrast agent test bolus to determine optimum bolus timing for three-dimensional (3D) gadolinium (Gd)-enhanced magnetic resonance angiography (MRA). Small test doses of ultrasound contrast agent (0.3 ml Optison) were injected intravenously followed immediately by a 20 ml saline flush. Arrival of the contrast agent was detected by spectral Doppler ultrasound (US). This technique was implemented in patients undergoing peripheral vascular MRA and carotid MRA. Arrival of the US contrast agent test bolus was readily detected by the change in amplitude of the Doppler spectrum and by a huge increase in the audio signal amplitude. This contrast travel time measurement accurately guided bolus timing for 3D Gd MRA. Bolus timing for 3D contrast-enhanced MRA can be performed using US, thereby eliminating the problems and MR scanner time required for injecting a test bolus of Gd contrast.     

Determination of optimal injection parameters for intraarterial gadolinium-enhanced MR angiography

PURPOSE: Rapid vascular depiction with use of a minimum of gadolinium (Gd) contrast agent will be required to generate road-map vascular images for magnetic resonance (MR) imaging-guided endovascular interventions. The objective of this study was to optimize intraarterial injections of MR contrast agent during magnetic resonance angiography (MRA), obtained during interventions, by determining the optimal Gd vascular concentration ([Gd]) for vessel depiction. MATERIALS AND METHODS: The authors derived theoretical expressions to estimate the [Gd] resulting in maximal signal in blood. A model was developed to account for flow dilution to estimate [Gd] given the injected Gd concentration, injection rate, and the blood flow rate. Experiments in four animals (three dogs, one pig) were conducted to verify this model with use of both time-resolved two-dimensional (2D) thick-slab and single-phase three-dimensional (3D) MRA acquisitions. The authors also determined the optimal [Gd] required for vessel depiction in animal models. RESULTS: The theoretical expressions yielded optimal [Gd] of 10.2 mmol/L in blood. The animal experiments used the flow dilution model and examined signal enhancement in the aorta and the renal and iliac arteries. Maximal enhancement occurred at [Gd] = 16.2 +/- 4.0 mmol/L (mean +/- SE). CONCLUSIONS: The theoretically predicted values for [Gd]optimal and the flow dilution model were successfully validated. The relationship between injected [Gd], injection rate, and blood flow rate permits rapid intraarterial administration of contrast material, using less overall contrast material than with standard intravenous Gd-enhanced MRA.