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

Shih Hsien Chen, Yu Ting Kuo, Gyan Singh, Tian Lu Cheng, Yu Zheng Su, Tzu Pin Wang, Yen Yu Chiu, Jui Jen Lai, Chih Ching Chang, Twei Shiun Jaw, Shey-Cherng Tzou, Gin Chung Liu*, Yun-Ming Wang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


β-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-FPβGu)]) for molecular imaging of ß-glucuronidase activity in tumor tissues. The contrast agent consists of two parts, a gadolinium complex and a β-glucuronidase substrate (β-D- glucopyranuronic acid). The binding association constant (KA) of [Gd(DOTA-FPβGu)] is 7.42 × 102, which is significantly lower than that of a commercially available MS-325 (KA = 3.0 × 104) RIME contrast agent. The low KA value of [Gd(DOTA-FPβGu)] is due to the pendant β-d-glucopyranuronic acid moiety. Therefore, [Gd(DOTA-FPβGu)] can be used for detection of β-glucuronidase through RIME modulation. The detail mechanism of enzymatic activation of [Gd(DOTA-FPβGu)] was elucidated by LC-MS. The kinetics of β-glucuronidase catalyzed hydrolysis of [Eu(DOTA-FPβGu)] at pH 7.4 best fit the Miechalis-Menten kinetic mode with Km = 1.38 mM, k cat = 3.76 × 103, and kcat/Km = 2.72 × 103 M-1 s-1. The low K m value indicates high affinity of β-glucuronidase for [Gd(DOTA-FPβGu)] at physiological pH. Relaxometric studies revealed that T1 relaxivity of [Gd(DOTA-FPβGu)] changes in response to the concentration of β-glucuronidase. Consistent with the relaxometric studies, [Gd(DOTA-FPβGu)] showed significant change in MR image signal in the presence of β-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 β-glucuronidase.

Original languageEnglish
Pages (from-to)12426-12435
Number of pages10
JournalInorganic Chemistry
Issue number22
StatePublished - 19 Nov 2012


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