Copper-D-penicillamine complex as potential contrast agent for MRI.

In vitro and in vivo proton T1 data are reported that demonstrate that the paramagnetic copper-D-penicillamine complex can be applied as a potential contrast agent to magnetic resonance imaging.     

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.     

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.     

pH-sensitive paramagnetic liposomes as MRI contrast agents: in vitro feasibility studies.

A novel type of pH-sensitive paramagnetic contrast agent is introduced; a low molecular weight gadolinium (Gd) chelate (GdDTPA-BMA) encapsulated within pH-sensitive liposomes. The in vitro relaxometric properties of the liposomal Gd chelate were shown to be a function of the pH in the liposomal dispersion and the membrane composition. Only a minor pH-dependency of the T1 relaxivity (r1) was observed for liposomal GdDTPA-BMA composed of the unsaturated lipids dioleoyl phosphatidyl ethanolamine (DOPE) and oleic acid (OA). On the other hand, the r1 of GdDTPA-BMA encapsulated within saturated dipalmitoyl phosphatidyl ethanolamine/palmitic acid (DPPE/PA) liposomes demonstrated a strong pH-dependency. At physiological pH and above, the r1 of this system was significantly lowered compared to that of non-liposomal Gd chelate, which was explained by an exchange limited relaxation process. Lowering the pH below physiological value, however, gave a sharp and 6-7 fold increase in r1, due to liposome destabilisation and subsequent leakage of entrapped GdDTPA-BMA. The pH-sensitivity of the DPPE/PA liposome system was confirmed in an in vitro magnetic resonance imaging (MRI) phantom study.     

Enhanced MRI of tumors utilizing a new nitroxyl spin label contrast agent

Nitroxyl spin labels have been shown to be effective in vivo contrast agents for magnetic resonance imaging (MRI) of the central nervous system, myocardium, and urinary tract. A new pyrrolidine nitroxyl contrast agent (PCA) with better resistance to in vivo metabolic inactivation than previously tested agents was studied for its potential to enhance subcutaneous neoplasms in an animal model. Twenty-two contrast enhancement trials were performed on a total of 15 animals 4-6 weeks after implantation with human renal adenocarcinoma. Spin echo imaging was performed using a .35 T animal imager before and after intravenous administration of PCA in doses ranging from 0.5 to 3mM/kg. The intensity of tumor tissue in the images increased an average of 35% in animals receiving a dose of 3 mM/kg. The average enhancement with smaller doses was proportionately less. Tumor intensity reached a maximum within 15 min of injection. The average intensity difference between tumor and adjacent skeletal muscle more than doubled following administration of 3 mM/kg of PCA. Well-perfused tumor tissue was more intensely enhanced than adjacent poorly perfused and necrotic tissue.     

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.     

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.     

MR imaging of pulmonary parenchyma and emboli by paramagnetic and superparamagnetic contrast agents

Using experimentally induced pulmonary emboli in an animal model, three intravenously administered contrast agents, Gd-DTPA-albumin microspheres (8-15 microns, 0.2 M particles/mg protein, 39-106 micrograms Gd/mg, 50 mg/ml), Gd-DTPA-liposomes (15-30 microns, 130 micrograms/mg lipid, 6 mg Gd/ml) and superparamagnetic ferrosome, (60 nm, 100 mM iron and 20 mg lipid/ml) were examined for MR imaging. Gd-DTPA entrapped in lung capillaries did not enhance the signal intensity of lung parenchyma, but liposomes (5 ml) served as better Gd-DTPA carriers and increased the parenchymal signal intensity by up to a factor of 2.3. However, neither agent improved delineation of pulmonary emboli. Ferrosome decreased the intensity of lung parenchyma, improving detectability of pulmonary emboli by several factors.     

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.     

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.     

Detection of hepatic malignancies using Mn-DPDP (manganese dipyridoxal diphosphate) hepatobiliary MRI contrast agent

A new hepatobiliary contrast agent (Mn-DPDP) was used in the detection of liver metastases in six rabbits with seven hepatic V2 carcinomas. This contrast agent is derived from pyridoxyl-5-phosphate which is biomimetically designed to be secreted by the hepatocyte. After Mn-DPDP administration, a 105% increase in liver signal to noise was obtained using a 200/20 (TR/TE) pulsing sequence, and a 62% decrease in intensity was observed using a 1200/60 pulsing sequence. Liver V2 carcinoma contrast enhancement increased 427% using the 200/20 pulsing sequence and 176% using the 1200/60 pulsing sequence. Four of seven V2 carcinomas were not detectable prior to the administration of Mn-DPDP (50 mumol/kg). Two neoplasms were only detectable in retrospect (after Mn-DPDP) on the 1200/60 sequence. The smallest neoplasms detected in this study were 1-4 mm. Mn-DPDP appears to be a promising MRI contrast agent.     

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.     

Assessment of acute myocardial infarction in man with magnetic resonance imaging and the use of a new paramagnetic contrast agent gadolinium-bopta

To assess the feasibility of and characterize the new paramagnetic contrast agent gadolinium-BOPTA/dimeglumine (Gd-BOPTA) to detect acute myocardial infarctions with MR imaging, 24 patients (53.3 ± 8.3 yr) were examined 9.3 ± 3.6 days after a first myocardial infarction. Short-axis T₁-weighted and T₂-weighted MR imaging was performed at three slice levels. T₁-weighted images were obtained before, immediately after, 15, 30, and 45 min after injection. Patients received either 0.05 or 0.1 mmol/kg body weight Gd-BOPTA. Images were qualitatively and quantitatively analyzed. Two patients showed no signs of infarction on T₂-weighted images as opposed to contrast-enhanced T₁-weighted images. Contrast-to-noise ratio was not affected by the dosage level. Signal intensity (SI) of normal to infarcted myocardium was significantly improved by both dosages (p < .0005) but a dosage of 0.05 mmol/kg produced significantly higher SI inf/norm (1.42 ± 0.07 vs. 1.34 ± 0.06, respectively, p = .015). SI of normal and infarcted myocardium enhanced immediately after administration of 0.05 mmol/kg (29.3 ± 5.1% and 53.8 ± 9.6% respectively), which decreased thereafter to 5.3 ± 4.8% and 40.2 ± 8.5% respectively, at 45 min (p < .002 for normal myocardium). SI enhancement immediately after 0.1 mmol/kg Gd-BOPTA showed no decrease within the first 45 min. Gd-BOPTA enables the detection of myocardial infarction. Optimal infarct delineation is achieved from 15 to 45 min after administration of 0.05 mmol/kg body weight Gd-BOPTA. Gd-BOPTA at 0.05 mmol/kg does improve image quality as measured by contrast-to-noise ratio and SI enhancement as compared to 0.10 mmol/kg.     

A reference agent model for DCE MRI can be used to quantify the relative vascular permeability of two MRI contrast agents

Dynamic Contrast Enhancement (DCE) MRI has been used to measure the kinetic transport constant, K^trans, which is used to assess tumor angiogenesis and the effects of anti-angiogenic therapies. Standard DCE MRI methods must measure the pharmacokinetics of a contrast agent in the blood stream, known as the Arterial Input Function (AIF), which is then used as a reference for the pharmacokinetics of the agent in tumor tissue. However, the AIF is difficult to measure in pre-clinical tumor models and in patients. Moreover the AIF is dependent on the Fahraeus effect that causes a highly variable hematocrit (Hct) in tumor microvasculature, leading to erroneous estimates of K^trans. To overcome these problems, we have developed the Reference Agent Model (RAM) for DCE MRI analyses, which determines the relative K^trans of two contrast agents that are simultaneously co-injected and detected in the same tissue during a single DCE-MRI session. The RAM obviates the need to monitor the AIF because one contrast agent effectively serves as an internal reference in the tumor tissue for the other agent, and it also eliminates the systematic errors in the estimated K^trans caused by assuming an erroneous Hct. Simulations demonstrated that the RAM can accurately and precisely estimate the relative K^trans (R^Ktrans) of two agents. To experimentally evaluate the utility of RAM for analyzing DCE MRI results, we optimized a previously reported multiecho ¹⁹F MRI method to detect two perfluorinated contrast agents that were co-injected during a single in vivo study and selectively detected in the same tumor location. The results demonstrated that RAM determined R^Ktrans with excellent accuracy and precision.