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dc.contributor.authorChen, Shih-Hsienen_US
dc.contributor.authorKuo, Yu-Tingen_US
dc.contributor.authorSingh, Gyanen_US
dc.contributor.authorCheng, Tian-Luen_US
dc.contributor.authorSu, Yu-Zhengen_US
dc.contributor.authorWang, Tzu-Pinen_US
dc.contributor.authorChiu, Yen-Yuen_US
dc.contributor.authorLai, Jui-Jenen_US
dc.contributor.authorChang, Chih-Chingen_US
dc.contributor.authorJaw, Twei-Shiunen_US
dc.contributor.authorTzou, Shey-Cherngen_US
dc.contributor.authorLiu, Gin-Chungen_US
dc.contributor.authorWang, Yun-Mingen_US
dc.description.abstractbeta-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] .en_US
dc.titleDevelopment of a Gd(III)-Based Receptor-Induced Magnetization Enhancement (RIME) Contrast Agent for beta-Glucuronidase Activity Profilingen_US
dc.identifier.journalINORGANIC CHEMISTRYen_US
dc.contributor.departmentDepartment of Biological Science and Technologyen_US
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