Novel intravascular macromolecular MRI contrast agent with generation-4 polyamidoamine dendrimer core: accelerated renal excretion with coinjection of lysine.

One of the major limitations to macromolecular MRI contrast agents (MRI-CAs) is their slow clearance and associated decreased excretion of gadolinium (Gd(III)). The effect of coinjecting lysine to accelerate renal excretion of a macromolecular MRI-CA (generation-4 PAMAM dendrimer (G4D-(1B4M-Gd)64)) was investigated. The biodistribution and urine and fecal excretion in athymic mice was evaluated with and without lysine coinjection. 3D-dynamic-micro-MRI with G4D-(1B4M-Gd)64 was obtained with and without lysine coinjection, and the serial signal intensity (SI) change in the blood and organs was evaluated. When lysine was coinjected, urinary excretion of G4D-(1B4M-Gd)64 increased 5.4-fold compared to that without lysine, resulting in decreased renal accumulation of G4D-(1B4M-Gd)64 from 150% to 40% injected dose per gram (P < 0.001). On dynamic MRI with G4D-(1B4M-Gd)64, when lysine was coinjected, the kidney-to-blood SI ratio was significantly lower than that obtained without lysine (P < 0.001). When lysine was coinjected, the G4D-(1B4M-Gd)64 was excreted from the kidney intact.     

Pharmacokinetics and enhancement patterns of macromolecular MR contrast agents with various sizes of polyamidoamine dendrimer cores.

Four macromolecular contrast agents are synthesized to visualize small vessels by MRI using generation-3 (G3D), -4 (G4D), -5 (G5D), and -6 (G6D) polyamidoamine dendrimers conjugated to chelated gadolinium (Gd). The pharmacokinetics, enhancement patterns, and the ability of these constructs to visualize fine vessels is evaluated by dynamic MRI in relationship to their size. Gd-G6D and -G5D exhibit a prolonged high vascular (ventricular) signal intensity (SI) with high ventricle-to-organ SI ratios. The initial high vascular SI with Gd-G4D decreases to a value as low as that obtained with Gd-G3D and Gd-dimeglumine-diethylenetriaminepentaacetic acid (Gd-DTPA). Gd-G5D, -G4D, and -G3D show high renal SIs, and Gd-DTPA prominently enhances the skin. Gd-G6D and -G5D present fine vasculature significantly more clearly than Gd-G3D and -DTPA (P < 0.005). As the molecular size increases, the excretion of the 153Gd-conjugates is retarded. In conclusion, Gd-G6D and -G5D are retained in the blood and present fine vessels with high quality and detail, and should be adequate for visualizing small tumor vasculature.     

Micro-MR angiography of normal and intratumoral vessels in mice using dedicated intravascular MR contrast agents with high generation of polyamidoamine dendrimer core: reference to pharmacokinetic properties of dendrimer-based MR contrast agents.

Pharmacokinetic characteristics of intravascular macromolecular magnetic resonance imaging (MRI) contrast agents with polyamidoamine dendrimer cores smaller than generation-7 were previously studied in the literature. To evaluate the effects of greater hepatic uptake on the pharmacokinetics of the larger generation dendrimers, the MRI contrast agents GxD-(1B4M-Gd)(2(x+2)) were synthesized with generation-7, -8, and -9 polyamidoamine dendrimers and 2-(p-isothiocyanatobenzyl)-6-methyl-diethylenetriaminepentaacetic acid (1B4M). Their pharmacokinetic characteristics in mice were compared with that of G6D-(1B4M-Gd)(256). In biodistribution and dynamic micro-MRI studies, significantly less renal accumulation of G7D-(1B4M-Gd)(512), G8D-(1B4M-Gd)(1024), and G9D-(1B4M-Gd)(2048) was shown compared to G6D-(1B4M-Gd)(256) (P < 0.01). There was a significantly greater accumulation of G8D-(1B4M-Gd)(1024) and G9D-(1B4M-Gd)(2048) in the liver compared to G6D-(1B4M-Gd)(256) and G7D-(1B4M-Gd)(512) (P < 0.01). The highest blood retention of all dendrimer-based MRI contrast agents was exhibited by G7D-(1B4M-Gd)(512) (P < 0.01). The normal and intratumoral fine vessels of approximately 100 microm diameter were visualized in normal or tumor-bearing mice by high resolution three-dimensional-micro-MR angiographs with G7D-(1B4M-Gd)(512) and G8D-(1B4M-Gd)(1024) with good vessel-to-soft tissue contrast. In summary, increased accumulation in the liver with concomitant decreased uptake in the kidney was caused by increased molecular sizes of the dendrimer-based MRI contrast agents.     

Gadolinium-DTPA-dextran: a macromolecular MR blood pool contrast agent

RATIONALE AND OBJECTIVES: Magnetic resonance (MR) imaging blood pool agents offer numerous advantages for vascular and tumor imaging. The purpose of this study was to test gadolinium-diethylenetriaminepentaacetate-dextran ([Gd]DTPA-dextran) as a new water soluble macromolecular blood pool agent for MR imaging. MATERIALS AND METHODS: [Gd]DTPA-dextran (187 gadolinium atoms per dextran, molecular weight 165 kD, diameter 17.6 nm) was synthesized. Fifteen anesthetized New Zealand White rabbits with thigh VX2 tumors were scanned in a knee coil at 1.5T. Coronal 3D MR angiographic sequences were obtained before and at several time points up to 72 hours after the intravenous bolus injection of [Gd]DTPA-dextran providing gadolinium at either 0.05 (n = 4) or 0.1 mmol/kg (n = 8) or [Gd]DTPA-bismethylamide (BMA) providing gadolinium at 0.1 mmol/kg (n = 3). Time enhancement curves for aorta, cava, and tumor rim were compared by univariate General Linear Model. RESULTS: Contrast enhancement of cava and aorta relative to a water phantom were significantly greater at all time points after either dose of [Gd]DTPA-dextran than after [Gd]DTPA-BMA (P < 0.01). Tumor rim enhancement was less intense for either dose of [Gd]DTPA-dextran at peak than for [Gd]DTPA-BMA (P < 0.05). Tumor rim enhancement with both doses of [Gd]DTPA-dextran became equivalent to that of [Gd]DTPA-BMA at one hour and was greater at 24 hours (P < 0.05). CONCLUSION: [Gd]DTPA-dextran is a new macromolecular MR contrast agent that can be synthesized to carry a high density of gadolinium atoms without intra-molecular cross-linking. It provides significantly greater vascular residence time than a conventional gadolinium chelate and shows promise for MR blood pool imaging.     

Phantom and animal studies of a new hepatobiliary agent for MR imaging: comparison of Gd-DTPA-DeA with Gd-EOB-DTPA

PURPOSE: To investigate the characteristics of Gd-DTPA-DeA as a hepatobiliary contrast agent for MR imaging in comparison with those of Gd-EOB-DTPA. MATERIALS AND METHODS: We undertook phantom experiments to assess T1 relaxivity for Gd-DTPA-DeA, Gd-EOB-DTPA, and Gd-DTPA in human plasma. For Gd-DTPA-DeA and Gd-EOB-DTPA, we evaluated the contrast effect in rats using an SPGR sequence. The contrast ratios of liver and abdominal aorta were measured up to 21 minutes after intravenous administration of the agents. Visualization of the bile duct and renal pelvis was also assessed. RESULTS: In human plasma, T1 relaxivity was similar for Gd-DTPA-DeA and Gd-EOB-DTPA, and higher than those for Gd-DTPA. Whereas the contrast ratio of liver peaked about five minutes after the injection of Gd-EOB-DTPA and was followed by a subsequent decline, a continuous rise was shown for Gd-DTPA-DeA, resulting in a larger maximal contrast effect. Contrast ratios of the abdominal aorta were larger for Gd-DTPA-DeA. Biliary excretion was observed for both agents but occurred earlier with Gd-EOB-DTPA. While renal excretion was shown for all rats three minutes after the injection of Gd-EOB-DTPA, it was not observed for Gd-DTPA-DeA. CONCLUSION: Gd-DTPA-DeA may be used as a hepatobiliary contrast agent and shows different pharmacokinetics from Gd-EOB-DTPA.     

Positive effects of polyethylene glycol conjugation to generation-4 polyamidoamine dendrimers as macromolecular MR contrast agents.

Macromolecules conjugated with polyethylene glycol (PEG) acquire more hydrophilicity, resulting in a longer half-life in circulation and lower immunogenicity. Two novel conjugates for MRI contrast agents were synthesized from a generation-4 polyamidoamine dendrimer (G4D), 2-(p-isothiocyanatobenzyl)-6-methyl-diethylenetriaminepentaacetic acid (1B4M), and one or two PEG molecules with a molecular weight of 20000 Da (PEG(2)-G4D-(1B4M-Gd)(62) (MW: 96 kD), PEG(1)-G4D-(1B4M-Gd)(63) (MW: 77 kD)). Their pharmacokinetics, excretion, and properties as vascular MRI contrast agents were evaluated and compared with those of G4D-(1B4M-Gd)(64) (MW: 57 kD). PEG(2)-G4D-(1B4M-Gd)(62) remained in the blood significantly longer and accumulated significantly less in the liver and kidney than the other two preparations (P < 0.01). Although the blood clearance was slower, PEG(2)-G4D-(1B4M-Gd)(62) was excreted more readily without renal retention than the other two preparations. In conclusion, the positive effects of PEG conjugation on a macromolecular MRI contrast agent were found to be prolonged retention in the circulation, increased excretion, and decreased accumulation in the organs.     

Safety and efficacy of a novel hepatobiliary MR contrast agent, Gd-DTPA-DeA: results of phase I and phase II clinical trials

PURPOSE: To assess the safety, effective dose, and efficacy of a novel hepatobiliary MR contrast agent Gd-DTPA-DeA for imaging liver tumors, from the clinical phase I and phase II trials in Japan. MATERIALS AND METHODS: In a phase I trial, 33 healthy volunteers were intravenously administered a single dose of 0.03-10 micromol/kg of Gd-DTPA-DeA. In a nationwide phase II trial, 80 patients suspected to have hepatic mass were divided into three dosing groups: 2.5, 5.0, or 7.5 micromol/kg. T1-weighted gradient echo images were obtained before and after Gd-DTPA-DeA administration at three time points. Liver signal-to-noise ratio (SNR) and lesion-liver contrast-to-noise ratio (CNR) were calculated at each time point. A reading committee evaluated the contrast, diagnostic, and overall efficacy using a five-point scale. RESULTS: In a phase I trial, dosages up to 10 micromol/kg were well tolerated by healthy volunteers. In a phase II trial, the contrast, diagnostic, and overall efficacy increased dose-dependently. The overall efficacy was 63.0%, 85.2%, and 88.0%, for 2.5, 5, and 7.5 micromol/kg, respectively. Liver SNR and CNR increase was greater at late phase than at early phase. No serious adverse events occurred. CONCLUSION: Gd-DTPA-DeA is a well-tolerated and promising contrast agent for liver MR imaging.     

Pulmonary MR angiography with contrast agent at 4 Tesla: a preliminary result.

In this study, pulmonary MR angiography (MRA) using a tailored coil at 4 Tesla in conjunction with an intravenous injection of contrast agent is described. Three-dimensional gradient-echo images were obtained during the intravenous injection of 0.05, 0.1, and 0.2 mmol/kg body weight of gadodiamide to investigate the signal enhancement effect of the contrast agent in pulmonary arteries qualitatively and quantitatively. In the qualitative analysis, the subsegmental branches were visualized on every dose. In the quantitative analysis, the average contrast-to-noise ratios (CNRs) of the main pulmonary arteries increased in a dose-dependent manner. However, the CNRs of segmental arteries did not increase as the dose of contrast agent increased, as observed at 1.5 Tesla MRI. These observations demonstrate the feasibility of delineating the pulmonary vasculature using a contrast agent; however, our results also suggest possible high-field-related disabilities that need to be overcome before high-field (> or =4 Tesla) MRI can be used to full advantage.     

Assessment of a potential tumor-seeking manganese metalloporphyrin contrast agent in a mouse model.

The performance of a newly developed potential tumor-seeking magnetic resonance (MR) contrast agent alpha-Aqua-13,17-bis(1-carboxypropionyl) carbamoylethyl-3,8-bis(1-phenethyloxyethyl)-beta-hydroxy-2,7,12,18-tetramethyl-porphyrinato manganese (III) (HOP-8P) was tested using a mouse model. Tumor-bearing (SCC-VII) mice were imaged using a 1.5T MR imager before and after intravenous administration of 0.1 mmol/kg of HOP-8P. A biodistribution analysis was performed using an optical emission spectrometer. Significant enhancement of the transplanted tumor was observed in MR images 24 h after intravenous injection of HOP-8P. The biodistribution assessment of manganese also correlated with the results of the imaging study. During the 24-h period following contrast administration, HOP-8P was consistently cleared from the circulation, liver, kidneys, and muscle; however, it was progressively accumulated within the tumor. HOP-8P is a promising tumor-seeking metalloporphyrin MR contrast agent with a wide imaging window.     

3D-micro-MR angiography of mice using macromolecular MR contrast agents with polyamidoamine dendrimer core with reference to their pharmacokinetic properties.

Four novel macromolecular MRI contrast agents, all of which had the same chemical composition but different molecular weights, were prepared using generation-3, -4, -5, and -6 polyamidoamine (PAMAM) dendrimers conjugated with a bifunctional diethylenetriaminepentaacetic acid derivative to change the blood retention, tissue perfusion, and excretion. Size-dependent changes in the pharmacokinetics were observed in the biodistribution study. (153)Gd-labeled generation-6 PAMAM-conjugates remained in the blood significantly longer than all of the other preparations (P < 0.001). The increase in blood-to-organ ratio of the preparations was found to correlate with increasing molecular size (P < 0.001). Additionally, 3D-micro MR images and angiography of mice of high quality and detail were obtained using PAMAM-(1B4M-Gd)x as a macro-molecular MRI contrast agent with a 1.5-T clinical MRI instrument. Numerous fine vessels of approximately 200 microm diameter were visualized on subtracted 3D-MR angiographms with G6D-(1B4M-Gd)(192). The quality of the images was sufficient to estimate the microvasculature of cancerous tissue for anti-angiogenesis therapy and to investigate knockout mice. Magn Reson Med 45:454-460, 2001.     

Whole-heart coronary magnetic resonance angiography at 3 Tesla in 5 minutes with slow infusion of Gd-BOPTA, a high-relaxivity clinical contrast agent.

T(1)-shortening contrast agents have been used to improve the depiction of coronary arteries with breath-hold magnetic resonance angiography (MRA). The spatial resolution and coverage are limited by the duration of the arterial phase of the contrast media passage. In this study we investigated the feasibility of acquiring free-breathing, whole-heart coronary MRA during slow infusion of the contrast media (0.3 ml/s) for prolonged blood signal enhancement time. Ultrashort TR (3 ms) and parallel data acquisition were used to allow the whole-heart MRA in approximately 5 min. A newly approved gadolinium (Gd)-based high T(1) relaxivity contrast agent, gadobenate dimeglumine ([Gd-BOPTA](2-)), was used and coronary MRA was performed on a whole-body 3 Tesla (T) system to improve the signal-to-noise ratio (SNR). Results from eight volunteers demonstrate that this coronary MRA method is capable of imaging the whole heart in 4.5 +/- 0.6 min. Major coronary arteries are well depicted with high SNR (42.4 +/- 12.5) and contrast-to-noise ratio (CNR; 27.1 +/- 7.6).     

Polyamine dendrimer-based MRI contrast agents for functional kidney imaging to diagnose acute renal failure

PURPOSE: To choose an efficacious renal functional MRI contrast agent to image early renal tubular damage. We synthesized and compared smaller polyamine dendrimer-based MRI contrast agents (<60 kD) that, unlike Gd-[DTPA], transiently accumulate in renal tubules and can be used to visualize renal structural and functional damage. MATERIALS AND METHODS: Six dendrimer-based MRI contrast agents smaller than 60 kD were studied by high resolution dynamic micro-MRI and compared to Gd-[DTPA]-dimeglumine and Gadomer-17. The best agent, DAB-G2, was further tested in a mouse ischemia/reperfusion model to validate its efficacy. RESULTS: Despite unequal renal clearance rates, all polyamine dendrimer agents visualized the renal functional anatomy of the mice better than Gd-[DTPA]-dimeglumine and Gadomer-17. DAB-G2 was excreted most rapidly, yet was able to visualize mild renal tubular injury very early after injury. CONCLUSION: DAB-G2 was found to be the best candidate for functional kidney imaging and enabled early diagnosis of acute renal injury.     

Enhancement of liver parenchyma after injection of hepatocyte‐specific MRI contrast media: A comparison of gadoxetic acid and gadobenate dimeglumine

Purpose:

To compare enhancement of liver parenchyma in MR imaging after injection of hepatocyte‐specific contrast media.

Materials and Methods:

Patients (n = 295) with known/suspected focal liver lesions randomly received 0.025 mmol gadoxetic acid/kg body weight or 0.05 mmol gadobenate dimeglumine/kg body weight by means of bolus injection. MR imaging was performed before and immediately after injection, and in the delayed phase at approved time points (20 min after injection of gadoxetic acid and 40 min after injection of gadobenate dimeglumine). The relative liver enhancement for the overall population and a cirrhotic subgroup was compared in T1‐weighted GRE sequences. An independent radiologist performed signal intensity measurements. Enhancement ratios were compared using confidence intervals (CIs).

Results:

The relative liver enhancement in the overall population was superior with gadoxetic acid (57.24%) versus gadobenate dimeglumine (32.77%) in the delayed‐imaging phase. The enhancement ratio between the contrast media was statistically significant at 1.75 (95% CI: 1.46–2.13). In the delayed phase, the enhancement of cirrhotic liver with gadoxetic acid (57.00%) was comparable to that in the overall population. Enhancement with gadobenate dimeglumine was inferior in cirrhotic liver parenchyma (26.85%).

Conclusion:

In the delayed, hepatocyte‐specific phase, liver enhancement after injection of gadoxetic acid was superior to that obtained with gadobenate dimeglumine. J. Magn. Reson. Imaging 2010; 31: 356–364. © 2010 Wiley‐Liss, Inc.

     

Pelvic lymph node visualization with MR imaging using local administration of ultra-small superparamagnetic iron oxide contrast

PURPOSE: To determine if interstitial injection of iron oxide particles improves visualization of pelvic lymph nodes at magnetic resonance imaging (MRI) and to determine the effect of injection site on location of visualized nodes. MATERIALS AND METHODS: In nine healthy volunteers, ferumoxtran-10 iron oxide (0.28 mg iron per kg) was injected into the anterior thigh (three subjects) or perianal (three subjects) or periprostatic tissues (three subjects). MRI at 1.5 T was performed before injection and one, three, and seven days after injection. RESULTS: The mean of 30 nodes seen post-injection was greater than the mean of 5.8 seen pre-injection (P < 0.001). After thigh injection, a mean of three internal vs. 36 external nodes were seen. Compared with thigh injection, there was a higher fraction of internal nodes with perianal (mean of nine internal vs. 14 external, P < 0.001) and periprostatic injection (mean of 11 internal vs. five external, P < 0.001). More nodes were seen with gradient-echo sequences than with other sequences (P < 0.001). CONCLUSION: Interstitial injection of iron oxide particles increases visualization of pelvic lymph nodes. Perianal and periprostatic injection increases the number of internal pelvic lymph nodes seen compared with thigh injection.     

Value of a blood pool contrast agent in MR venography of the lower extremities and pelvis: preliminary results in 12 patients.

The purpose of this study was to determine the value of a blood-pool contrast media (NC100150, Nycomed Imaging (now Amersham Health) Oslo, Norway) for evaluation of venous thrombosis of the deep veins of the pelvis and lower extremities. Twelve patients were prospectively evaluated with conventional X-ray venography (XRV) and MR venography (MRV) after injection of NC100150 (2 ml/kg body weight). The source images and 3D maximum intensity projection (MIP) were viewed on an independent workstation. Diagnosis was made in consensus from two radiologists. Diagnostic image quality was achieved in 87 veins with XRV and MRV. As determined by XRV, thrombus was present in 30 out of 87 veins (34.5%). There was agreement concerning absence or presence of thrombi in 83 out of 87 veins (95.4%; kappa = 0.9 +/- 0.05). Compared to XRV, overall sensitivity and specificity of blood-pool MRV were 93.3% and 96.5%, respectively. Two venous thromboses of the popliteal and posterior tibial vein were diagnosed in MRV, but not in XRV. Conversely, two venous thromboses below the knee had been missed by MRV. NC100150 allows prolonged and improved visualization of the peripheral vasculature and may overcome some limitations of gadolinium contrast media. A more complete examination of the proximal venous tree may be possible than with conventional XRV. Arterial and venous enhancement and motion artifacts can limit image interpretation.     

Usefulness of Gd‐EOB‐DTPA‐enhanced MR imaging in the evaluation of simple steatosis and nonalcoholic steatohepatitis

Purpose:

To evaluate the usefulness of gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd‐EOB‐DTPA)‐enhanced MR imaging (EOB‐MRI) in differentiating between simple steatosis and nonalcoholic steatohepatitis (NASH), as compared with MR in‐phase/out‐of‐phase imaging. The correlations between the MR features and histological characteristics were preliminarily investigated.

Materials and Methods:

From April 2008 to October 2011, 25 patients (13 simple steatosis and 12 NASH) who underwent both EOB‐MRI and in‐phase/out‐of‐phase imaging were analyzed. The hepatobiliary‐phase enhancement ratio and signal intensity loss on opposed‐phase T1‐weighted images (fat fraction) were compared between the simple steatosis and NASH groups. In the simple steatosis and NASH groups, the correlations between enhancement ratio and histological grade/stage were explored. In the NASH group, fat fraction was correlated with the steatosis score.

Results:

The enhancement ratio in NASH was significantly lower than that in simple steatosis (P = 0.03). In the simple steatosis and NASH groups, the enhancement ratio was significantly correlated with the fibrosis stage (r = ?0.469, P = 0.018). Fat fraction in NASH was strongly correlated with the steatosis score (r = 0.728, P = 0.007).

Conclusion:

In simple steatosis and NASH, the hepatobiliary‐phase enhancement ratio of EOB‐MRI showed significant association with fibrosis stage, and may be a useful discriminating parameter compared with the fat fraction measured by in‐phase/out‐of‐phase imaging. J. Magn. Reson. Imaging 2012;37:1137–1143. © 2012 Wiley Periodicals, Inc.

     

Detection and quantification of breast tumor necrosis with MR imaging: value of the necrosis-avid contrast agent Gadophrin-3

RATIONALE AND OBJECTIVES: The authors evaluated the use of T1-weighted magnetic resonance (MR) imaging with Gadophrin-3 enhancement and of plain T2-weighted MR imaging to detect and quantify breast tumor necrosis. MATERIALS AND METHODS: Twenty EMT-6 tumors (mouse mammary sarcoma), implanted into the mammary fat pad of BALB/c-AnNCrl mice, underwent MR imaging with plain T2-weighted and T1-weighted fast field echo sequences before and 24 hours after injection of Gadophrin-3, a new necrosis-avid contrast agent. Tumor necrosis on MR images was quantified by means of a dedicated segmentation program and was correlated with histologic findings. RESULTS: In all tumors a central necrosis was revealed by histopathologic analysis, and central enhancement was seen with Gadophrin-3 on T1-weighted images. Small tumors (diameter, < 1 cm) showed an inhomogeneous central enhancement, whereas larger tumors (diameter, > 1 cm) enhanced mainly in the periphery of necrotic tissue. Plain T2-weighted images showed a hyperintense central area in only three of 20 cases with a large central necrosis. CONCLUSION: Gadophrin-3-enhanced T1-weighted images are superior to plain T2-weighted images for the detection of necrosis in a murine tumor xenograft model.     

Hepatobiliary MR imaging with gadolinium-based contrast agents

The advent of gadolinium-based "hepatobiliary" contrast agents offers new opportunities for diagnostic magnetic resonance imaging (MRI) and has triggered great interest for innovative imaging approaches to the liver and bile ducts. In this review article we discuss the imaging properties of the two gadolinium-based hepatobiliary contrast agents currently available in the U.S., gadobenate dimeglumine and gadoxetic acid, as well as important pharmacokinetic differences that affect their diagnostic performance. We review potential applications, protocol optimization strategies, as well as diagnostic pitfalls. A variety of illustrative case examples will be used to demonstrate the role of these agents in detection and characterization of liver lesions as well as for imaging the biliary system. Changes in MR protocols geared toward optimizing workflow and imaging quality are also discussed. It is our aim that the information provided in this article will facilitate the optimal utilization of these agents and will stimulate the reader's pursuit of new applications for future benefit.