In vivo magnetic resonance imaging of mice liver tumors using a new gadolinium-based contrast agent.

We compared the enhancement effect between a newly synthesized tissue-specific contrast agent, [Gd-DOTA-FPßG], and a commercially available agent, [Gd(DOTA)](-), in a murine model of liver tumor using a clinical magnetic resonance imaging scanner. The colon cancer cell lines with and without ß-glucuronidase (ßG) expression were implanted into the liver of mice. Self-synthesized gadolinium-based magnetic resonance contrast agent, [Gd(DOTA-FPßG)], was administered to measure enhancement on magnetic resonance images using a commercially available agent, [Gd(DOTA)](-), as control in a clinical 3.0 tesla (T) magnetic resonance scanner. In vivo fluorescence imaging and histopathology of the liver were also performed to compare and correlate with the magnetic resonance studies. The in vivo fluorescence imaging failed to depict a sufficiently intense signal for liver or liver tumor of mice without exposure of the liver following an incision on the abdominal wall. The tissue-specific magnetic resonance agent, [Gd(DOTA-FPßG)], caused significantly stronger enhancement in tumors expressing ßG (CT26/mßG-eB7) than in tumors not expressing ßG (CT26) (p < 0.05). In the magnetic resonance imaging studies using control agent [Gd(DOTA)](-), the tumors with and without ßG expression depicted no significant difference in enhancement on the T1-weighted images. The [Gd(DOTA-FPßG)] also provided significantly more contrast uptake in the CT26/mßG-eB7 tumor than in the normal liver parenchyma, whereas the [Gd(DOTA)](-) did not. This study confirms that better contrast enhancement can be readily detected in vivo by the use of a tissue-specific magnetic resonance contrast agent to target tumor cells with specific biomarkers in a clinical magnetic resonance imaging scanner.

Development of a Gd(III)-based receptor-induced magnetization enhancement (RIME) contrast agent for ß-glucuronidase activity profiling.

ß-Glucuronidase is a key lysosomal enzyme and is often overexpressed in necrotic tumor masses. We report here the synthesis of a pro receptor-induced magnetization enhancement (pro-RIME) magnetic resonance imaging (MRI) contrast agent ([Gd(DOTA-FPßGu)]) for molecular imaging of ß-glucuronidase activity in tumor tissues. The contrast agent consists of two parts, a gadolinium complex and a ß-glucuronidase substrate (ß-d-glucopyranuronic acid). The binding association constant (KA) of [Gd(DOTA-FPßGu)] is 7.42 × 10(2), which is significantly lower than that of a commercially available MS-325 (KA = 3.0 × 10(4)) RIME contrast agent. The low KA value of [Gd(DOTA-FPßGu)] is due to the pendant ß-d-glucopyranuronic acid moiety. Therefore, [Gd(DOTA-FPßGu)] can be used for detection of ß-glucuronidase through RIME modulation. The detail mechanism of enzymatic activation of [Gd(DOTA-FPßGu)] was elucidated by LC-MS. The kinetics of ß-glucuronidase catalyzed hydrolysis of [Eu(DOTA-FPßGu)] at pH 7.4 best fit the Miechalis-Menten kinetic mode with Km = 1.38 mM, kcat = 3.76 × 10(3), and kcat/Km = 2.72 × 10(3) M(-1) s(-1). The low Km value indicates high affinity of ß-glucuronidase for [Gd(DOTA-FPßGu)] at physiological pH. Relaxometric studies revealed that T1 relaxivity of [Gd(DOTA-FPßGu)] changes in response to the concentration of ß-glucuronidase. Consistent with the relaxometric studies, [Gd(DOTA-FPßGu)] showed significant change in MR image signal in the presence of ß-glucuronidase and HSA. In vitro and in vivo MR images demonstrated appreciable differences in signal enhancement in the cell lines and tumor xenografts in accordance to their expression levels of ß-glucuronidase.

Comparison of Gd-Bz-TTDA, Gd-EOB-DTPA, and Gd-BOPTA for dynamic MR imaging of the liver in rat models.

To evaluate the competitive potential of a new lipophilic paramagnetic complex, Gd-Bz-TTDA [4-benzyl-3,6,10-tri (carboxymethyl)-3,6,10-triazado-decanedioic acid] compared with two other commercially available MR hepatobiliary contrast agents, gadobenate dimeglumine (Gd-BOPTA) and gadoxetic acid (Gd-EOB-DTPA), dynamic MR imaging studies were performed on normal and hepatocellular carcinoma (HCC) rat models using a 1.5-Tesla MR scanner. The results indicate that normal rats that were injected with 0.1 mmol/kg Gd-Bz-TTDA showed significantly more intense and persistent liver enhancement than those that were injected with the same dose of Gd-EOB-DTPA or Gd-BOPTA. All of these agents showed similar enhancement patterns in the implanted HCC. The liver-lesion contrast-to-noise ratios were higher and more persistent in rats that were injected with Gd-Bz-TTDA. These results indicate that Gd-Bz-TTDA is comparable with the commercially available hepatobiliary agents, Gd-EOB-DTPA and Gd-BOPTA, and can result in more intense and prolonged liver enhancement while still providing better liver-lesion discrimination. These results warrant further large-scale studies.

Quantification of choline compounds in human hepatic tumors by proton MR spectroscopy at 3 T.

The quantification of choline-containing compounds (Cho) in hepatic tumors by (1)H MR spectroscopy (MRS) is of great interest because such compounds have been linked to malignancy. In this study, a practical external phantom replacement method for the absolute quantification of hepatic metabolites is demonstrated. We performed experiments at 3 T using a body coil, and used an external phantom containing choline chloride for calibration. We first tested the quantification strategy to confirm its suitability in vivo using a phantom of known concentration and normal brain tissue. The results obtained after coil loading and T(1) and T(2) effects were corrected for were consistent with the known concentration and previously published values. To demonstrate its feasibility, we applied the technique to liver studies conducted on five normal volunteers and four patients with hepatocellular carcinoma, and one patient (also in the latter group) who had undergone post-transcatheter arterial chemoembolization (TACE). The Cho concentrations in the four patients were estimated to be 3.4, 6.3, 7.4, and 14.0 mM, respectively. These values are substantially higher than those obtained from the healthy volunteers (1.3 +/- 0.9 mM (mean +/- SD)). The results indicate that the proposed method is accurate and requires fewer tedious procedures for MRS; therefore, it may be a promising technique for evaluating response to treatment in liver cancer.