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.     

A self-assembled complex with a titanium(IV) catecholate core as a potential bimodal contrast agent

A ditopic chelating ligand (H(6)4) that bears catechol and diethylenetriamine-N,N,N',N',N'-pentaacetate (DTPA) has been designed and shown to specifically bind lanthanide(III) ions at the DTPA core ([Ln(H(2)4)(H(2)O)](-)) and further self-assemble with titanium(IV), thereby giving rise to the formation of a supramolecular metallostar complex with a lanthanide(III)-to-titanium(IV) ratio of 3:1, [(Ln4)(3)Ti(H(2)O)(3)](5-) (Ln=La, Eu, Gd). The efficacy of the metallostar complex as a potential bimodal optical/magnetic resonance imaging (MRI) agent has been evaluated. Nuclear magnetic relaxation dispersion (NMRD) measurements for the [(Gd4)(3)Ti(H(2)O)(3)](5-) complex have demonstrated an enhanced r(1) relaxivity that corresponds to 36.9 s(-1) mM(-1) per metallostar molecule at 20 MHz and 310 K, which is a result of a decreased tumbling rate. The ability of the complex to bind to human serum albumin (HSA) was also examined by relaxometric measurements. In addition, upon UV irradiation the [(Gd4)(3)Ti(H(2)O)(3)](5-) complex exhibits broad-band green emission in the range 400-750 nm with a maximum at 490 nm. Taking into account the high relaxivity and luminescence properties, the [(Gd4)(3)Ti(H(2)O)(3)](5-) complex is a good lead compound for the development of efficient bimodal contrast agents.     

Synthesis, thermodynamics stability constant and relaxation properties of neutral Gd(III) complex with derivative from diethylene triamine pentaacetic acid and p-hydroxybenzoyl hydrazine

A novel ligand, diethylenetriamine-N,N'-bis(acetyl-p-hydroxybenzoyl hydrazine)-N,N',N'-triacetic acid (H3L) was synthesized and characterized on the basis of elemental analysis, molar conductivity, 1H-NMR spectrum, FAB-MS, TG-DTA analysis and IR spectrum. Its complex of Gd(III) holding promise of magnetic resonance imaging (MRI) was synthesized, and relaxivity (R1) of complex and Gd(DTPA)2- used as a control was determined in water solution, respectively. The relaxivity of GdL (R1 = 6.39 l.mmol(-1).s(-1)) was larger than that of Gd(DTPA)2- (R1 = 4.34 l.mmol(-1).s(-1)). The relaxivity of GdL has also been investigated in human serum albumin (HSA) solution, the relaxivity of GdL was enhanced from 6.39 l.mmol(-1).s(-1) in water solution to 7.69 l.mmol(-1).s(-1) in HSA solution. In addition, thermodynamics stability constant of GdL was determined. The results showed that complex of GdL is a prospective MRI contrast agent, although the thermodynamic stability constant of GdL complex (K(GdL) = 10(19.56)) was a little less than that of Gd(DTPA)2- (K(Gd-DTPA) = 10(20.73)).     

A heterobimetallic ruthenium-gadolinium complex as a potential agent for bimodal imaging

Trinuclear heterobimetallic Ln(III)-Ru(II) complexes (Ln = Eu, Gd) based on a 1,10-phenanthroline ligand bearing a diethylenetriaminepentaacetic acid (DTPA) core have been synthesized and fully characterized by a range of experimental techniques. The (17)O NMR and proton nuclear magnetic relaxation dispersion (NMRD) measurements of Gd(III)-Ru(II) show that, in comparison to the parent Gd-DTPA, this complex exhibits improved relaxivity, which is the result of an increase of the rotational correlation time. Relaxometry and ultrafiltration experiments indicate that the 1,10-phenanthroline ligand has a high affinity for noncovalent binding to human serum albumin, which results in a high relaxivity r(1) of 14.3 s(-1) mM(-1) at 20 MHz and 37 °C. Furthermore, the Ln(III)-Ru(II) complexes (Ln = Eu, Gd) show an intense light absorption in the visible spectral region due to metal-to-ligand charge transfer (MLCT) transitions. Upon excitation into the MLCT band at 440 nm, the complexes exhibit a bright-red luminescence centered at 610 nm, with a quantum yield of 4.7%. The luminescence lifetime equals 540 ns and is therefore long enough to exceed the fluorescent background. Monometallic lanthanide complexes have also been synthesized, and the Eu(III) analogue shows a characteristic red luminescence with a quantum yield of 0.8%. Taking into account the relaxometric and luminescent properties, the developed Gd(III)-Ru(II) complex can be considered as a potential in vitro bimodal imaging agent.     

Synthesis and characterization of a hypoxia-sensitive MRI probe

Tissue hypoxia occurs in pathologic conditions, such as cancer, ischemic heart disease and stroke when oxygen demand is greater than oxygen supply. An imaging method that can differentiate hypoxic versus normoxic tissue could have an immediate impact on therapy choices. In this work, the gadolinium(III) complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) with a 2-nitroimidazole attached to one carboxyl group via an amide linkage was prepared, characterized and tested as a hypoxia-sensitive MRI agent. A control complex, Gd(DO3A-monobutylamide), was also prepared in order to test whether the nitroimidazole side-chain alters either the water proton T(1) relaxivity or the thermodynamic stability of the complex. The stabilities of these complexes were lower than that of Gd(DOTA)(-) as expected for mono-amide derivatives. The water proton T(1) relaxivity (r(1)), bound water residence lifetime (τ(M)) and rotational correlation time (τ(R)) of both complexes was determined by relaxivity measurements, variable temperature (17) O?NMR spectroscopy and proton nuclear magnetic relaxation dispersion (NMRD) studies. The resulting parameters (r(1) =6.38?mM(-1) s(-1) at 20?MHz, τ(M) =0.71?μs, τ(R) =141?ps) determined for the nitroimidazole derivative closely parallel to those of other Gd(DO3A-monoamide) complexes of similar molecular size. In vitro MR imaging experiments with 9L rat glioma cells maintained under nitrogen (hypoxic) versus oxygen (normoxic) gas showed that both agents enter cells but only the nitroimidazole derivative was trapped in cells maintained under N(2) as evidenced by an approximately twofold decrease in T(1) measured for hypoxic cells versus normoxic cells exposed to this agent. These results suggest that the nitroimidazole derivative might serve as a molecular reporter for discriminating hypoxic versus normoxic tissues by MRI.     

High-relaxivity magnetic resonance imaging (MRI) contrast agent based on supramolecular assembly between a gadolinium chelate, a modified dextran, and poly-beta-cyclodextrin

Nanosized contrast agents have great potential in magnetic resonance molecular imaging applications for clinical diagnosis. This study proposes new nanoparticles spontaneously formed under mild conditions and composed of a noncovalent adduct between a gadolinium complex, a polymer of beta-cyclodextrin (pbetaCD: MW 1.5 x 10(6) g mol(-1)) and a dextran grafted with alkyl chains (MD). The formation of this supramolecular nanoassembly is based upon a "lock-and-key" recognition process in which the hydrophobic alkyl chains of MD and the adamantyl moieties of macrocyclic Gd(III) chelates are included in the cavities of pbetaCD. The large number of betaCDs contained in the pbetaCD resulted in the formation of 200 nm diameter nanoparticles, each entrapping 1.8 x 10(5) molecules of a low-molecular-weight Gd complex. This system, which exhibits a great relaxivity enhancement (48.4 mM(-1) s(-1), at 20 MHz and 37 degrees C) compared to the Gd(III) chelate itself (5.2 mM(-1) s(-1)), appears to be a promising strategy for the in vivo targeted delivery of Gd(III) complexes. The mechanisms of particle formation, conjugation strategies, and relaxometric characterizations in the field of contrast-enhanced magnetic resonance imaging are discussed.     

Synthesis neutral rare earth complexes of diethylenetriamine-N,N'-bis(acetyl-isoniazid)-N,N',N'-triacetic acid as potential contrast enhancement agents for magnetic resonance imaging

A novel ligand, diethylenetriamine-N,N'-bis(acetyl-isoniazid)-N,N',N'-triacetic acid (H(3)L) has been synthesized from diethylene triamine pentaacetic acid (DTPA) and isoniazid. Ligand and its five neutral rare earth (RE=La, Sm, Eu, Gd, Tb) complexes holding promise of magnetic resonance imaging (MRI) were characterized on the basis of elemental analysis, molar conductivity, (1)H-NMR spectrum, FAB-MS, TG-DTA analysis and IR spectrum. The relaxivity (R(1)) of complexes and Gd(DTPA)(2-) used as a control were determined. The relaxivity of LaL, SmL, EuL, GdL, TbL and Gd(DTPA)(2-) were 0.14, 1.66, 3.14, 6.08, 2.79 and 4.34 l.mmol(-1).s(-1), respectively. The spin-lattice relaxivity of GdL was larger than that of Gd(DTPA)(2-). The relaxivity of GdL had also been investigated in human serum albumin (HSA) solution, the relaxivity of GdL was enhanced from 6.08 l.mmol(-1).s(-1) in water solution to 9.09 l.mmol(-1).s(-1) in HSA solution. In addition, thermodynamics stability constant of GdL complex was determined, the thermodynamic stability constant of GdL complex (K(GdL)=10(20.84)) was a few larger than that of Gd(DTPA)(2-) (K(Gd-DTPA)=10(20.73)). The results showed that complex of GdL may be a prospective MRI contrast agent with low osmotic pressure due to non-ion complex, high spin-lattice relaxivity, good stability and binding affinity for the serum protein.     

Synthesis, characterization, and pharmacokinetic evaluation of a potential MRI contrast agent containing two paramagnetic centers with albumin binding affinity

A dinuclear gadolinium(III) complex of an amphiphilic chelating ligand, containing two diethylenetriamine-N,N,N',N',N'-pentaacetate (DTPA) moieties bridged by a bisindole derivative with three methoxy groups, has been synthesized and evaluated as a potential magnetic resonance imaging (MRI) contrast agent. Nuclear magnetic relaxation dispersion (NMRD) measurements indicate that at 20 MHz and 37 degrees C the dinuclear gadolinium(III) complex has a much higher relaxivity than [Gd(DTPA)] (6.8 vs 3.9 s(-1) mmol(-1)). The higher relaxivity of the dinuclear gadolinium(III) complex can be related to its reduced motion and larger rotational correlation time relative to [Gd(DTPA)]. In the presence of human serum albumin (HSA) the relaxivity value of the noncovalently bound dinuclear complex increases to 15.2 s(-1) per mmol of Gd3+, due to its relatively strong interaction with this protein. The fitted value of the binding constant to HSA (Ka) was found to be 10(4) M(-1). Because of its interaction with HSA, the dinuclear complex exhibits a longer elimination half-life from the plasma, and a better confinement to the vascular space compared to the commercially available [Gd(DTPA)] contrast agent. Transmetalation of the dinuclear gadolinium(III) complex by zinc(II) has been investigated. Biodistribution studies suggest that the complex is excreted by the renal pathway, and possibly by the hepatobiliary route. In vivo studies indicated that half of the normal dose of the gadolinium(III) complex enhanced the contrast in hepatic tissues around 40 % more effectively than [Gd(DTPA)]. The dinuclear gadolinium(III) complex was tested as a potential necrosis avid contrast agent (NACA), but despite the binding to HSA, it did not exhibit necrosis avidity, implying that binding to albumin is not a key parameter for necrosis-targeting properties.     

Synthesis and characterization of a novel paramagnetic macromolecular complex [Gd(TTDASQ-protamine)

Adenocarcinomas in rats and humans frequently contain perivascular, degranulating mast cells that release heparin. Protamine is a low-molecular weight, cationic polypeptide that binds to heparin and neutralizes its anticoagulant properties. A novel magnetic resonance imaging (MRI) contrast agent containing protamine was synthesized. TTDASQ, the derivative of TTDA (3,6,10-tri(carboxymethyl)-3,6,10-triazadodecanedioic acid), was also synthesized and the kinetic stability of [Gd(TTDASQ)]- chelate containing phosphate buffer and ZnCl2 to measure the relaxation rate (R1) at 20 MHz was studied by transmetallation with Zn(II). The water-exchange rate (k(ex)298) of [Gd(TTDASQ)]- is 6.4 x 10(6) s(-1) at 25.0 +/- 0.1 degrees C which was obtained from the reduced 17O relaxation rates (1/T(1r) and 1/T(2r)) and chemical shift (omega(r)) of H(2)17O, and it is compared with that previously reported for the other gadolinium(III) complex, [Gd(DO3ASQ)]. The binding affinity assay showed that the (TTDASQ)3-pro19 has higher activity toward heparin. On the other hand, the effect of heparin on the relaxivity of the [Gd(TTDASQ)3-pro19] conjugate shows the binding strength (K(A)) is 7669 dm3 mol(-1) at pH 7.4 and the relaxivity (r(b)1) of the [Gd(TTDASQ)3-pro19]-heparin adduct is 30.9 dm3 mmol(-1) s(-1).     

Preparation and characterization of two new water-soluble endohedral metallofullerenes as magnetic resonance imaging contrast agents

Two new water-soluble Gd-containing endohedral metallofullerenes [ScxGd3-xN@C80OmOHn (x = 1, 2; m approximately 12; n approximately 26)] were synthesized in a simple one-step reaction and characterized by Fourier transform (FT)-IR as well as X-ray photoelectron spectroscopy (XPS). Their observed longitudinal relaxivities (R1) for water protons are 20.7 and 17.6 mM(-1) s(-1), respectively, which are significantly higher than that of the commercial magnetic resonance imaging (MRI) contrast agent (Gd-DTPA, 3.2 mM(-1) s(-1)). These results indicate these trimetallic nitride endohedral fullerenols are potential next-generation high-efficiency MRI contrast agents.     

When are Two Waters Worse Than One? Doubling the Hydration Number of a Gd–DTPA Derivative Decreases Relaxivity

The synthesis of a novel ligand, based on N-methyl-diethylenetriaminetetraacetate and containing a diphenylcyclohexyl serum albumin binding group (L1) is described and the coordination chemistry and biophysical properties of its Gd(III) complex Gd-L1 are reported. The Gd(III) complex of the diethylenetriaminepentaacetate analogue of the ligand described here (L2) is the MRI contrast agent MS-325. The effect of converting an acetate to a methyl group on metal-ligand stability, hydration number, water-exchange rate, relaxivity, and binding to the protein human serum albumin (HSA) is explored. The complex Gd-L1 has two coordinated water molecules in solution, that is, [Gd(L1)(H2O)2]2- as shown by D-band proton ENDOR spectroscopy and implied by 1H and 17O NMR relaxation rate measurements. The Gd-H(water) distance of the coordinated waters was found to be identical to that found for Gd-L2, 3.08 A. Loss of the acetate group destabilizes the Gd(III) complex by 1.7 log units (log K(ML) = 20.34) relative to the complex with L2. The affinity of Gd-L1 for HSA is essentially the same as that of Gd-L2. The water-exchange rate of the two coordinated waters on Gd-L1 (k(ex) = 4.4x10(5) s(-1)) is slowed by an order of magnitude relative to Gd-L2. As a result of this slow water-exchange rate, the observed proton relaxivity of Gd-L1 is much lower in a solution of HSA under physiological conditions (r1(obs) = 22.0 mM(-1) s(-1) for 0.1 mM Gd-L1 in 0.67 mM HSA, HEPES buffer, pH 7.4, 35 degrees C at 20 MHz) than that of Gd-L2 (r1(obs) = 41.5 mM(-1) s(-1)) measured under the same conditions. Despite having two exchangeable water molecules, slow water exchange limits the potential efficacy of Gd-L1 as an MRI contrast agent.     

Mannan-coated liposome delivery of gadolinium-diethylenetriaminepentaacetic acid, a contrast agent for use in magnetic resonance imaging.

Gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA), a paramagnetic contrast agent for use in magnetic resonance imaging (MRI) was bound to stearylamine and incorporated into the liposomal membranes (Gd-DTPA liposomes). In addition, the Gd-DTPA liposomes were coated with mannan (cholesterol-aminoethylcarbamylmethyl mannan), a polysaccharide, to obtain the mannan-coated liposomes. An in vitro MRI study showed that the Gd-DTPA liposomes produced a greater intensity of contrast than did the Gd-DTPA solution with a reduced T1 relaxation time. Intravenous injection of the Gd-DTPA liposomes containing 153Gd or liposomes containing 153Gd or 14C-DTPA to mice showed an accumulation of Gd-DTPA primarily in the liver and lung. When the mannan-coated liposomes were administered, an increased uptake of Gd-DTPA by these tissues was demonstrated. The mannan-coated liposomes may enhance contrast of the liver in MRI at a lower dose of Gd-DTPA.     

EPR characterization of gadolinium(III)-containing-PAMAM-dendrimers in the absence and in the presence of paramagnetic probes

Gd(III)-containing dendrimers are promising contrast agents for magnetic resonance imaging (MRI). An important issue in the effectiveness and toxicity of a Gd(III) based MRI contrast agent is knowledge of the relative locations and concentrations of Gd(III) in dendrimer drug delivery hosts. In order to provide experimental information on this issue, we have investigated the electron paramagnetic resonance (EPR) of a stable Gd(III) complex with diethylenetriaminepentaacetic acid (DTPA) in various polyammidoamine (PAMAM) dendrimers as a function of dendrimer generation (G2, G4, and G6), dendrimer core (ethylenediamine = EDA, and cystamine = cys), and dendrimer surface functionality (NH(2), 5-oxo-3-pyrrolidinecarboxylic acid methyl ester = pyr, and tris(hydroxymethyl) methylamine = tris). The dendrimer systems were investigated in the presence and absence of paramagnetic probes, that is, Cu(II) and nitroxide radicals (4-(trimethylammonium and dodecyl-dimethylammonium) 2,2,6,6-tetramethylpiperidine 1-oxyl bromide = CAT1 and CAT12, respectively). The analysis of the EPR spectra revealed anisotropic locations of Gd-DTPA inside the dendrimer. Computer analysis of the EPR spectra of the probes identified the interactions of the Gd-dendrimers with ions and organic molecules. The interaction between the probes and the dendrimer internal and external surface depends on the type of core, the composition of the external surface and the generation of the dendrimer. The negatively charged Gd-DTPA complex attracts the positively charged species and this provokes spin-spin interactions between Gd and the probes, which increases with a decrease in generation, mainly from G6 to G4, and with an increase in both the Gd-dendrimer concentration and the probe concentration. The cys core increases the internal volume and decreases the packing of the branches.     

Phosphinic derivative of DTPA conjugated to a G5 PAMAM dendrimer: an 17O and 1H relaxation study of its Gd(III) complex

A DTPA-based chelate containing one phosphinate group was conjugated to a generation 5 polyamidoamine (PAMAM) dendrimer via a benzylthiourea linkage. The Gd(III) complex of this novel conjugate has potential as a contrast agent for magnetic resonance imaging (MRI). The chelates bind Gd3+via three nitrogen atoms, four carboxylates and one phosphinate oxygen, and one water molecule completes the inner coordination sphere. The monomer Gd(III) chelates bearing nitrobenzyl and aminobenzyl groups ([Gd(DTTAP-bz-NO2)(H2O)]2- and [Gd(DTTAP-bz-NH2)(H2O)]2-) as well as the dendrimeric Gd(III) complex G5-(Gd(DTTAP))63) were studied by multiple-field, variable temperature 17O and 1H NMR. The rate of water exchange is faster than that of [Gd(DTPA)(H2O)]2- and very similar on the two monomeric complexes (8.9 and 8.3 x 10(6) s-1 for [Gd(DTTAP-bz-NO2)(H2O)]2- and [Gd(DTTAP-bz-NH2)(H2O)]2-, respectively), while it is decreased on the dendrimeric conjugate (5.0 x 10(6) s-1). The Gd(III) complex of the dendrimer conjugate has a relaxivity of 26.8 mM-1 s-1 at 37 degrees C and 0.47 T (corresponding to 1H Larmor frequency of 20 MHz). Given the contribution of the second sphere water molecules to the overall relaxivity, this value is slightly higher than those reported for similar size dendrimers. The experimental 17O and 1H NMR data were fitted to the Solomon-Bloembergen-Morgan equations extended with a contribution from second coordination sphere water molecules. The rotational dynamics of the dendrimeric conjugate was described in terms of global and local motions with the Lipari-Szabo approach.     

Rational design of protein-based MRI contrast agents

We describe the rational design of a novel class of magnetic resonance imaging (MRI) contrast agents with engineered proteins (CAi.CD2, i = 1, 2,..., 9) chelated with gadolinium. The design of protein-based contrast agents involves creating high-coordination Gd(3+) binding sites in a stable host protein using amino acid residues and water molecules as metal coordinating ligands. Designed proteins show strong selectivity for Gd(3+) over physiological metal ions such as Ca(2+), Zn(2+), and Mg(2+). These agents exhibit a 20-fold increase in longitudinal and transverse relaxation rate values over the conventional small-molecule contrast agents, e.g., Gd-DTPA (diethylene triamine pentaacetic acid), used clinically. Furthermore, they exhibit much stronger contrast enhancement and much longer blood retention time than Gd-DTPA in mice. With good biocompatibility and potential functionalities, these protein contrast agents may be used as molecular imaging probes to target disease markers, thereby extending applications of MRI.     

Synthesis, characterization and examination of Gd[DO3A-hexylamine]-functionalized silica nanoparticles as contrast agent for MRI-applications

Spherical, nonporous and monodisperse silica nanoparticles (NPs) with a diameter of about 100 nm were synthesized and covalently functionalized with lanthanoid(III) (Ln=Gd or Y) chelate complexes, which serve as contrast agents (CAs) for magnetic resonance imaging (MRI). The materials were fully characterized after each synthetic step by different analytical methods, such as dynamic light scattering, scanning electron microscopy, DRIFT and NMR spectroscopy, thermogravimetry and elemental analysis, as well as zetapotential measurements. High surface concentrations of Gd(III) complexes (up to 50 μmol g(-1)) were determined by ICP-AES and T(1)-measurements, respectively. MRI experiments show the typical concentration-dependent increase of the longitudinal relaxation rate. T(1)-weighted images of samples with more than 25 μg NPs per 100 μL agar display a clear contrast enhancement in the agar layer. The transverse relaxivities r(2) of the materials are significantly higher than r(2) of the corresponding free Gd(III) complexes in water and medium, whereas the longitudinal relaxivities r(1) are slightly increased. Due to the high loading of Gd(III) complexes, the relaxivities per particle are remarkably high (up to 2.78×10(5) mM(-1) s(-1) for r(1)). Thus, new hybrid materials, based on nonporous silica NPs with high local relaxivity values were synthesized, which can serve as very effective CAs for MRI.     

Trace determination of gadolinium in biomedical samples by diode laser-based multi-step resonance ionization mass spectrometry

The application of high-resolution multi-step resonance ionization mass spectrometry (RIMS) to the trace determination of the rare earth element gadolinium is described. Utilizing three-step resonant excitation into an autoionizing level, both isobaric and isotopic selectivity of >10(7) were attained. An overall detection efficiency of approximately 10(-7) and an isotope specific detection limit of 1.5 x 10(9) atoms have been demonstrated. When targeting the major isotope (158)Gd, this corresponds to a total Gd detection limit of 1.6 pg. Additionally, linear response has been demonstrated over a dynamic range of six orders of magnitude. The method has been used to determine the Gd content in various normal and tumor tissue samples, taken from a laboratory mouse shortly after injection of gadolinium diethylenetriaminepentaacetic acid dimeglumine (Gd-DTPA), which is used as a contrast agent for magnetic resonance imaging (MRI). The RIMS results show Gd concentrations that vary by more than two orders of magnitude (0.07-11.5 microg mL(-1)) depending on the tissue type. This variability is similar to that observed in MRI scans that depict Gd-DTPA content in the mouse prior to dissection, and illustrates the potential for quantitative trace analysis in microsamples of biomedical materials.     

Silica microparticles as a solid support for gadolinium phosphonate magnetic resonance imaging contrast agents

Particle-based magnetic resonance imaging (MRI) contrast agents have been the focus of recent studies, primarily due to the possibility of preparing multimodal particles capable of simultaneously targeting, imaging, and treating specific biological tissues in vivo. In addition, particle-based MRI contrast agents often have greater sensitivity than commercially available, soluble agents due to decreased molecular tumbling rates following surface immobilization, leading to increased relaxivities. Mesoporous silica particles are particularly attractive substrates due to their large internal surface areas. In this study, we immobilized a unique phosphonate-containing ligand onto mesoporous silica particles with a range of pore diameters, pore volumes, and surface areas, and Gd(III) ions were then chelated to the particles. Per-Gd(III) ionic relaxivities ranged from ～2 to 10 mM(-1) s(-1) (37 °C, 60 MHz), compared to 3.0-3.5 mM(-1) s(-1) for commercial agents. The large surface areas allowed many Gd(III) ions to be chelated, leading to per-particle relaxivities of 3.3 × 10(7) mM(-1) s(-1), which is the largest value measured for a biologically suitable particle.     

Tetranuclear d-f Metallostars: Synthesis, Relaxometric, and Luminescent Properties

A novel ditopic ligand DTPA-ph-phen, based on 1,10-phenanthroline and diethylenetriaminepentaacetic acid (DTPA) units, has been designed and fully characterized by (1)H, (13)C, and 2D-COSY NMR spectroscopy, IR and electrospray ionization mass spectrometry (ESI-MS) techniques. The DTPA core of the ligand specifically binds Ln(III) ions (Ln = Eu, Gd) resulting in formation of the [Ln{DTPA-ph-phen}(H(2)O)](-) complex. The photophysical properties of the Eu(III) compound have been investigated, and the complex shows characteristic red luminescence with an overall quantum yield of 2.2%. Reaction of [Gd{DTPA-ph-phen}(H(2)O)](-) with Ru(II) leads to further self-assembly into a heterobimetallic metallostar complex containing Gd(III) and Ru(II) in a 3:1 ratio. This tetranuclear [(Gd{DTPA-ph-phen})(3)(H(2)O)(3)Ru](-) complex (Gd(3)Ru), formed by the coordination of Ru(II) to the 1,10-phenanthroline unit, has been characterized by a range of experimental techniques and evaluated toward its feasibility as a potential bimodal optical/MRI agent. The Gd(3)Ru metallostar shows intense metal-to-ligand charge transfer (MLCT) transition resulting in intense light absorption in the visible spectral region. Upon irradiation into this MLCT band at 450 nm, the Gd(3)Ru complex exhibits red broad-band luminescence in the range of 550-800 nm centered at 610 nm with a quantum yield of 4.8%. Proton nuclear magnetic relaxation dispersion (NMRD) measurements indicate that the Gd(3)Ru complex exhibits an enhanced relaxivity value r(1) of 36.0 s(-1) mM(-1) per metallostar molecule at 20 MHz and 310 K. The ability of the complex to noncovalently bind to human serum albumin (HSA) was investigated, but no significant interaction was detected.     

Enhancement of relaxivity rates of Gd-DTPA complexes by intercalation into layered double hydroxide nanoparticles

In this paper we report the preparation and characterization of [Gd(dtpa)](2-) intercalated layered double hydroxide (LDH) nanomaterials. [Gd(dtpa)](2-) (gadolinium(III) diethylene triamine pentaacetate) was transferred into LDH by anionic exchange. The intercalation of [Gd(dtpa)](2-) into LDH was confirmed by X-ray diffraction for the new phase with the interlayer spacing of 3.5-4.0 nm and by FTIR for the characteristic vibration peaks of [Gd(dtpa)](2-). The morphology of the nanoparticles was influenced by the extent of [Gd(dtpa)](2-) loading, in which the poly-dispersity quality decreased as the [Gd(dtpa)](2-) loading was increased. Compared with the morphology of the original Mg(2)Al-Cl-LDH nanoparticles (hexagonal plate-like sheets of 50-200 nm), the modified LDH-Gd(dtpa) nanoparticles are bar-like with a width of 30-60 nm and a length of 50-150 nm. LDH-Gd(dtpa) was expected to have an increased water proton magnetic resonance relaxivity due to the intercalation of [Gd(dtpa)](2-) into the LDH interlayer that led to slower molecular anisotropic tumbling compared with free [Gd(dtpa)](2-) in solution. Indeed, LDH-nanoparticle suspension containing approximately 1.6 mM [Gd(dtpa)](2-) exhibits a longitudinal proton relaxivity r(1) of approximately 16 mM(-1) s(-1) and a transverse proton relaxivity r(2) of approximately 50 mM(-1) s(-1) at room temperature and a magnetic field of 190 MHz, which represents an enhancement four times (r(1)) and 12 times (r(2)) that of free [Gd(dtpa)](2-) in solution under the same reaction conditions. We have thus tailored LDH-nanoparticles into a novel contrast agent with strong relaxivity, promising for great potential applications in magnetic resonance imaging.