Development of a Gd(III)-Based Receptor-Induced Magnetization Enhancement (RIME) Contrast Agent for 尾-Glucuronidase Activity Profiling

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• 作者：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
• 刊名：Inorganic Chemistry
• 出版年：2012
• 出版时间：November 19, 2012
• 年：2012
• 卷：51
• 期：22
• 页码：12426-12435
• 全文大小：501K
• 年卷期：v.51,no.22(November 19, 2012)
• ISSN：1520-510X

文摘

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