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Macromolecular drug conjugates II: chemical and enzymatic hydrolysis kinetics of the secondary 5-fluorouracil-1-acetic acid/β-cyclodextrin conjugate

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Abstract

The chemical and enzymatic hydrolysis of the secondary 5-fluorouracil-1-acetic acid/β-cyclodextrin conjugate were evaluated for potential application as a colon-targeted prodrug. In aqueous buffer solutions at a pH of 1–10, the pH-rate profile for hydrolysis of the conjugate was interpreted in terms of spontaneous or water-catalyzed, and specific base-catalyzed reactions. In the solutions of α-amylase, the conjugate was degraded to 5-fluorouracil-1-acetic acid/small saccharide conjugates. In the solutions of carboxyl esterase, the conjugate was gradually hydrolyzed to 5-fluorouracil-1-acetic acid at the similar rate as that in the absence of the carboxyl esterase. 5-Fluorouracil-1-acetic acid was rapidly released when the conjugate was hydrolyzed firstly by α-amylase and secondly by carboxyl esterase. On the other hand, the rate of hydrolysis of the conjugate was accelerated significantly by the colonic fluids of rats. It is important to note that the secondary conjugate released the parent drugs more slowly than the primary one.

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Acknowledgments

All the authors are grateful to Ningxia Medical University for financial support (No. XZ2015004).

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    Authors and Affiliations

    1. School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China

      Sheng Xia Luo, Rui Xia Zhang, Qing Huang, Li Sheng Xu & Zhi Zhong Wang

    2. Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Yinchuan, 750004, China

      Qing Huang & Zhi Zhong Wang

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    1. Sheng Xia Luo
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    2. Rui Xia Zhang
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    3. Qing Huang
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    Correspondence to Zhi Zhong Wang.

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    Sheng Xia Luo and Rui Xia Zhang contributed equally to this work, and are joint first authors.

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    Luo, S.X., Zhang, R.X., Huang, Q. et al. Macromolecular drug conjugates II: chemical and enzymatic hydrolysis kinetics of the secondary 5-fluorouracil-1-acetic acid/β-cyclodextrin conjugate. J Incl Phenom Macrocycl Chem 86, 167–171 (2016). https://doi.org/10.1007/s10847-016-0639-7

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