二乙三胺四乙酸双核钆磁共振成像造影剂的合成及其弛豫性能

合成了以对苯二甲酰基(TP)为连接体的双核Gd-DTTA(DTTA:二乙三胺四乙酸)线型磁共振造影剂Gd2(TP(DTTA)2)。 在20 MHz、37 ℃和pH=7的条件下,此造影剂对水质子的纵向弛豫效率为21.7 L/(mmol·s),比已有的双核Gd-DTTA型磁共振造影剂提高了70%。 荧光寿命测试显示,Tb2(TP(DTTA)2)的内配层水分子数q=1.4。 结果显示,刚性连接链有利于提高多核造影剂的弛豫效率。     

Gadolinium(III)-loaded nanoparticulate zeolites as potential high-field MRI contrast agents: relationship between structure and relaxivity

The effects of dealumination, pore size, and calcination on the efficiency (as expressed in the relaxivity) of Gd3+-loaded zeolites for potential application as magnetic resonance imaging (MRI) contrast agents were studied. Partial dealumination of zeolites NaY or NaA by treatment with (NH4)2SiF6 or diluted HCl resulted in materials that, upon loading with Gd3+, had a much higher relaxivity than the corresponding non-dealuminated materials. Analysis of the 1H NMR dispersion profiles of the various zeolites showed that this can be mainly ascribed to an increase of the amount of water inside the zeolite cavities as a result of the destruction of walls between cavities. However, the average residence time of water inside the Gd3+-loaded cavities did not change significantly, which suggests that the windows of the Gd3+-loaded cavities are not affected by the dealumination. Upon calcination, the Gd3+ ions moved to the small sodalite cavities and became less accessible for water, resulting in a decrease in relaxivity. The important role of diffusion for the relaxivity was demonstrated by a comparison of the relaxivity of Gd3+-loaded zeolite NaY and NaA samples. NaA had much lower relaxivities due to the smaller pore sizes. The transversal relaxivities of the Gd3+-doped zeolites are comparable in magnitude to the longitudinal ones at low magnetic fields (<60 MHz). However at higher fields, the transversal relaxivities steeply increased, whereas the longitudinal relaxivities decreased as field strength increased. Therefore, these materials have potential as T1 MRI contrast agents at low field, and as T2 agents at higher fields.     

用于疾病诊断的Gd~Ⅲ/量子点多模态成像探针的构建

结合核磁共振成像(MRI)和荧光成像技术,以钆离子、近红外低毒量子点、二氧化硅和聚丙烯酸(PAA)等为原料,采用一系列纳米载体自组装技术,构建出MRI弛豫率/荧光效率高和生物相容性好的GdⅢ/量子点多模态纳米探针.结果表明,与未螯合GdⅢ的量子点纳米探针相比,GdⅢ/量子点多模态纳米探针具有更高的弛豫率;t1-加权MRI成像也证实了GdⅢ/量子点多模态纳米探针具有很好的阳性造影功效.     

Multivalent, high-relaxivity MRI contrast agents using rigid cysteine-reactive gadolinium complexes

MRI contrast agents providing very high relaxivity values can be obtained through the attachment of multiple gadolinium(III) complexes to the interior surfaces of genome-free viral capsids. In previous studies, the contrast enhancement was predicted to depend on the rigidity of the linker attaching the MRI agents to the protein surface. To test this hypothesis, a new set of Gd-hydroxypyridonate based MRI agents was prepared and attached to genetically introduced cysteine residues through flexible and rigid linkers. Greater contrast enhancements were seen for MRI agents that were attached via rigid linkers, validating the design concept and outlining a path for future improvements of nanoscale MRI contrast agents.     

Synthesis and relaxivity of Gd(Ⅲ), Fe(Ⅲ) and Mn(Ⅱ)complexes with dihydropyridine derivative of diethylenetriaminepentaacetic acid

A novel ligand of DTPA-dihydropyridine derivative was synthesized by reaction of DTPA-dianhydride with 4-aniline-1,4-dihydropyridine. Its complexes of gadolinium, manganese and iron were prepared. Their spin-lattice relaxivities (T1) were investigated. The results show that the NMR T1 relaxivitives (R1) for complexes of Fe(Ⅲ), Mn(Ⅱ) are less than that of Gd(Ⅲ) complex,which has a high relaxivity (R1) on the surrounding water protons, indicating that the Gd(Ⅲ) complex possesses the precondition to be contrast agents for magnetic resonance imaging.     

(1)H relaxivity of water in aqueous suspensions of Gd(3+)-loaded NaY nanozeolites and AlTUD-1 mesoporous material: the influence of Si/Al ratio and pore size

The results of a (1)H nuclear magnetic relaxation dispersion (NMRD) and EPR study on aqueous suspensions of Gd(3+)-loaded NaY nanozeolites and AlTUD-1 mesoporous material are described. Upon increase of the Si/Al ratio from 1.7 to 4.0 in the Gd(3+)-loaded zeolites, the relaxation rate per mM Gd(3+) (r1) at 40 MHz and 25 degrees C increases from 14 to 27 s(-)1 mM(-1). The NMRD and EPR data were fitted with a previously developed two-step model that considers the system as a concentrated aqueous solution of Gd(3+) in the interior of the zeolite that is in exchange with the bulk water outside the zeolite. The results show that the observed increase in relaxivity can mainly be attributed to the residence lifetime of the water protons in the interior of the material, which decreased from 0.3 to 0.2 micros, upon the increase of the Si/Al ratio. This can be explained by the decreased interaction of water with the zeolite walls as a result of the increased hydrophobicity. The importance of the exchange rate of water between the inside and the outside of the material was further demonstrated by the relatively high relaxivity (33 s(-1) mM(-1) at 40 MHz, 25 degrees C) observed for a suspension of the Gd(3+)-loaded mesoporous material AlTUD-1. Unfortunately, Gd(3+) leaches rather easily from that material, but not from the Gd(3+)-loaded NaY zeolites, which may have potential as contrast agents for magnetic resonance imaging.     

Zeolite GdNaY nanoparticles with very high relaxivity for application as contrast agents in magnetic resonance imaging

In this paper we explore Gd(3+)-doped zeolite NaY nanoparticles for their potential application as a contrast agent in magnetic resonance imaging (MRI). The nanoparticles have an average size of 80-100 nm, as determined by TEM and XRD. A powdered sample loaded with La3+ was characterised by means of multinuclear solid-state NMR spectroscopy. The NMR dispersion (NMRD) profiles obtained from aqueous suspensions of samples with Gd3+ doping ratios of 1.3-5.4 wt% were obtaining at different temperatures. The relaxivity increases drastically as the Gd3+ loading decreases, with values ranging between 11.4 and 37.7 s-1 mM-1 at 60 MHz and 37 degrees C. EPR spectra of aqueous suspensions of the samples suggest that an interaction between neighbouring Gd3+ ions within the same particle produces a significant increase in the transversal electronic relaxation rates in samples with a high Gd3+ content. The experimental NMRD and EPR data are explained with the use of a model that considers the system as a concentrated aqueous solution of Gd3+ in the interior of the zeolite that is in exchange with the bulk water outside the zeolite. The results obtained indicate that the Gd3+ ion is immobilised in the interior of the zeolite and that the relaxivity is mainly limited by the relatively slow diffusion of water protons from the pores of the zeolite channels into the bulk water.     

Water Exchange and Rotational Dynamics of the Dimeric Gadolinium(III) Complex [BO{Gd(DO3A)(H(2)O)}(2)]: A Variable-Temperature and -Pressure (17)O NMR Study(1)

Rapid water exchange and slow rotation are essential for high relaxivity MRI contrast agents. A variable-temperature and -pressure (17)O NMR study at 14.1, 9.4, and 1.4 T has been performed on the dimeric BO(DO3A)(2), 2,11-dihydroxy-4,9-dioxa-1,12-bis[1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl]dodecane, complex of Gd(III). This complex is of relevance to MRI as an attempt to gain higher (1)H relaxivity by slowing down the rotation of the molecule compared to monomeric Gd(III) complexes used as contrast agents. From the (17)O NMR longitudinal and transverse relaxation rates and chemical shifts we determined the parameters characterizing water exchange kinetics and the rotational motion of the complex, both of which influence (1)H relaxivity. The rate constant and the activation enthalpy for the water exchange, k(ex) and DeltaH(), are (1.0 +/- 0.1) x 10(6) s(-)(1)and (30.0 +/- 0.2) kJ mol(-)(1), respectively, and the activation volume, DeltaV(), of the process is (+0.5 +/- 0.2) cm(3) mol(-)(1), indicating an interchange mechanism. The rotational correlation time becomes about three times longer compared to monomeric Gd(III) polyamino-polyacetate complexes studied so far: tau(R) = (250 +/- 5) ps, which results in an enhanced proton relaxivity by raising the correlation time for the paramagnetic interaction.     

A Gd3+-based magnetic resonance imaging contrast agent sensitive to beta-galactosidase activity utilizing a receptor-induced magnetization enhancement (RIME) phenomenon

Magnetic resonance imaging (MRI) permits noninvasive three-dimensional imaging of opaque organisms. Gadolinium (Gd(3+)) complexes have become important imaging tools as MRI contrast agents for MRI studies, though most of them are nonspecific and report solely on anatomy. Recently, MRI contrast agents have been reported whose ability to relax water protons is triggered or greatly enhanced by recognition of a particular biomolecule. This new class of MRI contrast agents could open up the possibility of reporting on the physiological state or metabolic activity deep within living specimens. One possible strategy for this purpose is to utilize the increase in the longitudinal water proton r(1) relaxivity that occurs upon slowing the molecular rotation of a small paramagnetic complex, a phenomenon which is known as receptor-induced magnetization enhancement (RIME), by either binding to a macromolecule or polymerization of the agent itself. Here we describe the design and synthesis of a novel beta-galactosidase-activated MRI contrast agent, the Gd(3+) complex [Gd-5], by using the RIME approach. beta-Galactosidase is commonly used as a marker gene to monitor gene expression. This newly synthesized compound exhibited a 57% increase in the r(1) relaxivity in phosphate-buffered saline (PBS) with 4.5% w/v human serum albumin (HSA) in the presence of beta-galactosidase. Detailed investigations revealed that RIME is the dominant factor in this increase of the observed r(1) relaxivity, based on analysis of Gd(3+) complexes [Gd-5] and [Gd-8], which is generated from [Gd-5] by the activity of beta-galactosidase, and spectroscopic analysis of their corresponding Tb(3+) complexes, [Tb-5] and [Tb-8].     

Strategies for increasing relaxivity of gold nanoparticle based MRI contrast agents

The factors limiting the relaxivity (r) of MRI contrast agents based on small (～2.0 nm) gold nanoparticles functionalised with paramagnetic chelates were explored using EPR spectroscopy. The EPR analysis suggested that nanoparticle-attached chelates exhibit relatively high tumbling rates which restrict their relaxivity. Two different strategies were employed in order to test this hypothesis and hence improve the relaxivity of the nanoparticle-based contrast agents. In the first approach, the particle diameter was increased. This resulted in lower surface curvature and hence tighter ligand packing, which in turn led to increased relaxivity. In the second approach, the nanoparticles were overcoated with multilayers of oppositely charged polyelectrolytes. The restricted motion of Gd(3+) chelates coated by 2-4 polymer layers led to increased relaxivity which was dramatically reduced for thicker layers, presumably due to restricted diffusion of water molecules.     

Gd-complexes of DTPA-bis(amide) conjugates of tranexamic acid and its esters with high relaxivity and stability for magnetic resonance imaging

The synthesis and the characterization of a series of DTPA-bis(amide) conjugates of tranexamic acid (L1), its esters (L2-L6), and their Gd(III) complexes of the type [Gd(L)(H2O)].nH2O (L = L1-L6) are described. Except for the case of , all Gd-complexes exhibit greatly enhanced R1 relaxivity. Highest R1 reaches up to 12.9 mM(-1) s(-1) for [Gd(L2)(H2O)]. Such high relaxivity is reflected in the intensity enhancement of the in vivo MRI study on H-ras transgenic mice bearing hepatic tumor when employing [Gd(L2)(H2O)] as an MRI contrast agent. Thermodynamic stability constants, conditional stability constants, and the pM values demonstrate higher stability of [Gd(L)(H2O)].nH2O (L =L1-L6) than Omniscan under physiological conditions. The MTT assay performed on these complexes reveals cytotoxicity as low as that for Omniscan in the concentration range required to obtain intensity enhancement in the in vivo MRI study.     

Platinum(II)–Gadolinium(III) Complexes as Potential Single‐Molecular Theranostic Agents for Cancer Treatment

Theranostic agents are emerging multifunctional molecules capable of simultaneous therapy and diagnosis of diseases. We found that platinum(II)–gadolinium(III) complexes with the formula [{Pt(NH₃)₂Cl}₂GdL](NO₃)₂ possess such properties. The Gd center is stable in solution and the cytoplasm, whereas the Pt centers undergo ligand substitution in cancer cells. The Pt units interact with DNA and significantly promote the cellular uptake of Gd complexes. The cytotoxicity of the Pt–Gd complexes is comparable to that of cisplatin at high concentrations (≥0.1 mM ), and their proton relaxivity is higher than that of the commercial magnetic resonance imaging (MRI) contrast agent Gd–DTPA. T₁‐weighted MRI on B6 mice demonstrated that these complexes can reveal the accumulation of platinum drugs in vivo. Their cytotoxicity and imaging capabilities make the Pt–Gd complexes promising theranostic agents for cancer treatment.     

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.     

Synthesis and relaxivity studies of a tetranuclear gadolinium(III) complex of DO3A as a contrast-enhancing agent for MRI

A tetranuclear gadolinium(III) complex, [Gd4(H2O)8], of DO3A appended onto the pentaerythrityl framework was synthesized to improve the water proton relaxivity for MRI application. The longitudinal relaxivity of [Gd4(H2O)8] is 28.13 mM-1 s-1 (24 MHz, 35+/-0.1 degrees C, pH 5.6) which is 5.86 times higher than that of [Gd(DO3A)(H2O)2]. The relaxivity is based on "molecular" relaxivity of the tetramer and the r1p value is "7 per Gd". The high relaxivity of the tetramer is the result of the decrease in the rotational correlation (tauR) and the presence of eight inner-sphere water molecules (q=8). The complex exhibits pH-dependent longitudinal relaxivity, and the high relaxivity both at low and high pH (r1p=28.13 mM-1 s-1 at pH 5.6 and 16.52 mM-1 s-1 at pH 9.5) indicates that it could be used as a pH-responsive MRI contrast agent. The transverse relaxivity of the tetramer is 129.97 mM-1 s-1 (24 MHz, 35+/-0.1 degrees C, pH 5.6), and the r2p/r1p ratio of 4.6 shows that it could be used as a T2-weighted contrast agent.     

Dendrimeric gadolinium chelate with fast water exchange and high relaxivity at high magnetic field strength

The synthesis and relaxivity properties of a new dendrimeric Gd chelate, Gd-TREN-bisHOPO-TAM-Asp-Asp2-12OH, are presented. The macromolecule demonstrates improved water solubility due to its 12 terminal hydroxyl groups and improved relaxivity due to its optimal water exchange rate and slower molecular tumbling. Unprecedented high relaxivity (r1p = 18 mM-1 s-1) is observed at high magnetic field (90 MHz), an important advance in the development of contrast agents for the next generation of MRI scanners.     

Synthesis,Relaxivity and MRI Enhancement of Linear Oligo‐Gd(III) Complexes with Poly (DTPA‐ester) Ligands Derived from Amino Acids

Six linear oligo‐DTPA‐ester Gd(III) complexes being used for potential MRI contrast agents were synthesized from amino adds and characterized. Their longitudinal relaxation rates were measured. One of them, die phenylalanine derivative, with high relaxivity, was chosen for the acute toxicity and T₁,‐weighted imaging test. The results indicated that there was no obvious toxicity for this new oligomeric Gd(III) complex, and it exhibits the highly enhanced MRI signal intensity and the increasing signal duration in the liver tissue compared to Gd‐DTPA.     

Gold nanoparticles functionalised with stable, fast water exchanging Gd3+ chelates as high relaxivity contrast agents for MRI

Gold nanoparticles functionalized with Gd(3+) chelates displaying fast water exchange, superb pH stability and inertness towards transmetalation with Zn(2+) have been prepared and characterized as a new high relaxivity (29 mM(-1) s(-1), 30 MHz, 25 °C) contrast agent potentially safe for in vivo MRI applications. The Lipari-Szabo treatment for internal rotation was used to evaluate the effect of linker flexibility on the relaxivity of the gold nanoparticles. The effect of fast water exchange on the relaxivity of gold nanoparticles functionalized with Gd(3+) chelates is also addressed in this communication.     

钆基富勒烯磁共振成像分子影像探针的研究进展

含有顺磁性金属钆离子及钆团簇的内嵌金属富勒烯(如Gd@C82,Gd@C60和Gd3 N@C80)及其衍生物是一类高效的MRI分子影像探针,其造影效率远优于传统钆基螯合物造影剂.重要的是,碳笼的高度稳定性保护了内嵌团簇,使之免受体内代谢物质的进攻和防止了外泄,从而大大提高了其生物安全性.同时,碳笼还是其它生物活性物质或分子影像探针的有效载体,易赋予其多功能性,从而提高疾病检测的灵敏度和准确性.本文介绍了多种钆内嵌金属富勒烯分子影像探针的研究进展,讨论了内嵌金属团簇和笼外化学修饰对其弛豫性能的影响,以及不同的功能基团对其生物相容性和动物体内分布的影响,并展望了其兼具多功能分子影像探针载体的应用前景.     

Structurally Defined Water-Soluble Metallofullerene Derivatives towards Biomedical Applications

Endohedral metallofullerenes (EMFs) are excellent carriers of rare-earth element (REE) ions in biomedical applications because they preclude the release of toxic metal ions. However, existing approaches to synthesize water-soluble EMF derivatives yield mixtures that inhibit precise drug design. Here we report the synthesis of metallobuckytrio (MBT), a three-buckyball system, as a modular platform to develop structurally defined water-soluble EMF derivatives with ligands by choice. Demonstrated with PEG ligands, the resulting water-soluble MBTs show superb biocompatibility. The Gd MBTs exhibit superior T₁ relaxivity than typical Gd complexes, potentially superseding current clinical MRI contrast agents in both safety and efficiency. The Lu MBTs generated reactive oxygen species upon light irradiation, showing promise as photosensitizers. With their modular nature to incorporate other ligands, we anticipate the MBT platform to open new paths towards bio-specific REE drugs.     

A new metallostar complex based on an aluminum(iii) 8-hydroxyquinoline core as a potential bimodal contrast agent

A ditopic DTPA monoamide derivative containing an 8-hydroxyquinoline moiety was synthesized and the corresponding gadolinium(iii) complex ([Gd(H5)(H(2)O)](-)) was prepared. After adding aluminum(iii), the 8-hydroxyquinoline part self-assembled into a heteropolymetallic triscomplex [(Gd5)(3)Al(H(2)O)(3)](3-). The magnetic and optical properties of this metallostar compound were investigated in order to classify it as a potential in vitro bimodal contrast agent. The proton nuclear magnetic relaxation dispersion measurements indicated that the relaxivity r(1) of [Gd(H5)(H(2)O)](-) and [(Gd5)(3)Al(H(2)O)(3)](3-) at 20 MHz and 310 K equaled 6.17 s(-1) mM(-1) and 10.9 s(-1) mM(-1) per Gd(iii) ion respectively. This corresponds to a relaxivity value of 32.7 s(-1) mM(-1) for the supramolecular complex containing three Gd(iii) ions. The high relaxivity value is prominently caused by an increase of the rotational tumbling time τ(R) by a factor of 2.7 and 5.5 respectively, in comparison with the commercially used MRI contrast agent Gd(iii)-DTPA (Magnevist?). Furthermore, upon UV irradiation, [(Gd5)(3)Al(H(2)O)(3)](3-) exposes green broad-band emission with a maximum at 543 nm. Regarding the high relaxivity and the photophysical properties of the [(Gd5)(3)Al(H(2)O)(3)](3-) metallostar compound, it can be considered as a lead compound for in vitro bimodal applications.