Development of hypoxia-sensitive Gd3+-based MRI contrast agents

Hypoxia occurs in various diseases, including cancer, ischemia, and acute and chronic vascular diseases. Here we describe the design and synthesis of the first hypoxia-sensitive MRI contrast agents, SAGds. SAGds showed a pH-dependent r(1) relaxivity change associated with intramolecular chelation of the nitrogen atom of the sulfonamide moiety to the Gd(3+) center. There was a correlation between the pK(a) of the r(1) relaxivity change and the sum of the Hammett σ constants of substituents on the aromatic ring. Among the synthesized compounds, 4NO(2)2MeOSAGd was selectively reduced to the amine by rat liver microsomes under hypoxic conditions, resulting in a 1.8-fold increment of the r(1) relaxivity owing to the change in pK(a) of the arylsulfonamide moiety. This enhancement of the r(1) relaxivity could be clearly detected in T(1)-weighted MR images. Thus, 4NO(2)2MeOSAGd is a 'smart' MRI contrast agent for the detection of hypoxia under physiological conditions.     

A robust and convergent synthesis of dipeptide-DOTAM conjugates as chelators for lanthanide ions: new PARACEST MRI agents

A generally applicable synthetic approach to dipeptide-DOTAM conjugates has been developed which is based on the peralkylation of 1,4,7,10-tetraazacyclododecane (cyclen) with protected N-iodoacetyl dipeptides. Standardized procedures were used for the alkylation, metalation, and purification of the resultant lanthanide complexes. Using this approach, we have been able to rapidly and reliably prepare and screen five different ligands each with up to six lanthanide ions. This preliminary investigation has identified several paramagnetic compounds with strong chemical exchange saturation transfer (PARACEST) properties in water at physiological temperature and pH. Extension of the synthetic approach to a wide variety of amino acids is possible.     

Cyclen-based Gd3+ complexes as MRI contrast agents: Relaxivity enhancement and ligand design

Magnetic Resonance Imaging (MRI) is a noninvasive radiology technique used to examine the internal organs of human body. It is useful for the diagnosis of structural abnormalities in the body. Contrast agents are used to increase the sensitivity of this technique. 1,4,7,10-Tetraazacyclododecane (cyclen) is a macrocyclic tetraamine. Its derivatives act as useful ligands to produce stable complexes with Gd³⁺ ion. Such chelates are investigated as MRI contrast agents. Free Gd³⁺ ion is extremely toxic for in vivo use. Upon complexation with a cyclen-based ligand, it is trapped in the preformed central cavity of the ligand resulting in the formation of a highly stable Gd³⁺-chelate. Better kinetic and thermodynamic stability of cyclen-based MRI contrast agents decrease their potential toxicity for in vivo use. Consequently, such agents have proved to be safest for clinical applications. Relaxivity is the most important parameter used to measure the effectiveness of a contrast agent. A number of factors influence this parameter. This article elucidates detailed strategies to increase relaxivity of cyclen-based MRI contrast agents. 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) are two key ligands derived from cyclen. They also act as building blocks for the synthesis of novel ligands. A few important methodologies for the synthesis of DOTA and DO3A derivatives are described. Moreover, the coordination geometry of chelates formed by these ligands and their derivatives is discussed as well. Novel ligands can be developed by the appropriate derivatization of DOTA and DO3A. Gd³⁺-chelates of such ligands prove to be useful MRI contrast agents of enhanced relaxivity, greater stability, better clearance, lesser toxicity and higher water solubility.     

Polymeric gadolinium chelate magnetic resonance imaging contrast agents: design, synthesis, and properties.

We have synthesized and evaluated five series of polymeric gadolinium chelates which are of interest as potential MRI blood pool contrast agents. The polymers were designed so that important physical properties including molecular weight, relaxivity, metal content, viscosity, and chelate stability could be varied. We have shown that, by selecting polymers of the appropriate MW, extended blood pool retention can be achieved. In addition, relaxivity can be manipulated by changing the polymer rigidity, metal content affected by monomer selection, viscosity by polymer shape, and chelate stability by chelator selection.     

Synthesis and evaluation of Gd-DTPA-labeled arabinogalactans as potential MRI contrast agents

Arabinogalactan derivatives conjugated with gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) by ethylenediamine (Gd-DTPA-CMAG-A2) or hexylamine (Gd-DTPA-CMAG-A6) have been synthesized and characterized by means of Fourier transform infrared spectra (FTIR), 13C nuclear magnetic resonance (13C NMR), size exclusion chromatography (SEC), and inductively coupled plasma atomic emission spectrometry (ICP-AES). Relaxivity studies showed that arabinogalactan-bound complexes possessed higher relaxation effectiveness compared with the clinically used Gd-DTPA, and the influence of the spacer arm lengths on the T1 relaxivities was studied. Their stability was investigated by competition study with Ca2+, EDTA, and DTPA. MR imaging of Wistar rats showed remarkable enhancement in rat liver and kidney after i.v. injection of Gd-DTPA-CMAG-A2 (0.079+/-0.002 mmol/kg Gd3+): The mean percentage enhancement of the liver parenchyma and kidney was 38.7+/-6.4% and 69.4+/-4.4% at 10-30 min. Our preliminary in vivo and in vitro study indicates that the arabinogalactan-bound complexes are potential liver-specific contrast agents for MRI.     

Water-soluble polysaccharides as carriers of paramagnetic contrast agents for magnetic resonance imaging: synthesis and relaxation properties.

Water-soluble, carbohydrate-based, paramagnetic metal chelate derivatives have been investigated as potential organ-selective contrast media for magnetic resonance imaging (m.r.i.). The in vitro proton spin-lattice relaxation properties of compounds with different paramagnetic metals, chelating agents, and carbohydrate matrixes have been studied. Typically, these complexes were 60-260% more efficient proton-relaxation agents than the corresponding low-molecular-weight metal chelates at 10 MHz, but less efficient than the corresponding protein derivatives. As expected, carbohydrates that contained manganese or gadolinium were more effective relaxation agents than iron, copper, erbium, or nickel derivatives.     

Strategies for the covalent conjugation of a bifunctional chelating agent to albumin: synthesis and characterization of potential MRI contrast agents

With the purpose to develop macromolecular magnetic resonance imaging contrast agents, we herein report three different synthetic approaches to the covalent attachment of bifunctional chelating agents to human serum albumin followed by coordination to contrast enhancing gadolinium(III). Applied methods cover active ester-mediated conjugation, linkage through glutaryl spacer, as well as the connection by the employment of glutaraldehyde. The content of gadolinium(III) was evaluated by inductively-coupled-plasma mass-spectrometry (ICP-MS) measurements and indicated reproducible amounts of conjugated contrast enhancing material. Small angle X-ray scattering (SAXS) experiments provided the size and altered shape of the gadolinium loaded proteins in comparison to unmodified albumin. Finally, the magnetic resonance properties of the protein conjugates were evaluated. The results indicated suitability of the gadolinium(III) loaded protein conjugates for use as macromolecular contrast agents in magnetic resonance imaging (MRI).     

Comparison between GdDTPA and two gadolinium polyoxometalates as potential MRI contrast agents

Two gadolinium polyoxometalates, Gd(2)P(2)W(18)O(62) and K(15)[(GdO)(3)(PW(9)O(34))(2)], have been evaluated by in vivo as well as in vitro experiments as the candidates of tissue-specific magnetic resonance imaging (MRI) contrast agents. T(1)-relaxivities of 28.4 mM(-1).s(-1) for Gd(2)P(2)W(18)O(62) and 11.2 mM(-1).s(-1) for K(15)[(GdO)(3)(PW(9)O(34))(2)] (400 MHz, 25 degrees C) were higher than that of the commercial MRI contrast agent (GdDTPA). Their relaxivities in bovine serum albumin and human serum transferrin were also reported. The favorable liver-specific contrast enhancement and renal excretion capability in in vivo MRI with Sprague-Dawley rats after i.v. administration of K(15)[(GdO)(3)(PW(9)O(34))(2)] was demonstrated. In vivo and in vitro assay showed that K(15)[(GdO)(3)(PW(9)O(34))(2)] is a promising liver-specific MRI contrast agent. However, Gd(2)P(2)W(18)O(62) did not show the favorable quality in vivo as expected from its high relaxivity in vitro, which was attributed to low bioavailability, indicating that it is of limited value as tissue-specific MRI contrast agent.     

Comparison between Gd-DTPA and several bisamide derivatives as potential MRI contrast agents

Four neutral gadolinium complexes of diethylenetriaminepentaacetic acid (DTPA)-bisamide derivatives have been synthesized and characterized. Their potential application as tissue-specific and low-osmolarity MRI contrast agents has been evaluated by in vitro and in vivo experiments. Their measured relaxivities in D(2)O, bovine serum albumin and human serum transferrin solutions showed favorable relaxation ability. In vivo studies have proven that Gd(DTPA-BDMA), Gd(DTPA-BIN), and Gd(cyclic-DTPA-1,2-pn) could be promising liver-specific MRI contrast agents and Gd(DTPA-BDMA), and Gd(cyclic-DTPA-1,2-pn) have favorable renal excretion capability. Among them, Gd(cyclic-DTPA-1,2-pn) is a more powerful hepatic contrast agent and Gd(DTPA-BIN) provides the stable imaging contrast for several hours. They also show a lower toxicity.     

Optical properties of Eu2+/Eu3+ mixed valence phosphor Ca2SiO2F2:Eu2+/Eu3+

The Eu²⁺/Eu³⁺ mixed valence phosphor Ca₂SiO₂F₂:Eu²⁺/Eu³⁺ was prepared using a solid‐state reaction synthesis method in a CO atmosphere, and the optical properties were investigated. The spectroscopic properties revealed that Ca²⁺ ions were occupied by both Eu²⁺ and Eu³⁺ ions in Ca₂SiO₂F₂, and both ions were able to generate their characteristic emissions. A broad 5d → 4f Eu²⁺ band at ~470 nm and narrow 4f → 4f Eu³⁺ peaks upon excitation with n‐UV light were observed. The ratio between Eu²⁺ and Eu³⁺ emissions changed regularly, and the relative intensity of the red component from Eu³⁺ became systematically stronger with increasing overall Eu content. As a result, the emission color of these phosphors can be tunable from blue to pink under n‐UV light excitation.     

Dendrimer-based macromolecular MRI contrast agents: characteristics and application

Numerous macromolecular MRI contrast agents prepared employing relatively simple chemistry may be readily available that can provide sufficient enhancement for multiple applications. These agents operate using a approximately 100-fold lower concentration of gadolinium ions in comparison to the necessary concentration of iodine employed in CT imaging. Herein, we describe some of the general potential directions of macromolecular MRI contrast agents using our recently reported families of dendrimer-based agents as examples. Changes in molecular size altered the route of excretion. Smaller-sized contrast agents less than 60 kDa molecular weight were excreted through the kidney resulting in these agents being potentially suitable as functional renal contrast agents. Hydrophilic and larger-sized contrast agents were found better suited for use as blood pool contrast agents. Hydrophobic variants formed with polypropylenimine diaminobutane dendrimer cores created liver contrast agents. Larger hydrophilic agents are useful for lymphatic imaging. Finally, contrast agents conjugated with either monoclonal antibodies or with avidin are able to function as tumor-specific contrast agents, which also might be employed as therapeutic drugs for either gadolinium neutron capture therapy or in conjunction with radioimmunotherapy.     

Polyaspartamide gadolinium complexes containing sulfadiazine groups as potential macromolecular MRI contrast agents

Both diethylenetriaminepentaacetic acid (DTPA) and sulfadiazine (SD) were incorporated into polyaspartamides with different side chains, including poly-alpha,beta-[N-(2-hydroxyethyl)-L-aspartamide] (PHEA), poly-alpha,beta-[N- (3-hydroxypropyl)-L-aspartamide] (PHPA), poly-alpha,beta-[N-(2-aminoethy1)-L-aspartamide] (PAEA), poly-alpha,beta-[N-(4-aminobuty1)-L-aspartamide] (PABA), and poly-alpha,beta-[N-(6-aminohexyl)-L-aspartamide] (PAHA). The polyaspartamide ligands containing DTPA and SD groups were further reacted with gadolinium chloride to give the corresponding macromolecular gadolinium complexes. Experimental data of 1H NMR, IR, UV, and elemental analysis exhibited the formation of the polyaspartamide ligands and gadolinium complexes. Relaxivity studies indicated that the macromolecular chelates possess higher relaxivities than that of the clinically used Gd-DTPA. MR imaging showed that the macromolecular chelate PAEA-Gd-DTPA-SD greatly enhanced the contrast of MR images of hepatoma in the lower limb of mice and provided prolonged intravascular duration. Thus the polyaspartamide gadolinium complex containing SD groups is expected to be used as the potential macromolecular MRI contrast agents for hepatoma in mice.     

Ultrasound assisted synthesis of CaF2:Eu3+ phosphor nanoparticles

In this work, the optical and structural properties of ultrasonically prepared CaF₂:Eu³⁺ nanoparticles have been reported. Ultrasonically prepared CaF₂:Eu³⁺ phosphor shows orange, red emission bands at 591 nm and 612 nm, respectively, when it is excited by 394 light‐emitting diode (LED) excitation wavelengths. Further phosphor materials are well characterized by X‐ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy and transmission electron microscopy (TEM) techniques to confirm the phase purity, metal oxygen (MO) bonding and crystallites size of the materials. Here synthesized materials show a tube‐like structure under 100 nm resolution and 0.1 mol% is the best doping value of the europium ion (Eu³⁺) in calcium fluoride (CaF₂) that shows highest intensity when prepared with an ultrasound assisted method.     

Combustion synthesis and luminescence properties of SrAl2O4:Eu2+, Dy3+, Tb3+ phosphor.

Eu(2+), Dy(3+) and Tb(3+) co-doped strontium aluminate phosphor with high brightness and long afterglow was synthesized by a combustion method, using urea as a reducer. The properties of SrAl(2)O(4):Eu(2+),Dy(3+),Tb(3+) phosphor with a series of initiating combustion temperatures, urea concentrations and boric acid molar fractions were investigated. The sample at initiating combustion temperature of 600 degrees C exhibited an intense emission peak at 513 nm, in which the phosphor existed as a single-phase monoclinic structure. The experimental results showed that the optimum ratio of urea is 2.0 times higher than theoretical quantities and that the suitable molar fraction of H(3)BO(3) is 0.08. The average particle size of the phosphor was 50-80 nm and its luminescence properties were studied systematically. Compared with SrAl(2)O(4):Eu(2+),Dy(3+) phosphor, the initial luminescence brightness improved from 2.50 candela (cd)/m(2) to 3.55 cd/m(2) and the long afterglow time was prolonged from 1290 s to 2743 s.     

Two‐ step synthesis and luminescent properties of BaB2O4:Eu3+ nano/microphosphors prepared from Ba‐B‐O:Eu3+ precursor

The BaB₂O₄:Eu³⁺ nano/microphosphors with sphere‐, rod‐, and granular‐like morphologies were successfully obtained by a two‐step method using Ba‐B‐O:Eu³⁺ as the precursor. The structure, morphology and photoluminescent properties of the products were characterized by Fourier transfer infrared spectroscopy (FT‐IR), X‐ray diffraction (XRD), thermogravimetry‐differential thermal analysis (TG‐DTA), scanning electron microscopy (SEM) and photoluminescence (PL). The formation mechanisms of Ba‐B‐O:Eu³⁺ and BaB₂O₄:Eu³⁺ were proposed. The results show that the BaB₂O₄:Eu³⁺ could retain the original morphologies of their respective precursors largely. The BaB₂O₄:Eu³⁺ prepared by this two‐step method exhibited better morphology, smaller particle size and better crystallinity than when prepared by a solid‐state method. The granular‐like BaB₂O₄:Eu³⁺ red phosphor prepared by this two‐step method exhibited stronger PL intensity and better red color purity than when prepared by a solid‐state method.     

Method for enhancing cell penetration of Gd3+-based MRI contrast agents by conjugation with hydrophobic fluorescent dyes

Gadolinium ion (Gd(3+)) complexes are commonly used as magnetic resonance imaging (MRI) contrast agents to enhance signals in T(1)-weighted MR images. Recently, several methods to achieve cell-permeation of Gd(3+) complexes have been reported, but more general and efficient methodology is needed. In this report, we describe a novel method to achieve cell permeation of Gd(3+) complexes by using hydrophobic fluorescent dyes as a cell-permeability-enhancing unit. We synthesized Gd(3+) complexes conjugated with boron dipyrromethene (BDP-Gd) and Cy7 dye (Cy7-Gd), and showed that these conjugates can be introduced efficiently into cells. To examine the relationship between cell permeability and dye structure, we further synthesized a series of Cy7-Gd derivatives. On the basis of MR imaging, flow cytometry, and ICP-MS analysis of cells loaded with Cy7-Gd derivatives, highly hydrophobic and nonanionic dyes were effective for enhancing cell permeation of Gd(3+) complexes. Furthermore, the behavior of these Cy7-Gd derivatives was examined in mice. Thus, conjugation of hydrophobic fluorescent dyes appears to be an effective approach to improve the cell permeability of Gd(3+) complexes, and should be applicable for further development of Gd(3+)-based MRI contrast agents.     

Mechanoluminescence properties of SrAl2O4:Eu2+ phosphor by combustion synthesis

In this paper, europium‐doped strontium aluminate (SrAl₂O₄:Eu²⁺) phosphors were synthesized using a combustion method with urea as a fuel at 600°C. The phase structure, particle size, surface morphology and elemental analysis were studied using X‐ray diffractometry (XRD), transmission electron microscopy (TEM), energy‐dispersive X‐ray spectroscopy (EDX) and Fourier transform infrared (FTIR) spectra. The EDX and FTIR spectra confirm the elements present in the SrAl₂O₄:Eu²⁺ phosphor. The optical properties of SrAl₂O₄:Eu²⁺ phosphors were investigated by photoluminescence (PL) and mechanoluminescence (ML). The excitation and emission spectra showed a broad band with peaks at 337 and 515 nm, respectively. The ML intensities of SrAl₂O₄:Eu²⁺ phosphor increased proportionally with the increase in the height of the mechanical load, which suggests that this phosphor could be used in stress sensors. The CIE colour chromaticity diagram and ML spectra confirm that the SrAl₂O₄:Eu²⁺ phosphor emitted green coloured light. Copyright © 2015 John Wiley & Sons, Ltd.     

Role of Li+ ions on the surface morphology and thermoluminescence properties of Y2O3:Tm3+ nanophosphor

Y₂O₃:Tm³⁺ and Li⁺ co‐doped Y₂O₃:Tm³⁺ nanopowders were synthesized using the solution combustion method for possible application in ultraviolet (UV) light dosimetry. X‐ray diffraction revealed the crystallite sizes to be in the range 21–44 nm and 30–121 nm using the Scherrer equation and the W‐H plot relationship, respectively. Field emission scanning electron microscopy confirmed that, after co‐doping with 4 mol% concentration of Li⁺, the particles were spherical in nature with an average size of ~30 nm. Fourier transformed infrared spectroscopy results showed bands at wavenumbers of 556, 1499, 1704, 2342, 2358, 2973, 3433, and 3610 cm^?1 that corresponded to the stretching and bending vibrations of Y–O, C=O and O–H. Thermoluminescence (TL) glow peaks for Y₂O₃:Tm³⁺ nanophosphors observed at 399 and 590 K were attributed to oxygen defects caused using UV irradiation. These oxygen defects firstly resulted in an increased prominent peak TL intensity for up to 270 min of irradiation and then a decrease. This was attributed to the presence of oxygen defect clusters that caused a reduction in recombination centres. The Li⁺ co‐doped sample showed peaks at 356, 430, and 583 K and its intensity sublinearly increased up to 90 min and then thereafter decreased. The TL trapping parameters were calculated using computerized glow curve deconvolution methods. The Li⁺ co‐doped sample exhibited less fading and high trap density under the UV radiation.     

Cross-linked, degradable starch microspheres as carriers of paramagnetic contrast agents for magnetic resonance imaging: synthesis, degradation, and relaxation properties.

Biodegradable particles were produced by the cross-linking of starch with epichlorohydrin. Diethylenetriaminepenta-acetic acid (DTPA) was covalently linked to the particles by using DTPA bisanhydride. The small, gadolinium-labelled particles were 40-260% more efficient in vitro proton relaxation agents than the corresponding unbound chelate gadolinium-DTPA. The relaxation properties were dependent on the metal chelate, the particle size, the metal content, and the degree of substitution (d.s.). For the small gadolinium-DTPA particles, an increased d.s. decreased the rate of degradation by alpha-amylase.     

Rapid synthesis of BaMoO4:Eu3+ red phosphors using microwave irradiation

This study synthesized BaMoO4:Eu³⁺ red phosphors using the microwave method. In addition, the phase composition, morphology, and luminescence properties of the red phosphors were characterized using X-ray diffraction, field-scanning electron microscopy, and photoluminescence spectroscopy. The results revealed that doping red phosphors with different concentrations of Eu³⁺ does not change the crystal structure of the matrix material. The BaMoO₄:Eu³⁺ phosphors exhibited micron-scale irregular polyhedra, which could be excited by ultraviolet light with a wavelength of 395 nm to induce red-light emission. The optimal dosage of Eu³⁺ was 0.08, and the chromaticity coordinates of BaMoO₄:0.08Eu³⁺ phosphors were (0.5869, 0.3099). White light-emitting diode (w-LED) devices manufactured by using a combination of BaMoO₄:0.08Eu³⁺ phosphor and commercially available phosphors exhibited good white-light emission under the excitation of an ultraviolet chip. The BaMoO₄:0.08Eu³⁺ red phosphors that rapidly synthesized under the microwave field are expected to be used in w-LED devices.