Liver Contrast Agent Research Articles

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.

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.

Efficacy of the Iodine-Free Computed Tomography Liver Contrast Agent, Dy-EOB-DTPA, in Comparison With a Conventional Iodinated Agent in Normal and in Tumor-Bearing Rabbits

To investigate the efficacy of the new liver-specific x-ray contrast agent, Dy-EOB-DTPA, in rabbits with VX2 liver tumors by spiral computed tomography (CT) in comparison to iopromide. The time course of liver enhancement was determined in five groups of two normal anesthetized rabbits, which received intravenous injections of Dy-EOB-DTPA before anesthesia at a dose of 0.5 mmol/kg. Fifteen, 30, 45, 60, and 90 minutes after administration spiral CT images were obtained and the attenuation in the livers were determined. A second group of ten rabbits with implanted VX2 tumors received in a random crossover design either Dy-EOB-DTPA at a dose of 0.5 mmol/kg or, 1 day later, iopromide at a dose of 600 mg iodine/kg. CT images were obtained 60 minutes after Dy-EOB-DTPA administration and both in the arterial and portal-venous phases after iopromide injection. Three radiologists evaluated the images. The rabbits were killed, and their livers were investigated histologically for liver tumors. In normal animals, 0.5 mmol/kg Dy-EOB-DTPA resulted in a liver enhancement of 30 HU during the whole observation period of 90 minutes. In tumor-bearing animals, histology revealed 14 implanted tumors of 3-20 mm diameter. Sixty-five percent of the tumors were below 10 mm. Dy-EOB-DTPA was able to detect 13 tumors (93%), iopromide 11 (79%) both in the arterial and in the portal-venous phase. The difference was statistically not significant. In plain CT, seven tumors (50%) were found (P < 0.01 vs iopromide and Dy-EOB-DTPA). One scar and two sites of necrosis were detected by each of the methods. Dy-EOB-DTPA injection at a dose of 0.5 mmol/kg resulted in a long-lasting detectability of 93% of all implanted tumors versus 79% found with iopromide.

Mechanisms of action of liver contrast agents: impact for clinical use.

New contrast agents for magnetic resonance imaging are continually being developed by pharmaceutical companies in order to better image the liver. These agents can be divided into hepatobiliary agents directed to the hepatocytes and nanoparticulate agents directed to the reticulo-endothelial system. After intravenous injection, all these agents concentrate in the liver and induce profound changes in signal intensity. Particulate agents induce predominantly a darkening of the liver parenchyma, while hepatobiliary agents induce a brightening. In both cases, liver-lesion conspicuity is enhanced, leading to a better visualization of the lesion. After a brief description of the principal characteristics of the agents, this paper will attempt to summarize the utility of these agents for the detection and characterization of focal liver disease.

Clinical implications of studies with MnDPDP in animal models of hepatic abnormalities.

Mangafodipir trisodium (manganese dipyridoxal diphosphate or MnDPDP) has been introduced as a hepatobiliary MR contrast agent (Teslascan). Its potential to assist in the characterisation of focal liver lesions, the diagnosis of local and global obstructive cholestasis and the evaluation of hepatic function in diffuse liver diseases has been explored in multiple pre-clinical experiments with appropriate animal models. The prompt negative contrast enhancement and delayed peritumoural rim-enhancement seen after i.v. injection of MnDPDP are 2 typical features of primary and secondary liver tumours with high malignancy, while the persistent positive enhancement is a sign of liver tumours of well preserved hepatocytic nature. Liver with local and total biliary obstruction can be visualized in MnDPDP-enhanced MR images as a region with prolonged signal enhancement. This agent could also be used to non-invasively evaluate diffuse liver diseases of different causes. In the present paper, we review the experimental data in the literature, provide some unpublished results and discuss the potential impact on the clinical use of MnDPDP in the liver. We conclude that MnDPDP is a promising MR liver contrast agent for the detection and characterisation of focal and diffuse liver diseases.

Contrast agents for MR imaging of the liver.

The evolution of contrast agents for MR imaging of the liver has proceeded along several different paths with the common goal of improving liver-lesion contrast. These contrast agents are used to accentuate the inherent differences in liver-lesion signal intensity through differential enhancement of proton relaxation within adjacent tissues. Contrast agents used for hepatic MR imaging can be broadly categorized into those that target the extracellular space, the hepatobiliary system, and the reticuloendothelial system. Although only a small number of liver contrast agents are currently available, others are rapidly proceeding through clinical trials and may soon be added to our clinical armamentarium. This article will briefly review the current clinical experience with these agents, discussing their mechanism of contrast enhancement, pharmacokinetics, and efficacy in the evaluation of focal liver lesions.

Liver contrast enhancement in primates using iopromide liposomes

We studied the feasibility of using iodinated liposomes as computed tomography (CT) liver contrast agents in nonhuman primates. Iopromide-containing liposomes were investigated as reticuloendothelial (RES) contrast agents for CT scanning of the liver in normal adult baboons. For intravenous (i.v.) injection, liposomes were resuspended in mannitol solution, filtered under sterile conditions, and injected i.v. at doses of 200 and 400 mg l/kg to each of five anesthetized adult baboons. Animals tolerated the injections without measurable electrocardiographic changes and recovered uneventfully from anesthesia. Sequential CT scans of the baboons' upper abdomen acquired up to 60 min postinjection showed persistent enhancement of the liver 10-60 min after injection. Maximum enhancement levels were 36 and 61 delta Hounsfield units (delta H) after the 200- and 400-mg/kg doses, respectively. The mean time to plateau enhancement was 20 min with the 200-mg/kg dose and 10 min with the 400-mg/kg dose. The greatest splenic enhancements were 181 and 301 delta H after the 200- and 400-mg/kg doses, respectively. Iopromide liposomes are effective as RES contrast agents in primates.

MR-Tomographie fokaler Leberläsionen mit dem superparamagnetischen Kontrastmittel AMI-25 bei 1,5 Tesla

Superparamagnetic iron oxide particles (AMI-25) were evaluated as a liver contrast agent in high-field MR imaging (1.5 T). 16 patients with up to 5 presumed focal liver lesions (liver metastases n = 8, HCC n = 5, Klatskin tumours n = 2, FNH n = 1) received 15 mumol Fe/kg BW intravenously and were examined via standard T1- and T2-weighted spin-echo sequences. Quantitative image analysis showed a post-contrast increase of the contrast-to-noise ratio (C/N) from 1.6 to 7.4 on SE 2,500/15 images (p < .05). However, C/N was in the same range on plain SE 2,500/90 scans. Blind evaluation by two independent readers revealed that AMI-25-enhanced images did not provide a significantly increased number of lesions. Two patients reported minor, self-limited side-effects (flush, back pain). We conclude that in contrast to reports at mid-field MR imagers, the use of AMI-25 at 1.5 T does not significantly improve the detection of focal liver lesions on conventional SE images.

Evaluation of a nitroxyl fatty acid as liver contrast agent for magnetic resonance imaging

In this study, we report the synthesis and the evaluation as MRI contrast agent of a new compound (nitroxyl fatty acid, NFA), where a pyrrolidinoxyl radical (3-carboxy-proxyl, PCA) is linked to a fatty acid moiety. Fatty acids were selected as vector because they present a high affinity for the liver, their efficient cellular uptake being the result of a specific interaction with a transmembrane transporter (liver plasma membrane-fatty acid binding protein). The uptake of 3H-oleic acid is inhibited after the injection of 1 mmol/kg of NFA, suggesting that NFA recognizes the same transmembrane transporter as the natural fatty acids. The higher relaxivity R1 of NFA in albumin solutions, compared with PCA, was explained by the immobilization of the nitroxyl radical in the protein. MR imaging was performed using T1-weighted images on mice in order to compare the contrast effect obtained after the injection of 1 mmol/kg of radical. The % signal enhancement in the liver 5 min after intravenous injection was 49 +/- 4 and 14 +/- 5 for NFA and PCA, respectively. NFA allowed a better delimitation of some necrotic tumors (Novikoff hepatocarcinoma) due to its preferential uptake by the nontumorous tissue.

Dextran magnetite as a liver contrast agent

The superparamagnetic particle dextran magnetite was studied as a liver tumor contrast agent for magnetic resonance imaging (MRI). The effects of dextran magnetite on the longitudinal (T1) and transverse (T2) relaxation times in liver, spleen, and an implanted rat liver tumor were measured at 0.47 T (IBM/Bruker PC-20 relaxometer) over the dose range of 23 to 69 mumol Fe/kg. Dextran magnetite substantially reduced the T2 of the liver and spleen, but not of the tumor, thereby providing a basis for improved tumor imaging. The T1 of the tumor was not affected following injection of dextran magnetite in the dose range studied, while the spleen T1 was reduced substantially more than the T1 of the liver. Histological studies using the iron reaction for Prussian blue clearly showed dextran magnetite in the liver and spleen, but not in the tumor. While dextran magnetite was sequestered in macrophages in both liver and spleen, the distribution in the liver was more diffuse (70 microns average particle separation) than that in the spleen (25 microns separation). The lack of a T1 effect in the liver is consistent with the fact that a majority of the water in the tissue cannot diffuse to the relaxational centers on the time scale of the liver's intrinsic T1 (280 ms). In the spleen, however, the dextran magnetite is more densely packed in the red pulp allowing a significant fraction of the water to be relaxed by a T1 mechanism. Spin-echo images of the implanted tumor (mammary adenocarcinoma. R3230AC) in the livers of Fischer 344 rats were obtained at 0.50 T (Siemens Magnetom). The tumor-to-liver contrast was improved for both T1 and T2-weighted spin-echo images after intravenous injection of the dextran magnetite contrast agent. The contrast determined from these images agreed with that predicted by the measured T1 and the T2 (Hahn spin-echo) values. In addition, gradient-echo T2-weighted images with good contrast were obtained in a much shorter imaging time than was needed for T2-weighted spin-echo images. These results demonstrate that the MRI contrast enhancement observed with dextran magnetite is based on its selective uptake and distribution in the macrophages in the liver and spleen and that this agent has substantial potential as a superparamagnetic MR contrast agent.

Biodistribution and Clearance of Liposomal Gadolinium-DTPA

Gadolinium-DTPA (Gd-DTPA) liposomes have been studied previously as liver contrast agents and have been shown to improve the detection of hepatic metastases in rats. We synthesized 100-nm and 50-nm liposomes that encapsulated Gd-DTPA and did biodistribution and clearance studies in rats. Parallel magnetic resonance imaging (MRI) studies were also done. Biodistribution showed a prolonged blood pool phase for Gd-DTPA liposomes with a blood pool half-life of approximately 4 hours for the 100-nm liposomes. The highest uptake per gram of tissue was achieved by the spleen. Clearance of gadolinium from the liver and spleen showed a half-life of 3 to 4 days. The smaller 50-nm Gd-DTPA liposomes resulted in a longer blood pool phase and a higher delivery of gadolinium to the liver, bone marrow, and spleen. Imaging studies after intravenous (IV) administration of liposomal Gd-DTPA showed organ enhancement that paralleled the data on biodistribution studies, with appreciable hepatic enhancement at doses as low as 0.025 mm/kg of liposomal Gd-DTPA.

Liposomal Gd-DTPA: Effect of encapsulation on enhancement of hepatoma model by MRI

Liposomes entrapping gadolinium-DTPA (Gd-DTPA) were synthesized from 60 mole percent egg phosphatidylcholine (EPC) and 40 mole percent cholesterol or EPC alone entrapping Gd-DTPA in diameters of 100 and 200 nm. Rats bearing Morris hepatoma in their flanks were imaged by MR pre- and post-contrast with free Gd-DTPA and liposomal Gd-DTPA for up to four hours after IV contrast. Comparison of images after free and liposomal Gd-DTPA showed dramatic differences in tumor and organ enhancement. Liposomal Gd-DTPA enhancement of tumor corresponded more closely to histologically proven vascularized portions of tumor than free Gd-DTPA. Hepatic enhancement was greater with liposomal than free Gd-DTPA and time course of liver, kidney and tumor enhancement was prolonged. The 100-nm EPC Gd-DTPA liposomes caused the greatest enhancement. Gd-DTPA liposomes may be useful as liver and blood pool contrast agents. By varying lipid composition and vesicle size, patterns of enhancement may be selectively modified.

Improved detection of focal lesions with computerized tomographic examination of the liver using ethiodized oil emulsion (EOE-13) liver contrast

A prospective study of computerized tomography (CT) of the liver using a liver contrast agent compared to conventional CT was undertaken. CT scanning without contrast agents (NC-CT), CT with water-soluble contrast (WSC-CT), and CT with ethiodized oil emulsion (EOE-CT) were performed on patients with possible or probable hepatic metastases. The findings on these three examinations were compared to the objective findings at surgery in 53 patients. Accuracy of these examinations was 80.7% for NC-CT, 77.1% for WSC-CT, and 84.9% for EOE-CT. The true-positive percentage for 129 hepatic lesions was 40.6% for the NC-CT, 33.6% for WSC-CT, and 76.7% for the EOE-CT. Eighty-three percent (44/53) of 1- to 2-cm liver lesions were detected by EOE-CT, whereas only 26.4% (14/53) lesions of this size were detected by the NC-CT and 20.4% (10/49) shown by WSC-CT. The likelihood that a lesion seen by CT scan was malignant was 84.6% for NC-CT, 89.4% for WSC-CT, and 81.8% for EOE-CT. The EOE contrast agent improves the sensitivity of liver CT for detecting hepatic metastases. The improvement occurs with lesions 1 cm and greater in diameter, but is particularly striking for lesions of 1 to 2 cm in diameter.