Browsing by Author "Chang, Chih-Ching"

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Development of a Gd(III)-Based Receptor-Induced Magnetization Enhancement (RIME) Contrast Agent for beta-Glucuronidase Activity Profiling
(2012-11-19)
Chen, Shih-Hsien
;
Kuo, Yu-Ting
;
Singh, Gyan
;
Cheng, Tian-Lu
;
Su, Yu-Zheng
beta-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-FP beta Gu)]) for molecular imaging of beta-glucuronidase activity in tumor tissues. The contrast agent consists of two parts, a gadolinium complex and a beta-glucuronidase substrate (beta-D-glucopyranuronic acid). The binding association constant (K-A) of [Gd(DOTA-FP beta Gu)] is 7.42 X 10(2), which is significantly lower than that of a commercially available MS-325 (K-A = 3.0 x 10(4)) RIME contrast agent. The low K-A value of [Gd(DOTA-FP beta Gu)] is due to the pendant beta-D-glucopyranuronic acid moiety. Therefore, [Gd(DOTA-FP beta Gu)] can be used for detection of beta-glucuronidase through RIME modulation. The detail mechanism of enzymatic activation of [Gd(DOTA-FP beta Gu)] was elucidated by LC-MS. The kinetics of beta-glucuronidase catalyzed hydrolysis of [Eu(DOTA-FP beta Gu)] at pH 7.4 best fit the Miechalis-Menten kinetic mode with K-m = 1.38 mM, K-cat = 3.76 x 10(3), and k(cat)/K-m = 2.72 x 10(3) M-1 s(-1). The low K-m value indicates high affinity of beta-glucuronidase for [Gd(DOTA-FP beta Gu)] FP beta Gu) at physiological pH. Relaxometric studies revealed that T-1 relaxivity of [Gd(DOTA-FP beta Gu)] changes in response to the concentration of beta-glucuronidase. Consistent with the relaxometric studies, [Gd(DOTA-FP beta Gu)] showed significant change in MR image signal in the presence of beta-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 beta-glucuronidase. [GRAPHICS] .
In vivo magnetic resonance imaging of mice liver tumors using a new gadolinium-based contrast agent
(2013-05-01)
Chen, Shih-Hsien
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Kuo, Yu-Ting
;
Cheng, Tian-Lu
;
Chen, Chiao-Yun
;
Chiu, Yen-Yu
We compared the enhancement effect between a newly synthesized tissue-specific contrast agent, [Gd-DOTA-FP beta G], 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 beta-glucuronidase (beta G) expression were implanted into the liver of mice. Self-synthesized gadolinium-based magnetic resonance contrast agent, [Gd(DOTA-FP beta G)], 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-FP beta G)], caused significantly stronger enhancement in tumors expressing beta G (CT26/m beta G-eB7) than in tumors not expressing beta G (CT26) (p < 0.05). In the magnetic resonance imaging studies using control agent [Gd(DOTA)](-), the tumors with and without beta G expression depicted no significant difference in enhancement on the T1-weighted images. The [Gd(DOTA-FP beta G)] also provided significantly more contrast uptake in the CT26/m beta G-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. Copyright (c) 2012, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. All rights reserved.