In vitro evaluation of novel SN-38 prodrug activated by α-rhamnosidase of exogenous enzyme

Teruki Nii; Shoichi Hijii; Ryosuke Kaneko; Kenta Tanito; Kota Yamanaka; Akihiro Kishimura; Takeshi Mori; Yoshiki Katayama

doi:10.1007/s44211-024-00593-9

In vitro evaluation of novel SN-38 prodrug activated by α-rhamnosidase of exogenous enzyme

Anal Sci. 2024 May 15. doi: 10.1007/s44211-024-00593-9. Online ahead of print.

Authors

Teruki Nii^#^{1

2}, Shoichi Hijii^#³, Ryosuke Kaneko⁴, Kenta Tanito³, Kota Yamanaka³, Akihiro Kishimura^{3

4

5

6}, Takeshi Mori^{3

4

5}, Yoshiki Katayama^{7

8

9

10

11}

Affiliations

¹ Graduate School of Systems Life Sciences, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan. nii.teruki.204@m.kyushu-u.ac.jp.
² Department of Applied Chemistry, Faculty of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fu-Kuoka, 819-0395, Japan. nii.teruki.204@m.kyushu-u.ac.jp.
³ Graduate School of Systems Life Sciences, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan.
⁴ Department of Applied Chemistry, Faculty of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fu-Kuoka, 819-0395, Japan.
⁵ Center for Future Chemistry, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan.
⁶ International Research Center for Molecular Systems, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan.
⁷ Graduate School of Systems Life Sciences, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan. katayama.yoshiki.958@m.kyushu-u.ac.jp.
⁸ Department of Applied Chemistry, Faculty of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fu-Kuoka, 819-0395, Japan. katayama.yoshiki.958@m.kyushu-u.ac.jp.
⁹ Center for Future Chemistry, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan. katayama.yoshiki.958@m.kyushu-u.ac.jp.
¹⁰ International Research Center for Molecular Systems, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan. katayama.yoshiki.958@m.kyushu-u.ac.jp.
¹¹ Department of Biomedical Engineering, Chung Yuan Christian University, 200 Chung Pei Rd., Chung Li, 3203 ROC, Taiwan. katayama.yoshiki.958@m.kyushu-u.ac.jp.

^# Contributed equally.

PMID: 38748393
DOI: 10.1007/s44211-024-00593-9

Abstract

This study introduces the α-rhamnose (Rham)-conjugated prodrug of SN-38 (Rham-SN-38) as a promising alternative to irinotecan. α-rhamnosidase, responsible for SN-38 release from Rham-SN-38, does not express in human cells, minimizing individual variability and side effects. The injection of the α-rhamnosidase into the tumor tissues makes it possible, for the first time, to activate the Rham-SN-38. Furthermore, α-rhamnosidase demonstrates significantly higher activity than carboxylesterase, the specific enzyme activating irinotecan. SN-38 release mediated by α-rhamnosidase completes within 2 h, with a k_cat/K_m value approximately 5.0 × 10⁴-fold higher than that of irinotecan. The 50% inhibition concentration (IC₅₀) of Rham-SN-38 against three types of cancer cells and one normal cell exceeds 4.5 × 10³ nM. The addition of α-rhamnosidase significantly increases cytotoxicity, with IC₅₀ comparable to free SN-38. The QIC₅₀, an index reflecting the difference in cytotoxicity with and without α-rhamnosidase, exceeds approximately 1.0 × 10²-fold. Rham-SN-38, synthesized in this study, demonstrates significant potential as a prodrug for cancer therapy.

Keywords: Cancer; Enzyme prodrug therapy; Exogenous enzyme; Prodrug.

Abstract

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