Liver-specific Magnetic Resonance Imaging Contrast Agent Research Articles

Preparation and performance of biocompatible gadolinium polymer as liver-targeting magnetic resonance imaging contrast agent

A biocompatible macromolecule-conjugated gadolinium chelate complex (PAV2-EDA-DOTA-Gd) as a new liver-specific contrast agent for magnetic resonance imaging (MRI) was synthesized and evaluated. An aspartic acid-valine copolymer was used as a carrier and ethylenediamine as a chemical linker, and the aspartic acid-valine copolymer was covalently linked to the small molecule MRI contrast agent Gd-DOTA (Dotarem) to synthesize a large molecule contrast agent. Invitro MR relaxation showed that the T1-relaxivity of PAV2-EDA-DOTA-Gd (13.7mmol-1Ls-1) was much higher than that of the small-molecule Gd-DOTA (4.9mmol-1Ls-1). Invivo imaging of rats showed that the enhancement effect of PAV2-EDA-DOTA-Gd (55.37 ± 2.80%) on liver imaging was 2.6 times that of Gd-DOTA (21.12 ± 3.86%), and it produced a longer imaging window time (40-70min for PAV2-EDA-DOTA-Gd and 10-30min for Gd-DOTA). Preliminary safety experiments, such as cell experiments and tissue sectioning, showed that PAV2-EDA-DOTA-Gd had low toxicity and satisfactory biocompatibility. The results of this study indicated that PAV2-EDA-DOTA-Gd had high potential as a liver-specific MRI contrast agent.

Manganese (II) Complex of 1,4,7-Triazacyclononane-1,4,7-Triacetic Acid (NOTA) as a Hepatobiliary MRI Contrast Agent.

Magnetic resonance imaging (MRI) is increasingly used to diagnose focal and diffuse liver disorders. Despite their enhanced efficacy, liver-targeted gadolinium-based contrast agents (GBCAs) raise safety concerns owing to the release of toxic Gd3+ ions. A π-conjugated macrocyclic chelate, Mn-NOTA-NP, was designed and synthesized as a non-gadolinium alternative for liver-specific MRI. Mn-NOTA-NP exhibits an r1 relaxivity of 3.57 mM-1 s-1 in water and 9.01 mM-1 s-1 in saline containing human serum albumin at 3 T, which is significantly greater than the clinically utilized Mn2+-based hepatobiliary drug, Mn-DPDP (1.50 mM-1 s-1), and comparable with that of GBCAs. Furthermore, the in vivo biodistribution and MRI enhancement patterns of Mn-NOTA-NP were similar to those of the Gd3+-based hepatobiliary agent, Gd-DTPA-EOB. Additionally, a 0.05 mmol/kg dose of Mn-NOTA-NP facilitated high-sensitivity tumor detection with tumor signal enhancement in a liver tumor model. Ligand-docking simulations further indicated that Mn-NOTA-NP differed from other hepatobiliary agents in their interactions with several transporter systems. Collectively, we demonstrated that Mn-NOTA-NP could be a new liver-specific MRI contrast agent.

A hepatocyte-targeting nanoparticle for enhanced hepatobiliary magnetic resonance imaging.

Hepatobiliary magnetic resonance imaging (MRI) can inform the diagnosis of liver tumours in patients with liver cirrhosis and hepatitis. However, its clinical utility has been hampered by the lack of sensitive and specific contrast agents, partly because hepatocyte-specific nanoparticles, regardless of their surface ligands, are readily sequestered by Kupffer cells. Here we show, in rabbits, pigs and macaques, that the performance of hepatobiliary MRI can be enhanced by an ultrasmall nanoparticle composed of a manganese ferrite core (3 nm in diameter) and poly(ethylene glycol)-ethoxy-benzyl surface ligands binding to hepatocyte-specific transmembrane metal and anion transporters. The nanoparticle facilitated faster, more sensitive and higher-resolution hepatobiliary MRI than the clinically used contrast agent gadoxetate disodium, a substantial enhancement in the detection rate (92% versus 48%) of early-stage liver tumours in rabbits, and a more accurate assessment of biliary obstruction in macaques. The nanoparticle's performance and biocompatibility support the further translational development of liver-specific MRI contrast agents.

Mn(II) Complex of Lipophilic Group-Modified Ethylenediaminetetraacetic Acid (EDTA) as a New Hepatobiliary MRI Contrast Agent.

Liver-specific contrast agents (CAs) can improve the Magnetic resonance imaging (MRI) detection of focal and diffuse liver lesions by increasing the lesion-to-liver contrast. A novel Mn(II) complex, Mn-BnO-TyrEDTA, with a lipophilic group-modified ethylenediaminetetraacetic acid (EDTA) structure as a ligand to regulate its behavior in vivo, is superior to Gd-EOB-DTPA in terms of a liver-specific MRI contrast agent. An MRI study on mice demonstrated that Mn-BnO-TyrEDTA can be rapidly taken up by hepatocytes with a combination of hepatobiliary and renal clearance pathways. Bromosulfophthalein (BSP) inhibition imaging, biodistribution, and cellular uptake studies confirmed that the mechanism of hepatic targeting of Mn-BnO-TyrEDTA is the hepatic uptake of the amphiphilic anion contrast agent mediated by organic anion transporting polypeptides (OATPs) expressed by functional hepatocytes.

Feasibility and efficacy study of microwave ablation of recurrent small HCC guided by enhanced liver-specific magnetic resonance imaging contrast agent

Objectives To investigate the feasibility and efficacy of liver-specific magnetic resonance imaging (MRI) with gadolinium-containing contrast agent guidance for microwave ablation (MWA) of recurrent small hepatocellular carcinoma (HCC). Materials and methods The Ethics Committee of the First Affiliated Hospital of Fujian Medical University approved this study. Eighteen patients presented with 30 recurrent small HCCs, at least one lesion per patient was undetectable on unenhanced MRI, but this was clearly demonstrated in the hepatobiliary phase after liver-specific MRI contrast agent administration. Gd-BOPTA (16 cases) or Gd-EOB-DTPA (2 cases) were injected half an hour before the procedure, and MWA was performed by percutaneous puncture of the target lesion with a magnetic resonance-compatible microwave antenna under 1.5 T MRI guidance. Results The technical success rate was 100%. The mean maximum diameter of the lesions was 9.7 ± 2.8 mm (5.0–15.4 mm). The mean follow-up time was 11.6 ± 4.7 months (range, 4–19 months), and no local recurrence was observed. Conclusions MWA of small HCCs guided by enhanced liver-specific MRI contrast agent is a safe and effective technique.

Diagnostic Efficacy and Safety of Gadoxetate Disodium vs Gadobenate Dimeglumine in Patients With Known or Suspected Focal Liver Lesions: Results of a Clinical Phase III Study.

Purpose:The aim of this study is to evaluate the diagnostic efficacy and safety of gadoxetate disodium vs gadobenate dimeglumine in patients with known or suspected focal liver lesions.Methods:This was a prospective, multicenter, double-blind, randomized, inter-individual Phase III study. The primary target—technical efficacy—was already published. Here, secondary efficacy parameters—sensitivity and specificity—and safety in specific patient populations are presented. Patients with suspected or known focal liver lesions scheduled for contrast-enhanced liver magnetic resonance imaging (MRI) were recruited and categorized in 4 a priori specified subgroups: (1) all patients, (2) patients with liver cancer (hepatocellular carcinoma [HCC]), (3) patients with cirrhosis, and (4) patients with HCC + cirrhosis. Dual multi-detector liver computed tomography (CT) served as standard of reference.Results:A total of 295 patients were included. While the overall increase in sensitivity across all 4 patient groups was comparable for gadoxetate disodium (increase from pre- to post-contrast ranging from 6.2% to 9.9%) and gadobenate dimeglumine (ranging from −2.9% to 10.0%), significant differences were seen for some of the subgroups. There was a significantly higher increase in sensitivity for gadoxetate disodium in patients with HCC (7%) and HCC + cirrhosis (12.8%) in comparison with gadobenate dimeglumine. Specificity decreased for both agents: gadoxetate disodium by −2.8% to −6.3% and gadobenate dimeglumine by −3.3% to −8.7%. Gadoxetate showed a significantly lower loss of specificity in all subgroups. Safety was comparable in both groups.Conclusions:Gadoxetate disodium proved to be an effective liver-specific MRI contrast agent. Some distinct advantages over gadobenate dimeglumine were demonstrated in patients with HCC and patients with HCC + liver cirrhosis for sensitivity and specificity in liver lesion detection.

Highly Sensitive Diagnosis of Small Hepatocellular Carcinoma Using pH-Responsive Iron Oxide Nanocluster Assemblies.

Iron oxide nanoparticle (IONP)-based magnetic resonance imaging (MRI) contrast agents have been widely used for the diagnosis of hepatic lesions. However, current IONP-based liver-specific MRI contrast agents rely on single-phase contrast enhancement of the normal liver, which is not sensitive enough to detect early stage small hepatocellular carcinomas (HCCs). We herein report i-motif DNA-assisted pH-responsive iron oxide nanocluster assemblies (termed RIAs), which provide an inverse contrast enhancemt effect to improve the distinction between normal liver and target HCC tissues. The acidic pH of the tumor microenvironment triggers the disassembly of the RIAs, which leads to a drastic decrease in their relaxivity ratio ( r2/ r1), thus converting the RIAs from a T2 to T1 contrast agent. This inverse contrast enhancement of normal liver darkening and HCC brightening under T1 imaging mode was validated on an orthotopic HCC model. Our design provides a novel strategy for the exploitation of the next-generation intelligent MRI contrast agents.

Diagnosis of hepatocellular carcinoma: An update on international guidelines

Imaging is essential for the successful management of patients with or at risk of developing hepatocellular carcinoma (HCC). If ultrasound remains the key screening modality, computed tomography and magnetic resonance imaging (MRI) can play a major role in the characterization and noninvasive diagnosis of nodules in patients at risk of developing HCC. Each technique has succeeded in adapting to the wide histological spectrum of focal liver lesions. In this review, we discuss recent advancements in imaging techniques and evaluation -notably diffusion-weighted imaging, contrast-enhanced ultrasound, and liver-specific MRI contrast agents- as well as their addition to international guidelines and reporting systems such as the Liver imaging reporting and data system (LI-RADS).

Dual-modal MRI contrast agent with aggregation-induced emission characteristic for liver specific imaging with long circulation lifetime.

We herein report a novel dual-modal MRI contrast agent, TPE-2Gd, for both magnetic and fluorescence imaging. TPE-2Gd consists of a hydrophobic tetraphenylethene (TPE) fluorophore and two hydrophilic gadolinium (Gd) diethylenetriaminepentaacetic acid moieties. As an amphiphilic molecule, TPE-2Gd aggregates into micelles at a high concentration in aqueous medium. These aggregates are highly emissive, showing an aggregation-induced emission (AIE) characteristic. TPE-2Gd is used as a fluorescent agent for cell imaging, which demonstrates negligible cytotoxicity and excellent photostability owing to its AIE property. As a magnetic resonance imaging (MRI) contrast agent, TPE-2Gd exhibits similar longitudinal relaxivity in water (R1,TPE-2Gd = 3.36 ± 0.10 s(-1) per mM of Gd(3+)) as those commercial agents (e.g., Magnevist, R1,magnevist = 3.70 ± 0.02 s(-1) per mM of Gd(3+)). Compared with Magnevist, the circulation lifetime of TPE-2Gd nanoaggregates in living rats is extended from 10 min to 1 h. With relatively high specificity to the liver, the MR imaging could remain hyperintense in liver even after 150 min post injection. These TPE-2Gd nanoparticles can be excreted gradually via renal filtration due to the disassembly of the nanoparticles into small molecules during circulation. TPE-2Gd could thus potentially be used as a liver specific MRI contrast agent for clinical diagnosis.

Gd-EOB-DTPA-enhanced magnetic resonance imaging for focal liver lesions in Chinese patients: a multicenter, open-label, phase III study

Contrast agents help to improve visibility in magnetic resonance (MR) imaging. However, owing to the large interstitial spaces of the liver, there is a reduction in the natural contrast gradient between lesions and healthy tissue. This study was undertaken to evaluate the efficacy and safety of the liver-specific MR imaging contrast agent gadoxetate disodium (Gd-EOB-DTPA) in Chinese patients. This was a single-arm, open-label, multicenter study in patients with known or suspected focal liver lesions referred for contrast-enhanced MR imaging. MR imaging was performed in 234 patients before and after a single intravenous bolus of Gd-EOB-DTPA (0.025 mmol/kg body weight). Images were evaluated by clinical study investigators and three independent, blinded radiologists. The primary efficacy endpoint was sensitivity in lesion detection. Gd-EOB-DTPA improved sensitivity in lesion detection by 9.46% compared with pre-contrast imaging for the average of the three blinded readers (94.78% vs 85.32% for Gd-EOB-DTPA vs pre-contrast, respectively). Improvements in detection were more pronounced in lesions less than 1 cm. Gd-EOB-DTPA improved diagnostic accuracy in lesion classification. This open-label study demonstrated that Gd-EOB-DTPA improves diagnostic sensitivity in liver lesions, particularly in those smaller than 1 cm. Gd-EOB-DTPA also significantly improves the diagnostic accuracy in lesion classification, and furthermore, Gd-EOB-DTPA is safe in Chinese patients with liver lesions.

Multifunctional Nanoprobe for MRI/Optical Dual‐Modality Imaging and Radical Scavenging

The development of novel nanomaterials for the diagnosis and/or treatment of human diseases has become an important issue. In this work, a multifunctional theranostic agent was designed by covalently binding hydroxyl- and amino-bearing C60 derivatives (C60 O∼10 (OH)∼16 (NH2 )∼6 (NO2 )∼6 ⋅24 H2 O) with gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) to yield C60 O∼10 (OH)∼16 (NH2 )∼6 (NO2 )∼6 ⋅24 H2 O/(Gd-DTPA)3 (DF1 Gd3 ). The obtained DF1 Gd3 shows more than fourfold contrast improvement over commercial Gd-DTPA along with multiwavelength fluorescent emission for dual-modality diagnosis. An inner-ear magnetic resonance imaging (MRI) study was designed as a model of biological barriers, including the blood/brain barrier (BBB) for DF1 Gd3 to investigate its in vivo behavior. This revealed that the fabricated contrast agent dramatically increases the local contrast but can not cross the middle ear/inner ear barrier and endolymph/perilymph barrier in the inner ear, and thus it is also BBB-prohibited in normal individuals. In vivo biodistribution studies suggested that 1) DF1 Gd3 could circulate in vessels for a relatively long time and is mainly eliminated through liver and kidney, 2) DF1 Gd3 may potentially function as a liver-specific MRI contrast agent. Interestingly, DF1 Gd3 also shows an excellent quenching effect on hydroxyl radicals, as revealed by the DMPO spin trap/ESR method. The combination of enhanced MRI/FL imaging and local treatment of lesions is unique to DF1 Gd3 and potentiates the medical paradigm of "detect and treat/prevent" in combating human diseases related to reactive oxygen.

Proper definitions of MRI contrast enhancement in liver tumors

Dear Editor, As researchers working in the field of contrast agents (CAs) for use in magnetic resonance imaging (MRI), we would like to congratulate Narita et al. on the results reported in their recently published article ‘‘Expression of OATP1B3 determines uptake of Gd-EOB-DTPA in hepatocellular carcinoma’’ [1] showing that overexpression of OATP1B3 is related to Gd-EOB-DTPA accumulation or positive contrast enhancement (CE) in certain hepatocellular carcinomas (HCCs). These results were obtained using biomics technologies on clinical patients. However, a number of apparent points in the article have drawn our attention and motivated us to initiate the discussion presented here. Originally, hepatobiliary MRI CAs, including gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA), were developed to improve lesion detectability by specifically enhancing liver signal intensity (SI) and leaving the hepatic tumor unenhanced, i.e., negative tumor contrast enhancement (TCE) on T1-weighted MRI [2]. However, 15 years ago Ni et al. [3] first reported the very rare but remarkable positive TCE, which was best distinguishable during the hepatobiliary phase around 30 min following the injection of Gd-EOB-DTPA in rats with chemically induced HCCs. This phenomenon was found to be associated with certain highly differentiated HCCs and with benign hepatocytic nodules, as evident by the histopathology [3, 4]. For many years, in the early clinical trials, this Gd-EOB-DTPA-induced positive TCE was either absent or ignored [5, 6], and it has only been recently reported after this agent has been widely applied in clinical patients [1, 7, 8]. The HCC lesion with positive TCE that is shown in Fig. 1D of the article by Narita et al. [1] is to date the closest clinical finding comparable to what has been reported in rats [3, 4, 9]. In contrast, other experimental studies have failed to convincingly demonstrate the true positive TCE in rodent hepatic tumor models [10, 11]. Hence, a proper definition of CE in liver tumors becomes crucial, particularly with regard to the use of liver-specific MRI CAs. Similar to the procedure adopted by Narita et al. in their study [1], a number of other researchers have used the enhancement ratio (ER), where ER = (SIpostcontrast SIprecontrast)/SIprecontrast, or the relative enhancement (RE), where RE(%) = (SIpost SIpre)/SIpre 9 100, in their experimental studies. This ratio only takes the tumor SI into account—irrespective of the changes in the SI of the surrounding liver, which is the main target of hepatobiliary CAs [11]. Other researchers have used criteria that do not reflect the real tumor-to-liver contrast on Gd-EOB-DTPAenhanced MR images, such as a tumor said to be positively enhanced did not really display a positive TCE pattern [10, 12]. Logically, a negative or positive TCE can only be defined when the SI of the tumor is measured as being either lower or higher than that of the liver, based on visualization on the postcontrast MRI scan, as shown in Fig. 1D of Narita et al. [1] and in animal results [3, 4, 9]. The most straightforward approach is to calculate the postcontrast tumor-to-liver contrast ratio (CR), i.e., CR = SItumor/SIliver. When CR [ 1 or CR \ 1, a positive An answer to this letter to the editor is available at doi: 10.1007/s00535-009-0176-x.

Hepatocellular carcinoma: development and early detection

Our eventual aim is to predict, using non-invasive imaging techniques, the biological behaviour of individual cirrhotic nodules. We are some distance away from this, so our current objective is to define imaging features which predict the histologic findings. This short review summarises the current capabilities and limitations of non-invasive imaging in detecting small hepatocellular carcinomas (HCCs) in cirrhosis. Extracellular contrast media used with ultrasound (US), computed tomography (CT) or magnetic resonance imaging (MRI) can characterise nodules according to the predominance of arterial or portal inflow, and most HCCs will be recognised by their arterial hypervascularity. Adding intracellular (liver-specific) MRI contrast agents provides a significant improvement in early detection and in specificity for HCC. Nodules can be classified on dual contrast MRI as clearly malignant, clearly benign, or borderline (needing careful surveillance). Future imaging research needs to establish the histology of small hypervascular nodules, the evolution of hypervascular nodules and of dysplastic nodules, and to seek imaging features which predict microvascular invasion. Currently, cirrhotic patients with either suspicious nodules on screening US or rising AFP should have cross-sectional imaging with multi-phase CT or preferably MRI. Dual-contrast MRI with liver-specific agents should be used to improve diagnostic specificity for small lesions. Borderline nodules should be followed at agreed intervals using the same imaging technique each time. Pre-operative staging in surgical candidates should include CT of thorax, abdomen and pelvis and bone scintigraphy.

Gadolinium heteropoly complex K17[Gd(P2W17O61)2] as a potential MRI contrast agent

Gadolinium heteropoly complex K17[Gd(P2W17O61)2] has been evaluated by in vitro and in vivo experiments as a potential contrast agent for magnetic resonance imaging (MRI). The thermal analysis and conductivity study indicate that this complex has good thermal stability and wide pH stability range. The T1 relaxivity is 7.59mM−1s−1 in aqueous solution and 7.97mM−1s−1 in 0.725mmoll−1 bovine serum albumin (BSA) solution at 25°C and 9.39T, respectively. MR imaging of three male Sprague–Dawley rats showed remarkable enhancement in rat liver after intravenous injection, which persisted longer than with Gd-DTPA. The signal intensity increased by 57.1±16.9% during the whole imaging period at 0.082mmolkg−1dose. Our preliminary in vitro and in vivo studies indicate that K17[Gd(P2W17O61)2] is a potential liver-specific MRI contrast agent.

Comparison between GdDTPA and two gadolinium polyoxometalates as potential MRI contrast agents

Two gadolinium polyoxometalates, Gd 2P 2W 18O 62 and K 15[(GdO) 3(PW 9O 34) 2], have been evaluated by in vivo as well as in vitro experiments as the candidates of tissue-specific magnetic resonance imaging (MRI) contrast agents. T 1-relaxivities of 28.4 mM −1·s −1 for Gd 2P 2W 18O 62 and 11.2 mM −1·s −1 for K 15[(GdO) 3(PW 9O 34) 2] (400 MHz, 25 °C) were higher than that of the commercial MRI contrast agent (GdDTPA). Their relaxivities in bovine serum albumin and human serum transferrin were also reported. The favorable liver-specific contrast enhancement and renal excretion capability in in vivo MRI with Sprague–Dawley rats after i.v. administration of K 15[(GdO) 3(PW 9O 34) 2] was demonstrated. In vivo and in vitro assay showed that K 15[(GdO) 3(PW 9O 34) 2] is a promising liver-specific MRI contrast agent. However, Gd 2P 2W 18O 62 did not show the favorable quality in vivo as expected from its high relaxivity in vitro, which was attributed to low bioavailability, indicating that it is of limited value as tissue-specific MRI contrast agent.