生物环境智能响应磁共振造影剂研究进展

随着生物医学领域的不断发展,人们对于在分子机理层面上研究生物体系中新陈代谢、疾病的发生和发展等过程的需求日益增长.磁共振成像因拥有其他成像方法所不具备的非侵入式、深层次的空间分辨能力,为生物体系分子层面的检测提供了有力的工具.分子层面的磁共振成像检测离不开生物环境智能响应磁共振造影剂的使用.生物环境智能响应磁共振造影剂的造影能力会随着特定生物环境变化而发生改变.此类造影剂使得人们可以根据磁共振图像上信号的改变分析得到生物体特定位置的pH、离子浓度、酶活力等相关信息.近20年来,生物环境智能响应磁共振造影剂得到了长足的发展.本文将按不同的响应对象分类总结近几年此类造影剂的研究进展,并对一些重要的研究成果进行较为详细的阐述和对比,分析目前生物环境智能响应磁共振造影剂研究中存在的困难和解决方案,最后对本领域的进一步发展进行展望.     

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.     

19F磁共振成像造影剂研究进展

19F磁共振成像(19F magnetic relaxation imaging, 19F MRI)技术因其无内源性背景噪声而被广泛应用于生物医学研究领域。磁共振成像技术被提出后,19F MRI造影剂的研究主要集中于全氟化碳类有机物,这类有机物具有高的19F载量、合适的弛豫时间、高的影像信噪比,同时可以通过修饰功能性的基团实现多模式造影。近年来,19F MRI造影剂由全氟化碳等有机物逐渐向无机物延伸,出现了无机氟化物纳米粒子造影剂。本文主要介绍了19F MRI造影剂的种类、研究现状和应用前景。     

医疗诊断新技术--磁共振成像术

本文介绍了2003年诺贝尔生理医学奖项的内容-磁共振成像技术。简述了核磁共振(NMR)和磁共振成像(MRI)的基本原理,介绍了目前MRI造影剂的研究进展。     

钆类造影剂用于肿瘤靶向性成像

核磁共振成像(MRI)是肿瘤诊断的重要手段,特别是各种造影剂的使用加速了临床应用范围.目前临床MRI检查所用各类造影剂如Gd-DTPA-BMA、Gd-DOTA等均为小分子造影剂,存在组织特异性低、体内停留时间短等缺点.构建具有组织特异性的新一代高效、低毒MRI造影剂成为材料界、医学界的研究热点之一.本文在综合最新文献的...     

氧化铁纳米颗粒在磁共振成像中的应用

目前临床诊断中钆基造影剂的应用十分广泛,然而其对人体的毒性无法忽视,因此研究者致力于低毒性造影剂的研发。氧化铁纳米颗粒(Iron Oxide Nanoparticles,IONP)因其超顺磁性在磁共振成像(Magnetic Resonance Imaging,MRI)中具有良好的暗对比效果,并且具有良好的生物相容性。随着生物材料和分子影像技术的发展,IONP在MRI成像中的应用愈发广泛。近年来,IONP在多模态成像和诊断治疗一体化方面取得了进展。本文将以IONP的MRI成像机理、制备和表面修饰为基础,阐述近年来IONP在MRI成像应用的研究成果和问题,期望IONP取得更好的发展。     

含钆杂多配合物对水氢核的弛豫性能

核磁共振成像(MRI)技术是继CT扫描仪后又一诊断肿瘤的有力工具,已广泛应用于临床.MRI成像时,不同组织间的区别是由于这些组织中水分子的1H核磁弛豫时间的差别引起的.但病变与正常组织的弛豫速率的差别常常达不到诊断的目的,因此诊断时常使用造影剂,其作用是改变体内局部组织中水质子弛豫时间,提高正常与患病部位的成像对比度[1].造影剂的使用要求具有较高的弛豫效率、较高的稳定性,无毒等条件.弛豫效率与化合物中顺磁原子的未成对电子数有关,未成对电子数越多,则配合物的电子自旋磁矩越大,对邻近水质子的弛豫能力越强.因此,研究较多的是…     

宽pH响应范围的比率荧光纳米探针的构建

基于化学剥离法制备MoS_2量子点,以荧光素和罗丹明B为pH荧光响应基团,经巯基共价修饰在MoS_2量子点表面后构建了宽pH检测范围的比率荧光纳米探针dl-MoS_2。对其光谱学性质和pH响应荧光性质进行了研究。结果表明,dl-MoS_2具有pH选择性识别作用,且对pH响应范围可以通过荧光配体和罗丹明配体的比例进行调节,当荧光素配体与罗丹明配体的摩尔比为1:10时,制备得到的dl-MoS_2探针具有最宽的pH响应范围(pH 4～9),该方法能有效的扩宽荧光探针的pH检测范围。进一步研究表明,dl-MoS_2探针对pH的检测可用作生命体内pH成像检测的荧光探针。     

基于硼酸酯的19F磁共振分子探针的设计合成及活体深组织活性氧物种的激活响应成像

活性氧簇(ROS), 如过氧化氢, 在生物体内的各种生理和病理过程中发挥着重要作用. 生物体内活性氧簇水平的异常与多种疾病(炎症、 肿瘤和器官损伤等)密切相关, 使ROS监测成为研究和诊断这些疾病的重要工具. 目前, 实现活体内深组织中的活性氧簇成像仍然面临挑战. 本文设计并合成了一种响应型的¹⁹F磁共振成像(MRI)探针(Gd-DPBF), 并将其用于实现对活体内通用活性氧簇的检测和成像. 该探针由钆螯合物通过活性氧簇响应的芳香硼酸酯键与含氟砌块相连接构成. 体外和体内成像实验结果证实, 该探针可以实现在活体荷瘤小鼠中针对肿瘤中高表达的活性氧进行检测和成像, 展示了其在生物体内对活性氧簇相关生理过程进行深组织、 零生物背景成像方面的潜力.     

T1-T2双模式磁共振造影剂的设计及应用

核磁共振成像作为一种无侵入的早期诊断方式早已在临床上得到了非常广泛的应用,其成像方式分为弛豫加权和扩散加权,其中弛豫加权又分为T₁加权成像和T₂加权成像。为了增强MR图像对比度,可通过引入造影剂,根据其增强类型可以分为阳性的T₁造影剂和阴性的T₂造影剂。虽然两种造影剂各有其优点,但是也存在着一些不足,因此一种全新的T₁-T₂双模态造影剂应运而生。T₁-T₂双模态造影剂的优势就在于可以利用同一台仪器,实现MRI成像在时间和空间上的精确匹配。本文系统地总结了T₁-T₂双模态造影剂的设计思路和其化学合成方法,并对其生物医学应用作了介绍。     

Relaxometric investigations and MRI evaluation of a liposome-loaded pH-responsive gadolinium(III) complex

Accurate measurement of the tissue pH in vivo by MRI may be of clinical value for both diagnosis and selection/monitoring of therapy. To act as pH reporters, MRI contrast agents have to provide responsiveness to pH that does not require prior knowledge of the actual concentration of the contrast agent. This work deals with the use of a paramagnetic gadolinium(III) complex, loaded into liposomes, whose relaxometric properties are affected by the pH of the medium. In this system, the amphiphilic metal complex, which contains a moiety whose protonation changes the coordination properties of the metal chelate, experiences a different intraliposomial distribution depending on the pH conditions. The pH of the solution can be unambiguously identified by exploiting the peculiar characteristics of the resulting NMRD profiles, and a ratiometric pH-responsive method has been set up by comparing the relaxation enhancement at different magnetic field strengths.     

Supramolecular aggregates of amphiphilic gadolinium complexes as blood pool MRI/MRA contrast agents: physicochemical characterization

In this paper, we present the development of a new potential blood pool contrast agent for magnetic resonance imaging applications (MRA/MRI) based on gadolinium complexes containing amphiphilic supramolecular aggregates. A novel amphiphilic unimer, containing the DTPAGlu chelating agent covalently bound to two C18 alkylic chains, has been synthesized. DTPAGlu is a well-known chelating agent for a wide number of ions such as the paramagnetic metal ion Gd3+ used as contrast agent in MRA/MRI. The wide aggregation behavior of this surfactant, as free base or as gadolinium complex, has been studied and compared by means of dynamic light scattering, small-angle neutron scattering and cryogenic transmission electron microscopy techniques. Near neutral pH in both cases, the dominant aggregates are micelles.The high negative actual charge of the surfactant headgroup causes a strong headgroups repulsion, promoting the formation of large and high curvature aggregates. By decreasing pH and less markedly increasing the ionic strength, we observe a micelle-to-vesicle transition driven by a decreased electrostatic repulsion. A straightforward switch between different aggregation states can be particularly useful in the development of pH-responsive MRA/MRI contrast agents.     

Recent advances on stimuli-responsive macromolecular magnetic resonance imaging (MRI) contrast agents

Magnetic resonance imaging(MRI) has been extensively used in clinical diagnosis and currently over 30% MRI runs are performed in the presence of contrast agents. However, commercially available contrast agents originated from small molecules typically exhibit relatively low relaxivities and insufficient circulation time. Therefore, there is a long pursuit to develop new contrast agents with high relaxivities to discriminate pathological tissues from normal ones. Compared with small molecule MRI contrast agents, the incorporation of small molecule contrast agents into macromolecular scaffolds allows for constructing macromolecular MRI contrast agents, remarkably elevating the relaxivities due in part to increased rotational correlation time(τR). Moreover, if the macromolecular scaffolds are responsive to external stimuli, the MRI signals could be selectively switched on at the desired sites(e.g., pathological tissues), further intensifying the imaging contrast. In this feature article, we outline the recent achievements in the fabrication of stimuli-responsive macromolecular MRI contrast agents. Specifically, macromolecular contrast agents being responsive to acidic p H, redox potentials, and other stimuli including photoirradiation, pathogens, and salt concentration are discussed. These smart contrast agents could affect either longitudinal(T1) or transverse(T2) relaxation times of water protons or other nuclei(e.g.,19 F), exhibiting enhanced signals in pathological tissues yet suppressed signals in normal ones and displaying promising potentials in in vitro and in vivo MRI applications.     

Lanthanide(III) chelates as MRI contrast agents: A brief description

Magnetic resonance imaging (MRI) has become a prominent imaging technique in medicine. Gadoliniumbased contrast agents are extensively used to enhance the contrast between normal and diseased tissues through MRI scans. The article illustrates the paramount significance of such contrast agents in MRI applications. Clinically approved contrast agents as well as those in trial period are discussed. Important parameters, i.e. hydration number, rotational correlation time, and mean residence lifetime, influencing the relaxivity (sensitivity) of such agents are described in detail. Various approaches towards relaxivity enhancement are discussed with appropriate examples from the recent literature. A decrease in the Gdwater proton distance results in significant relaxivity enhancement. A comprehensive classification and explanation of Gd³⁺-based contrast agents are presented. Each class is explained with suitable examples. The stability of contrast agents is dependent on their chemical structure. Future contrast agents need to be tissue specific of high relaxivity, low toxicity, and lower administered dose for in vivo use.     

A conjugated polymer-Gd (III) complex as pH sensitive contrast agent in magnetic resonance imaging

A novel pH-responsive contrast agent (PFP-aa/Gd) for magnetic resonance imaging (MRI) was prepared by binding Gd(III) to a water-soluble conjugated polyfluorene with pendant carboxylate and amine moieties. The PFP-aa is a good chelator for Gd³⁺ and the PFP-aa/Gd complex has good stability. As the pH changes from 10.0 to 4.0, both the carboxylate and amine are protonated, thus PFP-aa exhibits positive charges and forms tight aggregation, which reduces molecular tumbling and accelerates the exchange of bound water leading to the increase of relaxivity R ₁. More importantly, the R ₁ increases by about eight fold as the pH changes from 8.0 to 6.0, which makes PFP-aa/Gd suitable as a potential marker of the pH below physiological level. In comparison to other contrast agents, the unique sensitivity of the water relaxivity of PFP-aa/Gd indicates that this complex could be used in MRI experiments to monitor physiological pH change.     

Cellular delivery of MRI contrast agents

Magnetic resonance imaging (MRI) is a powerful tool for acquiring images of opaque living animals with the benefit of tracking events over extended periods of time on the same specimen. Contrast agents are used to enhance regions, tissues, and cells that are magnetically similar but histologically distinct. A principal barrier to the development of MRI contrast agents for investigating biological questions is the delivery of agents across cellular membranes. Here, we describe the synthesis and in vitro testing of Gd(III)-based MRI contrast agents containing varying length polyarginine oligomers capable of permeating cell membranes. We examine the effect of the length of oligomer on T(1) enhancement and cellular uptake. Furthermore, the effect of incubation time, concentration, and cell type on uptake is explored. Toxicity and washout studies are performed in addition to MRI phantom studies.     

Development of Macrocyclic Mn(II)−Bispyridine Complexes as pH-Responsive Magnetic Resonance Imaging Contrast Agents

In this study, macrocyclic complexes of Mn (II) with pH-responsive relaxivities were developed. The ligands were based on the rigid MPi platform, which was composed of a triazacyclononane (TACN) macrocycle and two picolyl pendant arms. An aryl sulfonamide moiety introduced in the skeleton of MPi endowed the final Mn complex (Mn−MPA) with pH-sensitive relaxivities. Mn−MPA showed a ∼3-fold increase in longitudinal relaxivity associated with the protonation and decoordination of the sulfonamide group in an acidic environment. We found that it was feasible to tune the pH window of the complexes by choosing proper substituents on the aromatic ring or modifying on the picolyl pendants. Considering the good kinetic inertness, rapid and efficient response to pH stimuli, and easy modulation characteristics, Mn−MPAs can be considered ideal candidates for use as acidic microenvironment-specific MRI contrast agents.     

Rotaxane Probes for the Detection of Hydrogen Peroxide by 129Xe HyperCEST NMR Spectroscopy

The development of sensitive and chemically selective MRI contrast agents is imperative for the early detection and diagnosis of many diseases. Conventional responsive contrast agents used in ¹H MRI are impaired by the high abundance of protons in the body. ¹²⁹Xe hyperCEST NMR/MRI comprises a highly sensitive complement to traditional ¹H MRI because of its ability to report specific chemical environments. To date, the scope of responsive ¹²⁹Xe NMR contrast agents lacks breadth in the specific detection of small molecules, which are often important markers of disease. Herein, we report the synthesis and characterization of a rotaxane‐based ¹²⁹Xe hyperCEST NMR contrast agent that can be turned on in response to H₂O₂, which is upregulated in several disease states. Added H₂O₂ was detected by ¹²⁹Xe hyperCEST NMR spectroscopy in the low micromolar range, as well as H₂O₂ produced by HEK 293T cells activated with tumor necrosis factor.     

Synthesis and relaxometric studies of a dendrimer-based pH-responsive MRI contrast agent

The design of effective pH responsive MRI contrast agents is a key goal in the development of new diagnostic methods for conditions such as kidney disease and cancer. A key factor determining the effectiveness of an agent is the difference between the relaxivity of the "on" state compared to that of the "off" state. In this paper, we demonstrate that it is possible to improve the pH-responsive action of a low molecular weight agent by conjugating it to a macromolecular construct. The synthesis of a bifunctional pH responsive agent is reported. As part of that synthetic pathway we examine the Ing-Manske reaction, identifying an undesirable by-product and establishing effective conditions for promoting a clean and effective reaction. Reaction of the bifunctional pH responsive agent with a G5-PAMAM dendrimer yielded a product with an average of 96 chelates per dendrimer. The relaxivity of the dendrimer conjugate rises from 10.8 mM(-1) s(-1) (pH 9) to 24.0 mM(-1) s(-1) (pH 6) per Gd(3+) ion. This more than doubles the relaxivity pH response, Deltar(1), of our agent from just 51 % for the original low molecular weight chelate to 122 % for the dendrimer.     

Dual MRI-SPECT agent for pH-mapping

A new dual MRI/SPECT pH-responsive agent where the SPECT active moiety acts as reporter of the concentration making it possible to exploit the responsiveness of the MRI probe.