Emerging applications for ferumoxytol as a contrast agent in MRI

Ferumoxytol is an ultrasmall superparamagnetic iron oxide (USPIO) agent initially approved by the Food and Drug Administration (FDA) as an iron replacement therapy for patients with anemia due to chronic renal failure. Recently, ferumoxytol has been investigated extensively as an intravenous contrast agent in magnetic resonance imaging (MRI). Since it causes regional T₁ and T₂* shortening in vivo, conventional pulse sequences can be used following ferumoxytol administration to demonstrate signal enhancement or loss. Ferumoxytol can be administered as a rapid bolus and has a long intravascular half‐life on the order of 14–15 hours, making it a potentially useful agent for vascular and perfusion‐weighted MRI. In comparison to other USPIOs, ferumoxytol is less limited by allergic and idiosyncratic reactions. Furthermore, since ferumoxytol is an iron‐based agent with no potential for causing nephrogenic systemic fibrosis, it may be useful as an alternative to gadolinium‐based contrast agents in patients with compromised renal function. Ferumoxytol is ultimately taken up by macrophages/the reticuloendothelial system in the liver, spleen, and lymph nodes, and this uptake mechanism is being explored as a novel imaging technique for vascular lesions, tumors, and lymph nodes. This article reviews the properties of ferumoxytol relevant to MRI as well as many of the uses for the agent currently under investigation. J. Magn. Reson. Imaging 2015;41:884–898 . © 2014 Wiley Periodicals, Inc .     

A multicenter clinical trial of gadolite oral suspension as a contrast agent for MRI

The purpose of this study was to assess the effectiveness and safety of Gadolite Oral Suspension as a gastrointestinal (GI) contrast agent for MRI in a phase II and two phase III multicenter clinical trials. Gadolite was administered to 306 patients with known or suspected abdominal and/or pelvic disease. MRI with T1- and T2-weighted sequences was performed before and after ingestion. Efficacy was evaluated by having two masked readers rate the certainty of their MR diagnosis (0 = uncertain, 1 = probable, 2 = definite) on randomly presented pre- and post-Gadolite Oral Suspension enhanced images. Principal investigators also evaluated the images and established the final diagnosis. Vital signs, clinical chemistries, and adverse events were documented. Blood and urine samples were analyzed for gadolinium content to determine whether Gadolite Oral Suspension was absorbed systemically. Certainty in MR diagnosis increased significantly (P < .001) for both blinded readers between pre- and post-Gadolite images (.49–1.18 for reader 1; .46–1.53 for reader 2). Sensitivity, specificity, and accuracy also increased for both masked readers. No gadolinium was detected in blood or urine samples. There were no serious adverse events and no apparent drug-related trends in mean vital signs or laboratory values. Gadolite is a highly effective, safe, and well tolerated contrast agent for clinical use with MRI.     

A liposomal MRI contrast agent: phosphatidylethanolamine-DTPA

The chelating agent, diethylenetriaminepentaacetic acid (DTPA), was attached via one -COOH group to the amino headgroup of phosphatidylethanolamine to produce a phospholipid which is also a powerful chelating agent. It readily assembles into the walls of lipid bilayer structures as a liposome-associated carrier of cations for MR contrast or radioisotope studies. Freeze-etch electron microscopy showed that phosphatidylethanolamine-DTPA formed satisfactory sonicated vesicles when mixed with natural phospholipids at up to 50 wt%. The resultant structures with bound gadolinium effectively shortened T1 and T2 of surrounding water protons. When sonicated liposomes bearing chelating agent with bound 111In3+ were injected intravenously into rats, uptake was primarily by liver and spleen. By 24 h postinjection there was biliary excretion of this material. Phosphatidylethanolamine-DTPA may have some general utility as an amphiphilic liposomal chelating agent for polyvalent cations.     

Pyrroxamide, a nonionic nitroxyl spin label contrast agent for magnetic resonance imaging. Mutagenesis and cell survival

Pyrroxamide [N-(1-hydroxymethyl-2,3-dihydroxypropyl)-2,2,5,5-tetramethyl pyrrolidine-1-oxyl-3-carboxyamide] is a newly tested nonionic monomeric nitroxyl compound with demonstrated effectiveness for MRI contrast enhancement at doses as low as 10(-3) M. Pyrroxamide and its hydroxylamine metabolic derivative were tested in concentrations from 10(-9) to 10(-2) M with a battery of cytotoxic and mutagenic assays using mammalian Chinese hamster ovary cells. Loci-specific mutation induction was examined at the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and the Na+/K+ ATPase loci, both in the presence and absence of a liver microsomal metabolic activating mixture (S-9 mix). Cell survival and induction of sister chromatid exchanges also were studied. All tests yielded negative results indicating that pyrroxamide and and hydroxylamine derivative were both noncytotoxic and nonmutagenic at the doses tested.     

Investigation of the magnetic properties of iron oxide nanoparticles used as contrast agent for MRI.

Superparamagnetic iron oxide particles, a new class of contrast agents for MRI, are extremely good enhancers of proton relaxation. However, the development of such particle systems has resulted in a wide range of preparations whose physico-chemical properties differ greatly. We have conducted a set of physical experiments: X ray diffraction analysis, relaxivity measurements, susceptibility determinations, and thermomagnetic cycling on different preparations of superparamagnetic particles. Our results demonstrate a good correlation between susceptibilities measured in liquid samples at room temperature and the R2/R1 ratio. Susceptibility measurements between liquid nitrogen temperature and room temperature show three different types of behavior dependent on the size of iron oxide crystals. Comparison of heating and cooling curves from strong field thermomagnetic cycles provides information about the maghemite/magnetite crystal content. The information on magnetic properties reported in this study may help to characterize and to select these materials for use as MRI contrast agents.     

Gd-DOTA as a gastrointestinal contrast agent for gastric emptying measurements with MRI

Current MR meal markers may interfere with gastric motility and secretion restricting the use of MRI in the measurement of gastric physiology. We therefore evaluated Gd-DOTA as a liquid phase marker, in vitro by determining dissociation, and adherence to the solids, and in vivo by simultaneous MRI (0.35 T scanner, multiple T₁-weighted sections of the upper abdomen) and double indicator (perfusion marker PEG 4000, meal marker ^99mTc-DTPA) measurements of emptying and secretion, following ingestion of 500 ml 10% glucose. In vitro Gd-DOTA was stable at a pH > 2 with < 2% dissociation at 24 h during incubation with HCI. Dissociation during incubation with HCI was linearly dependent on H⁺ concentration (0.77 < pH < 2.02). Less Gd-DOTA was absorbed onto the solid phase than ^99mTc-DTPA (25% cf 36%). in vivo Gd-DOTA marked gastric contents provided strong positive contrast. Similar emptying curves were observed with both MRI and double-indicator techniques (r = 0.987, P < 0.001). Gd-DOTA has the potential to be a useful liquid phase contrast agent in MR studies on gastric function.     

Perfusion-weighted MRI using gadobutrol as a contrast agent in a rat stroke model

The purpose of this study was to examine the new nonionic contrast agent gadobutrol in MR perfusion-weighted imaging, including the influence of different concentrations and dosages of the agent on the sensitivity to perfusion alterations. Sixteen rats were examined within 35 to 105 minutes after endovascular occlusion of the middle cerebral artery. A fast T2*-weighted fast low-angle shot (FLASH) sequence was used to acquire four images before and 16 images after bolus injection of .1, .2, .3, and .4 mmol/kg gadobutrol as .5 molar and 1.0 molar formulation. From user-defined regions, we obtained the maximum signal decrease, the relative regional cerebral blood volume, and the bolus delay. Contrast between ischemic and nonischemic regions during bolus passage increased with dose and concentration of the contrast agent. For low doses (.1 and .2 mmol/kg), the ischemic lesion could not or could barely be discerned. For higher doses (.3 and .4 mmol/kg), administration of the 1 molar contrast agent yielded a better contrast between ischemic and nonischemic tissue. Our results suggest that administration of gadobutrol at higher dosage and higher concentration increases sensitivity to perfusion alterations. These results are potentially useful for perfusion-weighted imaging of the human brain, because the volume of contrast agent will be reduced if a solution with higher concentration is used. When using contrast agents in higher concentrations for human examinations, a significant signal decrease may be achieved also with the low doses (.1–.15 mmol/kg).     

Gadolinium-DTPA liposomes as a potential MRI contrast agent. Work in progress

To evaluate the use of liposomes containing Gadolinium-DTPA (Gd-DTPA) as potential intravascular contrast agents, we synthesized and tested Gd-DTPA liposomes. A freeze-thaw extrusion process was used to synthesize neutral unilamellar vesicles. Using this technique, we prepared 0.4 micron vesicles with encapsulation efficiency as high as 39% for Gd-DTPA. In vitro dialysis showed that essentially 100% of the Gd-DTPA was retained with the liposomes after 72 hours of dialysis. MR imaging of in vitro samples showed concentration-dependent increase in signal intensity with Gd-DTPA liposomes. Imaging of rats after intravenous injection of Gd-DTPA liposomes showed sustained intravascular contrast enhancement of vascular structures and liver greater than free Gd-DTPA. There was no evidence of acute toxicity in rats during the imaging experiments or on follow-up of two months. Paramagnetic liposomes may be useful to enhance the vasculature, liver, and spleen.     

The value of gadoterate meglumine as a gastrointestinal contrast agent in MRI

To evaluate the safety and efficacy of a gadoterate meglumine formulation as an oral contrast agent, MRI (0.5 T) was performed on 29 patients with abdominal disease before and after administration of contrast material. The patients ingested 16 ml/kg of a gadoterate meglumine solution (10 g/l glucose, 2 mmol/l gadoterate meglumine) over 1 h. Fourteen per cent of patients had mild side effects related to the contrast agent. Significant hyperintense contrast enhancement was achieved for the stomach and duodenum allowing better delineation of gastric and duodenal walls, entire pancreas and spleen on T1- and T2-weighted spin echo sequences. In 5 patients more diagnostic information was available from post-contrast images compared with precontrast images. This study shows that gadoterate meglumine is a safe and well-tolerated contrast agent that improves MRI of the proximal gastrointestinal tract and upper abdomen.Presented at the European Congress of Radiology, Vienna, Austria, 15–20 September 1991 Correspondence to: Y. Miaux     

Evaluation of methemoglobin as an autologous intravascular MRI contrast agent

Methemoglobin (MetHb) was evaluated as an intravascular paramagnetic contrast agent. Methemoglobin formation was induced by 4-dimethylaminophenol (4-DMAP), causing a reduction in blood T₂* in vitro. The 4-DMAP generated metHb with a time constant of 62 s. A 4-DMAP bolus did not decrease measurably the signal intensity in the in vivo rabbit kidney in the first pass. At steady state, a MetHb concentration of 24.8 ± 2.3% resulted in a signal decrease of 9.2 ± 2.6% in the kidney. Methemoglobin is an effective vascular T₂* relaxation agent, but the formation of MetHb by 4-DMAP is too slow for first-pass imaging. A more effective conversion agent resulting in a bolus of at least 25% MetHb within 5 s would result in a detectable first-pass signal and a viable contrast technique.     

Use of nutritional support formula as a gastrointestinal contrast agent for MRI.

The objective of this study was to evaluate the potential utility of a nutritional support formula to serve as a practical means of enhancing the gastrointestinal tract on abdominal MR images. Nutritional support formula (Ensure Plus) was administered to 29 patients prior to abdominal MRI. Standard T1-weighted and T2-weighted pulse sequences were performed, in addition to fat suppression and inversion recovery sequences in selected patients. Images in these patients were evaluated for degree and uniformity of gastrointestinal tract enhancement and delineation of the bowel wall and pancreas. Results were compared with those obtained in 10 control patients. Marked enhancement of gastric contents was present in nearly all patients who received nutritional support formula on both T1-weighted and T2-weighted sequences, with mild to moderate enhancement of small bowel and colon in most patients. Although gastrointestinal and respiratory motion artifacts often limited bowel wall delineation, excellent delineation of the gastric wall and pancreas was provided. Phantom experiments demonstrated that gastrointestinal tract enhancement with nutritional support formula is due to the paramagnetic trace elements, corn syrup, and lipid material it contains. Such a formula requires no preparation, is safe, inexpensive, palatable, readily available, and represents a practical means of enhancing the gastrointestinal tract on MRI.     

A potentially artifact-free oral contrast agent for gastrointestinal MRI

The combination of diamagnetic barium sulfate and superparamagnetic iron oxide (SPIO) in one suspension produces a macroscopic cancellation of positive and negative magnetic susceptibility components that can potentially eliminate susceptilbllity artifacts even with gradient echo pulse sequences. The relaxation properties that make the SPIO suspension a useful negative contrast agent are retained.     

Dextran-magnetite: a contrast agent for sodium-23 MRI

Dextran-magnetite, a superparamagnetic compound, is a powerful relaxation reagent for sodium. Administered intravenously, it is confined mainly to the vasculature and eliminates the signal from plasma sodium, a significant component of the tissue sodium signal. Applications of dextran-magnetite for in vivo sodium imaging of a normal rat and rats with a tumor and experimentally induced peripheral edema are shown. Our results indicate that dextran-magnetite may be useful for improving tumor detection and for imaging of edema. To our knowledge, this is the first report of a contrast agent suitable for sodium magnetic resonance imaging.     

Superparamagnetic particles as an MRI contrast agent for the gastrointestinal tract

Non-biodegradable superparamagnetic particles containing magnetite were evaluated as a potential contrast agent for the gastrointestinal tract. The particles were administered to pigs perorally either suspended in water or mixed with food. The gastrointestinal tract structures were excellently depicted through a lowered signal intensity of their content in both T1 and T2 weighted images. Relatively large volumes with low particle concentration seemed to give a good contrast agent distribution, especially when the administration was extended over a period of time. Problems with artefacts and blurring in the images caused by a too high local concentration of the contrast agent should also be minimized by using low particle concentrations.     

Gadolinium-DTPA as a contrast agent in MRI: initial clinical experience in 20 patients

Magnetic resonance imaging (MRI) was performed in 20 patients before and after intravenous administration of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) in a dose of 0.1 mmol/kg. Twelve of the patients had clinical and histologic diagnoses of cerebral tumor, six had hepatic tumors, one had hepatic cysts, and one had transitional cell carcinoma of the bladder. Contrast enhancement was seen with all tumors, but not with the hepatic cysts. The degree of enhancement was greater than that seen with computed tomography (CT) in 13 cases, equal to it in six, and less in one. Contrast enhancement was detectable as long as 18 hr after injection of Gd-DTPA in one case of cerebral tumor. The margin between cerebral tumor and peritumoral edema could be delineated with contrast-enhanced MRI to the degree possible with contrast-enhanced CT. In the liver isointense enhancement was seen with saturation-recovery (SR), inversion-recovery (IR), and spin-echo (SE) sequences although not with all three sequences simultaneously. In general IR sequences were most sensitive for display of the contrast agent, but the enhancement often decreased the difference between abnormal and normal tissue. No short-term side effects were encountered and no significant change was seen in urea, creatinine, electrolytes, liver function tests, blood coagulation, or urine testing after injection of Gd-DTPA. Although much more work will be required to evaluate this contrast agent, these initial experiences are very promising.     

肝胆特异性磁共振对比剂Gd-EOB-DTPA的临床研究进展

Gd-EOB-DTPA为一种新型肝细胞特异性对比剂,除了具有非特异性细胞外对比剂的性质,在体内还可以特异性地被肝细胞所摄取,并通过肾脏和胆道双重系统排泄。由于其具有细胞特异性和独特的代谢特点,Gd-EOB-DTPA肝脏增强MRI检查对肝胆系统疾病的诊断具有明显的优势,对小病灶的检出和肝内占位病变的鉴别诊断具有更高的准确性;对显示肝内外胆道系统的解剖结构与通畅情况等亦可提供更多信息,因此对胆管疾病的诊断亦具有明显优势。     

肝胆特异性磁共振对比剂Gd-EOB-DTPA的临床研究进展

Gd-EOB-DTPA为一种新型肝细胞特异性对比剂,除了具有非特异性细胞外对比剂的性质,在体内还可以特异性地被肝细胞所摄取,并通过肾脏和胆道双重系统排泄。由于其具有细胞特异性和独特的代谢特点,Gd-EOB-DTPA肝脏增强MRI检查对肝胆系统疾病的诊断具有明显的优势,对小病灶的检出和肝内占位病变的鉴别诊断具有更高的准确性;对显示肝内外胆道系统的解剖结构与通畅情况等亦可提供更多信息,因此对胆管疾病的诊断亦具有明显优势。