MRI Contrast Enhancement Agents Research Articles

Mechanisms for cellular uptake of nanosized clinical MRI contrast agents

Engineered Nanomaterials (NMs), such as Superparamagnetic Iron Oxide Nanoparticles (SPIONs), offer significant benefits in a wide range of applications, including cancer diagnostic and therapeutic strategies. However, the use of NMs in biomedicine raises safety concerns due to lack of knowledge on possible biological interactions and effects. The initial basis for using SPIONs as biomedical MRI contrast enhancement agents was the idea that they are selectively taken up by macrophage cells, and not by the surrounding cancer cells. To investigate this claim, we analyzed the uptake of SPIONs into well-established cancer cell models and benchmarked this against a common macrophage cell model. In combination with fluorescent labeling of compartments and siRNA silencing of various proteins involved in common endocytic pathways, the mechanisms of internalization of SPIONs in these cell types has been ascertained utilizing reflectance confocal microscopy. Caveolar mediated endocytosis and macropinocytosis are both implicated in SPION uptake into cancer cells, whereas in macrophage cells, a clathrin-dependant route appears to predominate. Colocalization studies confirmed the eventual fate of SPIONs as accumulation in the degradative lysosomes. Dissolution of the SPIONs within the lysosomal environment has also been determined, allowing a fuller understanding of the cellular interactions, uptake, trafficking and effects of SPIONs within a variety of cancer cells and macrophages. Overall, the behavior of SPIONS in non-phagocytotic cell lines is broadly similar to that in the specialist macrophage cells, although some differences in the uptake patterns are apparent.

Novel facets of multifunctional Ag@Fe3O4 core-shell nanoparticles for multimodal imaging applications

Biocompatible nanoparticles, with magnetic cores and optically active shells, acting as multifunctional materials with a core size of 6 nm encapsulated in silver shells of varying thickness were synthesized through a novel single phase microemulsion method. Incorporation of silver shells onto the magnetite core enhances the intensity of the highest luminescence peak observed for magnetite by a significant luminescence enhancement factor. A blue photoluminescence peak observed in the visible region of spectrum brightens further with the increase in the thickness of silver shell. The magnetic properties of these core-shell nanomaterials show superparamagnetic behavior at room temperature, which is a mandatory criterion for MRI contrast enhancement agents. The hyperthermic response of synthesized magnetite nanoparticles elevates its temperature to 43 °C in a sharp span of time, which is above the desired temperature for the therapeutic application of these multifunctional nanomaterials. These excellent optical and magnetic properties, of the material having a size range suitable for cellular uptake, make it a potential candidate for both diagnostic and therapeutic uses in biomedical applications.

Folic acid-conjugated Fe3O4 magnetic nanoparticles for hyperthermia and MRI in vitro and in vivo

Abstract The folic acid (FA)-conjugated Fe 3 O 4 magnetic nanoparticles (MNPs) were synthesized by co-precipitation of Fe 3+ and Fe 2+ solution followed by surface modification with carboxymethyl dextran (CMD) to form carboxymethyl group terminated MNPs, then FA was conjugated with the carboxyl group functionalized MNPs. The morphology and properties of obtained nanoparticles were characterized by X-ray powder diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), UV–visible spectra (UV–vis), transmission electron microscopy (TEM), dynamic light scattering (DLS), vibrating sample magnetometer (VSM) and thermogravimetric analysis (TGA). The FA-conjugated MNPs exhibited relatively high saturation magnetization and fast magneto-temperature response which could be applied to hyperthermia therapy. To determine the accurate targeting effect of FA, we chose FA-conjugated MNPs as MRI contrast enhancement agent for detection of KB cells with folate receptor over-expression in vitro and in vivo . The results show that these magnetic nanoparticles appear to be the promising materials for local hyperthermia and MRI.

Optical and magnetic properties of Fe2O3 nanoparticles synthesized by laser ablation/fragmentation technique in different liquid media

Iron oxide (Fe2O3) bulk powder have been ablated/fragmented in different liquid medium by Nd:YAG laser beam using 1064nm wavelength. Sodium dodecyl sulfate (SDS), cetyltrimethyl ammonium bromide (CTAB) and double distilled water (DDW) are used as liquid medium. Crystalline size, lattice strain, phase and structure of ablated particles have been investigated using synchrotron X-ray diffraction. Optical band gap energy of as purchased Fe2O3 found 1.92eV that increased to 2.03eV after ablation in CTAB determined by UV–vis absorption spectroscopy. Magnetic properties have been analyzed by hysteresis loops using vibrating sample magnetometer (VSM). Crystalline sizes have been found in the range of 29.23–16.54nm and coercivity tailored in the range of 206.91–298.36Oe using laser ablation. Saturation magnetization and remanence have been found in the range of 0.013–3.41emu/g and 0.0023–.0.51emu/g respectively. Particle shape and size have been examined by scanning electron microscopy (SEM). CTAB (cationic) and SDS (anionic) surfactants are used as capping agent. CTAB produces phase transformation in ablated iron oxide (Fe2O3). Crystallinity and crystalline size of ablated particles in DDW increased due to presence of rich oxygen in it due to oxidation. Ablated Fe2O3 nanoparticles have been widely used experimentally for numerous in vivo applications such as MRI contrast enhancement agent, tissue repair, immunoassay, detoxification of biological fluids, hyperthermia, drug delivery and cell separation.

Blocked-micropores, surface functionalized, bio-compatible and silica-coated iron oxide nanocomposites as advanced MRI contrast agent

Biocompatible magnetic nanoparticles have been found promising in several biomedical applications for tagging, imaging, sensing and separation in recent years. In this article, a systematic study of the design and development of surface-modification schemes for silica-coated iron oxide nanoparticles (IONP) via a one-pot, in situ method at room temperature is presented. Silica-coated IONP were prepared in a water-in-oil microemulsion, and subsequently the surface was modified via addition of organosilane reagents to the microemulsion system. The structure and the morphology of the as synthesized nanoparticles have been investigated by means of transmission electron microscopy (TEM) and measurement of N2 adsorption–desorption. Electron diffraction and high-resolution transmission electron microscopic (TEM) images of the nanoparticles showed the highly crystalline nature of the IONP structures. Nitrogen adsorption indicates microporous and blocked-microporous structures for the silica-coated and amine functionalized silica-coated IONP, respectively which could prove less cytotoxicity of the functionalized final product. Besides, the colloidal stability of the final product and the presence of the modified functional groups on top of surface layer have been proven by zeta-potential measurements. Owing to the benefit from the inner IONP core and the hydrophilic silica shell, the as-synthesized nanocomposites were exploited as an MRI contrast enhancement agent. Relaxometric results prove that the surface functionalized IONP have also signal enhancement properties. These surface functionalized nanocomposites are not only potential candidates for highly efficient contrast agents for MRI, but could also be used as ultrasensitive biological-magnetic labels, because they are in nanoscale size, having magnetic properties, blocked-microporous and are well dispersible in biological environment.

Nanotechnology and Mri Contrast Enhancement

Technical advances in nanotechnology are creating novel classes of MRI contrast-enhancing agents. These nanomaterials offer much higher relaxivities than most current clinical contrast agents, which translates into greater MRI contrast enhancement. These nanoscale agents also have the potential to revolutionize in vivo applications of contrast-enhanced MRI since they offer the multiple advantages of low toxicities, extremely high relaxivities and cell internalization capabilities. In this review, we discuss three types of such contrast agents currently in use or under development for medical imaging: small particles of iron oxide, fullerenes encapsulating Gd(3+) ions (gadofullerenes) and single-walled carbon nanotube nanocapsules encapsulating Gd(3+) ion clusters (gadonanotubes). The latest developments and projected future applications of these nanotechnology-inspired contrast agents in the field of medical imaging are also discussed.

Gadolinium-containing phosphatidylserine liposomes for molecular imaging of atherosclerosis

Exteriorized phosphatidylserine (PS) residues in apoptotic cells trigger rapid phagocytosis by macrophage scavenger receptor pathways. Mimicking apoptosis with liposomes containing PS may represent an attractive approach for molecular imaging of atherosclerosis. We investigated the utility of paramagnetic gadolinium liposomes enriched with PS (Gd-PS) in imaging atherosclerotic plaque. Gd-PS-containing Gd-conjugated lipids, fluorescent rhodamine, and PS were prepared and characterized. Cellular uptake in RAW macrophages (fluorescent uptake of rhodamine) was studied on a fluorescence plate reader, while Gd-PS-induced alteration in T1 relaxivity was evaluated using a 1.5 T MRI scanner. RAW cells demonstrate PS-dependent uptake of across a range of concentrations (2, 6, 12, and 20%) in comparison to control liposomes with no PS (0%). In vivo performance of Gd-PS was evaluated in the ApoE(-/-) mouse model by collection of serial T1 weighted gradient echo MR images using an 11.7 T MRI system and revealed rapid and significant enhancement of the aortic wall that was seen for at least 4 h after injection. Gd-PS-enriched liposomes enhance atherosclerotic plaque and colocalize with macrophages in experimental atherosclerosis.

Synthesis of an hexadentate tricyclic tetraazadiacetic ligand as precursor for MRI contrast enhancement agents

A tricyclic tetraazadiacetic compound, which is a rigidified derivative of cyclo-PCTA12 ligand with an oxo-ethylene bridge replacing an ethylene one, was prepared. The synthetic route involved the macrocyclization between an activated amido-disulfonamide and the 2,6-bis(bromomethyl)pyridine. The acetate side chains were grafted on the macrocyclic backbone to lead to the highly rigid tricyclic ligand in 34% overall yield in four steps from the linear amido-disulfonamide precursor. The corresponding Gd(III) and Mn(II) complexes were then prepared in order to evaluate their potential as contrast agent for MRI.

Ultra-Small Superparamagnetic Iron Oxide Nanoparticles as MRI Contrast Enhancing Agents

Ultrasmall superparamagnetic iron oxide nanoparticles (USPION) as magnetic resonance imaging were synthesized through a sonochemical co-precipitation method with poly (ethyleneimine) (PEI). The size of the USPION was controlled by poly (ethyleneimine) (PEI) contents, ultrasonic exposure time, and Na4OH concentration. The characteristics of PEI-USPION were studied by X-ray diffractometry, magnetic property measurement system, scanning electron microscopy, transmission electron microscopy, and particle size analysis. The PEI-USPION had an average size of 5~10nm with a narrow size distribution, a perfect magnetite crystal structure, and high saturation magnetization.

Gadofullerene MRI Contrast Agents

A promising new class of MRI contrast-enhancing agents with high relaxivities is based on gadolinium-containing metallofullerenes, which are also termed gadofullerenes. Detailed study of the water-proton relaxivity properties and intermolecular nanoclustering behavior of gadofullerene derivatives has revealed valuable information about their relaxivity mechanisms and given a deeper understanding of this new class of paramagnetic contrast agent. Here, the latest findings on water-solubilized gadofullerene materials and how these findings relate to their future applications in MRI are reviewed and discussed.

A novel cholic acid-based contrast enhancement agent for targeted MRI

The novel Gd(III) complexes of heptadentate ligands NE3TA and NE3TA-Bn were prepared, and their relaxivities were measured and favorably compared to the commercially available MRI contrast enhancement agent Gd(DOTA). NE3TA was conjugated with cholic acid (CA) to produce CA-NE3TA. TEM images of Gd(CA-NE3TA) indicate that the complex self-assembles forming nano-sized micelles and displays an over threefold increased relaxivity compared to Gd(DOTA). The new cholic acid-conjugated nanoparticle MR contrast enhancement agent, Gd(CA-NE3TA) possesses great promise for use in targeted MRI.

The Preparation, Characterization, and Magnetism of Copper 15-Metallacrown-5 Lanthanide Complexes

The preparation and characterization of a series of encapsulated-lanthanide 15-metallacrown-5 complexes are reported. Planar ligands such as picoline hydroxamic acid (picha) or nonplanar alpha-amino hydroxamic acids (e.g., glycine hydroxamic acid (glyha)) led to one-step syntheses of metallacrowns in yields as high as 85%. The reaction of the appropriate hydroxamic acid with copper acetate and (1)/(5) equiv of gadolinium(III) or europium(III) nitrates in DMF or water yielded crystals of Gd(NO(3))(3)[15-MC(Cu(II)N(picha))-5], 1, Eu(NO(3))(3)[15-MC(Cu(II)N(picha))-5], 2, and Eu(NO(3))(3)[15-MC(Cu(II)N(glyha))-5], 3. Several other 15-metallacrown-5 complexes were synthesized with (1) Cu(II) or Ni(II) in the metallacrown ring metal position, (2) various lanthanides (La(III), Nd(III), Sm(III), Eu(III), Gd(III), Dy(III), Ho(III), Er(III), and Yb(III)) encapsulated in the center of the ring, and (3) chiral alpha-amino hydroxamic acids (e.g., phenylalanine hydroxamic acid (H(2)pheha), leucine hydroxamic acid (H(2)leuha), and tyrosine hydroxamic acid (H(2)tyrha)). It is believed that all of the complexes containing Cu(II) ions have the ring metals either in four-coordinate, square-planar environments, bound to two tetradentate hydroximate ligands, or in five-coordinate, square-pyramidal geometries if solvent is bound. Spectroscopic and magnetic characterization of the Ni(II) complexes suggests that they are either five- or six-coordinate. The encapsulated lanthanides are generally pentagonal bipyramidal, with five oxygen donors from the metallacrown ring and solvent or bidentate nitrate ions in the axial positions. The circular arrangement of ions results in interesting magnetic behavior. With Dy(III) encapsulated in the center of the ring, a magnetic moment as high as 10.9 &mgr;(B) is achieved. Analysis of the variable-temperature susceptibility of La(NO(3))(3)[15-MC(Cu(II)N(picha))-5] indicates that the five Cu(II) ions are antiferromagnetically coupled, forming an S = (1)/(2) ground spin state with a moment of 1.7 &mgr;(B) at liquid helium temperatures. Complex 1 shows ferromagnetic coupling of the Gd(III) ion to the five Cu ions at temperatures below 15 K. Studies of the metallacrown complexes in solution show that they are stable and soluble in DMF and water. A proton relaxation study on complex 1 has revealed a relaxivity of 9.8 mM(-)(1) s(-)(1) (20 degrees C and 30 MHz), a value that is comparable to those of clinically useful MRI contrast enhancement agents. Complex 1 crystallizes in the triclinic space group P&onemacr;, with a = 12.657(3) Å, b = 14.833(3) Å, c = 17.707(3) Å, alpha = 79.65(2) degrees, beta = 86.06(2) degrees, gamma = 68.69(2) degrees, V = 3046.6(12) Å, and Z = 2 (R1 = 0.0534, wR2 = 0.1289). Complex 2 crystallizes in the monoclinic space group P2(1)/n, with a = 16.319(2) Å, b = 21.863(2) Å, c = 18.410(3) Å, beta = 96.85(1) degrees, V = 6522(2) Å(3), and Z = 4 (R1 = 0.0463, wR2 = 0.0750). Complex 3 crystallizes in the triclinic space group P&onemacr;, with a = 11. 173(6) Å, b = 11.534(6) Å, c = 13.311(5) Å, alpha = 93.81(3) degrees, beta = 94.82(4) degrees, gamma = 107.20(4) degrees, V = 1625(2) Å(3), and Z = 2 (R1 = 0.1230, wR2 = 0.2979).

New non-ionic water-soluble porphyrins: evaluation of manganese(III) polyhydroxylamide porphyrins as MRI contrast agents

A new series of metalloporphyrins (M = zinc(II) and manganese(III)), utilizing polyhydroxylamide substituents to achieve water solubility, has been synthesized and spectroscopically characterized. Two of these compounds, [Mn III(TPPAS)Cl] and (Mn III (TPPIS)Cl], have been evaluated as potential MRI contrast enhancement agents. The water proton magnetic relaxation rate, (1/ T 1), of aqueous [Mn III(TPPAS)Cl] solutions has been measured as a function of field strength over the range of Larmor frequencies from 0.01 to 30 MHz. Results show a typical relaxation rate pattern, similar to other water-soluble manganese (III) porphyrin compounds, over this frequency range. Conductivity and osmolality measurements for [Mn III(TPPAS)Cl] in water demonstrate complete dissociation of the chloride ion to yield [Mn III(TPPAS)(H 2O) 2) +. The two axial water ligands provide a reasonable explanation as to the source of the greater than expected proton relaxation rate of manganese(III) porphyrin compounds, in general. Variable-temperature NMR studies of the H 2TPPAS and H 2TPPIS free ligands reveal the occurrence of proton tautomerism, as indicated by two temperature dependent H β pyrrole proton signals. Actual magnetic resonance images of Sprague-Dawley rats, to which [Mn III(TPPAS))Cl] had been administered, showed significant image enhancement in the heat, liver, lungs and gastrointestinal tract. However, with an acute toxicity of 0.1 mmol kg −1, the cationic [Mn III(TPPAS)(H 2O) 2] + compound is too toxic for clinical use.

Gadolinium(III) Di- and Tetrachelates Designed for in Vivo Noncovalent Complexation with Plasma Proteins: A Novel Molecular Design for Blood Pool MRI Contrast Enhancing Agents

A new series of gadolinium chelates designed as blood pool contrast enhancing agents for magnetic resonance imaging applications is described. Complexes having four Gd(III) chelate units display a significant increase in molecular relaxivity per gadolinium ion in water (9-13 L x mmol(-1) x (s-1) compared to Gd(III)-DTPA (5 L x mmol(-1) x s(-1). A further jump in relaxivity (25 L x mmol(-1) x sec(-1) in 4% BSA solution was observed in the case of a fatty acid-containing tetrachelate and is attributed to noncovalent binding of the tetrachelate to serum albumin. This agent was successfully used for imaging the rat circulatory system.

Relaxometry, Luminescence Measurement, Electrophoresis, and Animal Biodistribution of Lanthanide(III) Complexes of Some Polyaza Macrocyclic Acetates Containing Pyridine

Four Gd{sup 3+} complexes [Gd(BP2A){sup +}, Gd(PC2A){sup +}, Gd(PCTA){sup 0}, and Gd(BPO4A){sup {minus}}] with polyazamacrocyclic ligands that contain a pyridine moiety were prepared and examined for possible use as MRI contrast enhancement agents. The authors estimated the number of inner sphere water molecules (q{sub Gd}) for the Gd{sup 3+} complexes from the values of q found for the Tb{sup 3+} and/or Eu{sup 3+} complexes by luminescence lifetime measurements. It was estimated that q{sub Gd} = 3.5, 3.3, 2.4, and 0.2 for Gd(BP2A){sup +}, Gd(PC2A){sup +}, Gd(PCTA){sup 0}, and Gd(BPO4A){sup {minus}}, respectively. The inner sphere relaxivities (r{sub 1,inner}) of these tetraaza macrocyclic complexes were higher than that of Gd(DOTA){sup {minus}} [i.e. 6.79 for Gd(BP2A){sup +}, 6.21 for Gd(PC2A){sup +}, and 4.60 for Gd(PCTA){sup 0} mM{sup {minus}1}s{sup {minus}1} at 40 MHz and 25{degrees}C], but the normalized relaxivities per q{sub Gd} (1.94, 1.88, and 1.92 mM{sup {minus}1}s{sup {minus}1}, respectively) were comparable to that of Gd(DOTA){sup {minus}}. A quantitative treatment of the NMRD profiles based on Solomon-Bloembergen-Morgan theory, using the NMRD profile of Gd(BPO4A){sup {minus}} to correct for an outer sphere contribution, showed that the complexes exhibit characteristics similar to that of Gd(DOTA){sup {minus}} but with shorter electronic relaxation times. Tissue biodistribution results usingmore » radioactive {sup 153}Sm and {sup 159}Gd complexes in rats indicate that the cationic [{sup 153}Sm-(BP2A){sup +} and {sup 153}Sm(PC2A){sup +}] complexes accumulate preferably in the bone tissue while the neutral [{sup 153}Sm-(PCTA){sup 0}] and anionic [{sup 153}Sm(BPO4A){sup {minus}}] complexes appear to have renal clearances similar to those of other low molecular weight contrast agents [i.e. Gd(DTPA){sup 2{minus}} and Gd(DOTA){sup {minus}}].« less

Gadolinium‐labeled liposomes containing various amphiphilic Gd‐DTPA derivatives: Targeted MRI contrast enhancement agents for the liver

Unique paramagnetic liposomal contrast agents were synthesized and utilized for selective augmentation of T1 MR imaging of the livers of normal Balb/c mice. A series of amphipathic gadolinium complexes, which mimic phospholipids, was incorporated into the lamella of small unilamellar liposomes such that they become an integral part of its surface. The amphipathic complexing agents consisted of DTPA reagents in which two stearyl chains are attached via amide, ester, and thioester linkages. The in vitro stability and the in vivo lifetimes of the new amphipathic agents were dependent on the method used to attach the long-chain alkyl groups.

Gadolinium-labeled liposomes containing amphiphilic Gd-DTPA derivatives of varying chain length: Targeted MRI contrast enhancement agents for the liver

Paramagnetic liposomal contrast agents were synthesized and utilized for selective augmentation of T 1 MR imaging of the livers of normal Balb c mice. Amphiphilic gadolinium complexes, which mimic phospholipids, were incorporated into the lamella of small unilamellar liposomes (SUV) such that they become an integral part of its surface. The amphiphilic complexing agents consisted of DTPA reagents in which a pair of alkyl chains of varying lengths are attached via amide linkages. The in vivo lifetimes of the amphiphilic agents were found to be dependent on the chain length of the alkyl groups.

Interactions of nitroxides with plasma and blood: Effect on 1/T1 of water protons

Nitroxide stable free radicals (nitroxides) have potential utility as MRI contrast-enhancing agents with the additional capability of reflecting redox metabolism. In order to gain a better understanding of their potential interactions in vivo, we have studied the longitudinal NMRD profiles (1/T1 as a function of field strength) and ESR spectra for lipophilic and aqueous-soluble nitroxides in blood, plasma, and plasma components. Typical water-soluble nitroxides do not interact appreciably with blood, plasma, or plasma proteins. Fatty acid nitroxides do interact physically with blood, predominantly by intercalation within red blood cell membranes and binding to albumin. The latter interaction results in significantly enhanced relaxivity for the nitroxide/HSA complex. Relaxation of water protons in this case is dominated by inner sphere processes, ostensibly due to water molecules hydrogen bonded to nitroxide moieties. The rotational reorientation time for the complex, the electronic relaxation time, and the exchange time for the water molecule reversably bound to the nitroxide, all appear significantly to influence the correlation time (approximately 16 ns) for this inner sphere contribution.

A comparative study of manganese meso-sulfonatophenyl porphyrins: Contrast-enhancing agents for tumors

Four manganese meso-sulfonatophenyl porphyrins were prepared, characterized and investigated for their potential as tumor-specific MRI contrast-enhancing agents in mice bearing subcutaneous implants of a mammary carcinoma (SMT-F). The trisulfonated tetraphenyl porphyrin, MnTPPS 3 presented the most favorable profile: biodistribution, tumor concentration and tumor relaxivity, when compared at 24 hr postinjection. Imaging experiments revealed that a time-dependent delineation of tumor morphology occurs in response to MnTPPS 3 that appears to correlate with necrotic regions of the tumor.

MRI of the head and neck

The thoroughly revised and updated Second Edition of this text is part of the popular Lippincott Williams and Wilkins MRI Teaching File Series. The book presents 100 actual case studies that cover a wide range of head and neck disorders and demonstrate the use of current MRI techniques and contrast enhancement agents to aid in diagnosis. Each case study is illustrated with high-resolution MR images and presented in an easy-to-follow format on a two-page spread.On the left-hand page are the images and the clinical history. On the right-hand page are concise descriptions of the radiographic findings, the diagnosis, and the pathology. This format is ideal for teaching readers how to interpret MR images or for everyday reference at the view box. Praise for the previous edition: 'The book is packed with pearls...It should be useful to residents and generalists in radiology and to those in other disciplines in which MR imaging is used...This book is well worth the investment' - American Journal of Roentgenology.