An albumin-based gold nanocomposites as potential dual mode CT/MRI contrast agent

In pursuit of the biological detection applications, recent years have witnessed the prosperity of novel multi-modal nanoprobes. In this study, biocompatible bovine serum albumin (BSA)-coated gold nanoparticles (Au NPs) containing Gd (III) as the contrast agent for both X-ray CT and T₁-weighted MR imaging is reported. Firstly, the Au NPs with BSA coating (Au@BSA) was prepared through a moderate one-pot reduction route in the presence of hydrazine hydrate as reducer. Sequentially, the BSA coating enables modification of diethylenetriaminepentaacetic acid (DTPA) as well as targeting reagent hyaluronic acid (HA), and further chelation of Gd (III) ions led to the formation of biomimetic nanoagent HA-targeted Gd-Au NPs (HA-targeted Au@BSA-Gd-DTPA). Several techniques were used to thoroughly characterize the formed HA-targeted Gd-Au NPs. As expected, the as-prepared nanoagent with mean diameter of 13.82 nm exhibits not only good colloid stablility and water dispersibility, but also satisfying low cytotoxicity and hemocompatibility in the tested concentration range. Additionally, for the CT phantoms, the obtained nanocomplex shows an improved contrast in CT scanning than that of Au@BSA as well as small molecule iodine-based CT contrast agents such as iopromide. Meanwhile, for the T₁-weighted MRI images, there is a linear increase of contrast with concentration of Gd for the two cases of HA-targeted Gd-Au NPs and Magnevist. Strikingly, the nanoagent we explored displays a relatively higher r₁ relaxivity than that of commercial MR contrast agents. Therefore, this newly constructed nanoagent could be used as contrast agents for synergistically enhanced X-ray CT and MR phantoms, holding promising potential for future biomedical applications.     

An evaluation of gadolinium polyoxometalates as possible MRI contrast agent

Two gadolinium polyoxometalates, K(9)GdW(10)O(36) and K(11)[Gd(PW(11)O(39))(2)], have been evaluated both in vivo and in vitro as candidates for tissue-specific MRI contrast agents. T(1)-relaxivities of 6.89 mM(-1). s(-1) for K(9)GdW(10)O(36) and 5.27 mM(-1). s(-1) for K(11)[Gd(PW(11)O(39))(2)] are slightly higher than that of the commercial MRI contrast agent (Gd-DTPA). Both compounds bind with bovine serum albumin and human serum transferrin and favorable liver-specific contrast enhancement in in vivo MRI with Sprague-Dawley rats after i.v. administration has been demonstrated. Imaging studies demonstrate that the two agents have a long residence time, showing MR signal enhancement in the liver for more than 40 min, longer than commercially available contrast agents. In vivo and in vitro assays showed that GdW(10) and Gd(PW(11))(2) are promising liver-specific MRI contrast agents and GdW(10) may be used in the diagnosis of the pathological state. However, with the higher acute toxicity, the two gadolinium polyoxometalates need to be modified and studied further before clinical use.     

The gadolinium complexes with polyoxometalates as potential MRI contrast agents

The two gadolinium (Gd) polyoxometalates, K(15)[Gd(BW(11)O(39))(2)] [Gd(BW(11))(2)] and K(17)[Gd(CuW(11)O(39))(2)] [Gd(CuW(11))(2)] have been evaluated by in vivo and in vitro experiments as the candidates of potential tissue-specific magnetic resonance imaging (MRI) contrast agents. T(1) relaxivities of 17.12 mM(-1) x s(-1) for Gd(BW(11))(2) and 19.95 mM(-1) x s(-1) for Gd(CuW(11))(2) (400 MHz, 25 degrees C) were much higher than that of the commercial MRI contrast agent (GdDTPA). Their relaxivities in bovine serum albumin and human serum transferrin solutions were also reported. After administration of Gd(BW(11))(2) and Gd(CuW(11))(2) to Wistar rats, MRI showed longer and remarkable enhancement in rat liver and favorable renal excretion capability. The signal intensity increased by 37.63+/-3.45% for the liver during the whole imaging period (100 min) and by 61.47+/-10.03% for kidney within 5-40 min after injection at 40+/-1-micromol x kg(-1) dose for Gd(CuW(11))(2), and Gd(BW(11))(2) induced 50.44+/-3.51% enhancement in the liver in 5-50-min range and 61.47+/-10.03% enhancement for kidney within 5-40 min after injection at 39+/-4 micromol x kg(-1) dose. In vitro and in vivo study showed that Gd(BW(11))(2) and Gd(CuW(11))(2) are favorable candidates as tissue-specific contrast agents for MRI.     

Iron oxide nanoparticles for use as an MRI contrast agent: pharmacokinetics and metabolism

The pharmacokinetics and metabolism of a new preparation of superparamagnetic iron oxide nanoparticles were evaluated by 59Fe radiotracer studies and histologic examination of mice liver and spleen tissues (light and transmission electron microscopy). In the first 30 min following IV injection of the product half of the dose injected remains in the blood, the other part being sequestered mainly by the mononuclear phagocyte system (MPS). In the first five days following IV administration of the nanoparticles, early metabolization of the iron oxide cores occurs, revealed by modification of their aspect in the lysosomes of Kupffer cells and macrophages of the splenic red pulp. The incorporation of 59Fe is then observed in RBC of the mice. These results are discussed in relation with the physicochemical properties of this new preparation of nanoparticles, and compared with current pharmacokinetic data concerning injectable particle systems.     

Polymeric contrast agent with targeting potential

The Arg-Gly-Asp (RGD) peptide sequence was conjugated to poly (lactid acid), (PLA), microcapsules. These hollow, biodegradable PLGA microcapsules were developed in our laboratory for use as ultrasound contrast agents. By modifying the surface of the agent with a targeting ligand, it can be targeted to a specific address within the body. This application is ideal for both targeted imaging and/or targeted drug delivery. Integrins are membrane-spanning proteins in cells that play a vital role in cell attachment and many other processes. The RGD peptide sequence targets integrins expressed during angiogenesis, alphavbeta3 and alphavbeta5. The integrins specific to angiogenesis are more active during cancer and can be used as receptors for the RGD-conjugated contrast agents. Although the generic RGD sequence is not specific to only alphavbeta3 and alphavbeta5 integrins, it is an excellent candidate for proof of concepts studies such as described here. Preliminary in vitro results indicate that the modified capsules remain highly echogenic (maximum enhancement of 20 dB in vitro) and adhere specifically to a breast cancer cell line MDA-MB-231 in static experiments. However, no adherence is seen with either unmodified capsules (negative control), or when cells that have been pre-saturated with RGD ligand are contacted with modified capsules (positive control). Specific targeting of ultrasound contrast agents could lead the way to imaging as a method for discrimination of malignant from benign.     

Three-dimensional saltwater-freshwater fingering in porous media: contrast agent MRI as basis for numerical simulations

This study investigated miscible fingering phenomena in a saturated porous medium due solely to fluid density differences. The objective was to determine dissolved salt concentrations in the porous medium and, thus, local fluid density with high temporal resolution and covering substantial volume. A magnetic resonance imaging method, which can achieve this goal by adding Cu(II)SO(4) to salt solutions, has been developed. This method was applied here to observe and quantify three-dimensional miscible fingering for the initial unstable layering of saltwater above freshwater. Additionally, characteristic properties were defined and evaluated to facilitate a more meaningful comparison with numerical simulations.     

Activity revealed in MRI of multiple sclerosis without contrast agent. A preliminary report

Disease activity in multiple sclerosis is usually accompanied by blood-brain barrier disruption, which can be assessed with contrast-enhanced magnetic resonance imaging (MRI). This paper describes a technique that gives information about disease activity using magnetization transfer MRI. Image combination methods using follow-up scans, like the one presented here, have the potential to show MS lesions that correlate with enhancement.     

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

Quasi-critical fluctuations occur close to critical points or close to continuous phase transitions. In three-dimensional systems, precision tuning is required to access the fluctuation regime. Lowering the dimensionality enhances the parameter space for quasi-critical fluctuations considerably. This enables one to make use of novel properties emerging in fluctuating systems, such as giant susceptibilities, Casimir forces or novel quasi-particle interactions. Examples are discussed ranging from simple metal–adsorbate systems to unconventional superconductivity in iron-based superconductors.     

Vegetable oil as an MR contrast agent for rectal applications

The purpose of the study was to evaluate the feasibility of pure vegetable oil as an MR contrast agent for rectal applications. The hypothesis was that vegetable oil highlights the lumen of the rectum after rectal application as a positive contrast medium and offers additional contrast qualities using fat suppression techniques. Eleven MRI examinations were performed on 11 subjects (five healthy volunteers, all males, mean age 35 yr; and six patients, three males, three females, mean age 49 yr). Peanut oil, 200 ml, was applied rectally. In addition, 0.1 mmol/kg GD-DTPA was administered intravenously to the six patients only. Conventional T₁-weighted SE sequences and and T₁-weighted SE images with fat suppression were obtained. Criteria for image evaluation were: overall image quality; uniformity of contrast distribution; chemical shift artifact; and delineation of the rectal wall. Side effects were assessed. There were no complaints reported by the 11 subjects. The image quality was sufficient in all studies. In all five of the volunteers and five of the six patients, the distribution of oil was uniform. Chemical shift artifacts did not deteriorate image quality. After rectal application of vegetable oil, the delineation of the rectal wall was sufficient with and without fat suppression techniques. Vegetable oil highlights the lumen of the rectum in MRI studies and offers additional contrast qualities with fat suppression techniques, acting as a positive as well as a negative contrast agent, depending on the chosen sequence.     

Enhanced ferrite nanoparticles as MRI contrast agents

Enhanced ferrite nanoparticles are a new class of contrast agents for magnetic resonance imaging (MRI). The enhanced ferrites are synthesized by reverse micelles technique to form iron core and oxide or ferrite shell preventing further oxidation of the nanoparticles. The nanoparticles are further functionalized using dopamine and PEG-600 to increase the solubility of the high magnetic moment nanoparticles. ¹H relaxation measurements of aqueous solutions of the nanoparticles were conducted at 2.4 T. The relaxivities r₁ and r₂, representing the slopes of these curves, are 7.19 and 9.96 s⁻¹ mM⁻¹, respectively. These values should be compared with relaxivities of 4–5 s⁻¹ mM⁻¹ corresponding to commonly used commercial contrast agents in human MR examinations.     

Investigation of sandwiched gadolinium (III) complexes with tungstosilicates as potential MRI contrast agents

Two gadolinium-sandwiched complexes with tungstosilicates, K(13)[Gd(SiW(11)O(39))(2)] (Gd(SiW(11))(2)) and K(11)H(6)[Gd(3)O(3)(SiW(9)O(34))(2)] (Gd(3)(SiW(9))(2)), have been investigated by in vitro and in vivo experiments as potential contrast agents for magnetic resonance imaging (MRI). T(1)-relaxivity of Gd(SiW(11))(2)was 6.59 mM(-1).s(-1) in aqueous solution and 6.85 mM(-1).s(-1) in 0.725 mmol.L(-1) bovine serum albumin solution at 25 degrees C and 9.39 T, respectively. The corresponding T(1)-relaxivity of Gd(3)(SiW(9))(2) was 12.6 and 19.3 mM(-1).s(-1) per Gd, respectively. MRI for Sprague-Dawley rats showed longer and more remarkable enhancement in rat liver after i.v. injection of these two complexes: 39.4 +/- 3.9% and 57.4 +/- 11.6% within the first 30 min after injection, 31.2 +/- 2.6% and 39.9 +/- 7.6% in the next 60 min for Gd(SiW(11))(2) and Gd(3)(SiW(9))(2) at doses of 0.081 and 0.084 mmol Gd/kg, respectively. Our preliminary in vitro and in vivo study indicates that Gd(SiW(11))(2) and Gd(3)(SiW(9))(2) are favorable candidates for hepatic contrast agents for MRI. However, the two complexes exhibit higher acute toxicity and need to be modified and studied further before clinical use.     

Monitoring redox-sensitive paramagnetic contrast agent by EPRI, OMRI and MRI

A comparative study of tissue redox-status imaging using commonly used redox sensitive nitroxides has been carried out using electron paramagnetic resonance imaging (EPRI), Overhauser magnetic resonance imaging (OMRI) and conventional T(1)-weighted magnetic resonance imaging, MRI. Imaging studies using phantoms of different nitroxides at different concentration levels showed that EPRI and OMRI sensitivities were found to be linearly dependent on line width of nitroxides up to 2 mM, and the enhancement in MRI intensity was linear up to 5 mM. The sensitivity and resolution of EPRI and OMRI images depended significantly on the line width of the nitroxides whereas the MRI images were almost independent of EPR line width. Reduction of the paramagnetic 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (3CP) by ascorbic acid (AsA) to the diamagnetic by hydroxylamine was monitored from a sequence of temporal images, acquired using the three imaging modalities. The decay rates determined by all the three modalities were found to be similar. However the results suggest that T(1)-weighted MRI can monitor the redox status, in addition to providing detailed anatomical structure in a short time. Therefore, a combination of MRI with nitroxides as metabolically responsive contrast agents can be a useful technique for the in vivo imaging probing tissue redox status.     

Barium sulfate suspension as a negative oral MRI contrast agent: in vitro and human optimization studies

In vitro proton spectroscopy with line-width measurements and MR imaging were performed on various concentrations of commercially available single contrast (SC), double contrast, oral and rectal barium sulfate suspensions, as well as potassium sulfate, barium chloride, barium hydroxide, and 97% pure barium sulfate suspensions. Approximately 500 ml of 20%, 40%, 60%, and 70% w/w suspensions of SC oral barium sulfate suspensions were administered to four normal volunteers, respectively, and MR images were obtained at both 1.5 T and 0.15 T. Subsequently, 500 ml of 60% w/w suspensions of SC oral barium sulfate suspensions were administered to five normal volunteers and imaged at 1.5 T. All of the inert suspensions produced line-width broadening but the SC oral barium sulfate suspension at 50% and 70% stayed in suspension even after hours of standing undisturbed. As much as 80% of the small bowel and the entire colon were well visualized using the combination of 60% or 70% w/w SC barium sulfate suspensions with SE 550/22 and FISP pulse sequences. The effect was less at 0.15 T and also with the SE 2000/45/90 pulse sequences. We conclude that barium sulfate suspensions are useful as oral MRI contrast agents.     

Superparamagnetic iron oxide nanoparticles as a liver MRI contrast agent: Contribution of microencapsulation to improved biodistribution

We have developed a new method of synthetizing superparamagnetic iron oxide nanoparticles, consisting in the modifications of Molday's method, which ensures high relaxivity (2.4 10⁵ s⁻¹·M⁻¹·L), good chemical stability, singular biodistribution and a considerable safety margin. The ED (Efficace Dose) to LD50 ratio is instead of for Gd-DTPA. In order to develop a magnetite-delivery system to the liver we have incorporated the nanoparticles into biodegradable synthetic microcapsules. Encapsulated ⁵⁹Fe oxide nanoparticles are injected into rats; in these conditions the sequestration is 9-fold greater in liver and 6 and 5 times lower in blood and carcase, respectively. This modification of the biodistribution enables the use of magnetite containing microcapsules at only 0.3 mg/kg iron to obtain an improved contrast in liver.     

Gd complexes of diethylenetriaminepentaacetic acid conjugates of low-molecular-weight chitosan oligosaccharide as a new liver-specific MRI contrast agent

This study was to describe the synthesis of complexes of gadolinium diethylenetriaminepentaacetic acid conjugates of low-molecular-weight chitosan oligosaccharide Gd-DTPA-CSn (n = 6, 8, 11) as a new class of contrast agent as well as its magnetic property in a pilot magnetic resonance imaging. The efficacy of the contrast agent was assessed by measuring the longitudinal relaxivity (r₁), FLASH imaging in phantoms in vitro and signal intensity in vivo of the rat abdominal axial imaging. The r₁ of Gd-DTPA-CS₁₁ was up to 11.65 mM^− 1·s^− 1, which was 3 times higher than that of the analogous MRI contrast agent Gd-DTPA in commercial use. In vivo MR images of rat obtained with Gd-DTPA-CS₁₁ showed strong signal enhancement in liver and the vessels of the liver parenchyma during the extended period of time. The present study suggests that the new synthesized gadolinium complexes can be used as a new class of practical liver-specific MRI contrast agent because of its superior performance compared with Gd-DTPA.     

Ingested manganese chloride as a contrast agent for magnetic resonance imaging

Solutions of manganese chloride were force-fed to Sprague-Dawley rats. Magnetic resonance (MR) imaging was performed on (a) syringes containing different concentrations of manganese chloride, (b) rats after force feeding and (c) livers excised after sacrifice of the force-fed rats. Imaging was done with a 0.15-T resistive magnet. Multiple pulse sequences were used and T1 values were calculated. The signal intensity and T1 value obtained from a solution depended on the manganese concentration and the pulse sequence employed. At higher concentrations, no signal was produced due to extreme T2 shortening. Absorbed manganese affected the signal intensities and T1 values of the rats' livers. By appropriate selection of manganese concentration and pulse sequence, ingested manganese can serve as a combined gastrointestinal and hepatic MR contrast agent.     

Protein-based molecular contrast optical coherence tomography with phytochrome as the contrast agent

We report the use of phytochrome A (phyA), a plant protein that can reversibly switch between two states with different absorption maxima (at 660 and 730 nm), as a contrast agent for molecular contrast optical coherence tomography (MCOCT). Our MCOCT scheme builds up a difference image revealing the distribution of phyA within a target sample from pairs of consecutive OCT A-scans acquired at a probe wavelength of 750 nm, both with and without additional illumination of the target sample with 660-nm light. We demonstrate molecular imaging with this new MCOCT modality in a target sample containing a mixture of 0.2% Intralipid and 83 microM of phyA.     

Enteric MRI contrast agents: comparative study of five potential agents in humans.

We compared the effectiveness of 1 mM Geritol, 12% corn oil emulsion, Kaolin-pectin, single contrast oral barium sulfate, and effervescent granules as enteric magnetic resonance imaging (MRI) contrast agents. Five volunteers were recruited. Each volunteer ingested for examinations, separated by at least one week, either 500 ml of each of the liquid preparations or two packets of the CO2 granules (producing 400 ml of CO2 per packet). Abdominal MR images were then obtained using a 1.5 T Magnetom imager and SE 550/22, SE 2000/45/90 and FISP 40/18/40 degrees pulse sequences. The oil emulsions were best tolerated. Barium sulfate caused the greatest amount of nausea, followed by Geritol and Kaolin-pectin. With FISP 40/18/40 degrees, 60%-80% of the small bowel was well delineated using oil emulsion, Kaolin-pectin, or barium sulfate. We conclude that oil emulsion was by far the best enteric MR contrast agent in our study. Good delineation of the small bowel and pancreas can be achieved using oil emulsion and gradient echo pulse sequences. The lack of side-effects and the excellent taste make it highly acceptable to human subjects.     

Superparamagnetic FePt nanoparticles as excellent MRI contrast agents

Chemically disordered face-centered cubic (fcc) FePt nanoparticles (NPs) with a mean diameter of 9 nm were synthesized via pyrolysis of iron(III) ethoxide and platinum(II) acetylacetonate. The surface ligands of these NPs were then exchanged from oleic acid to tetramethylammonium hydroxide (TMAOH) to measure the longitudinal (T₁) and transverse (T₂) proton relaxation times of aqueous dispersion of FePt NPs. Magnetic resonance relaxometry reveals that TMAOH-capped FePt NPs have a higher T₂-shortening effect than conventional superparamagnetic iron oxide NPs, indicating that fcc-phase FePt NPs might be superior negative contrast agents for magnetic resonance imaging.