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

IF 1.8 4区化学 Q3 CHEMISTRY, ANALYTICAL

Analytical Sciences Pub Date : 2024-05-15 DOI:10.1007/s44211-024-00593-9

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

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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.

Graphical abstract

Abstract Image

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体外评估由外源酶的α-鼠李糖酶激活的新型 SN-38 原药。

α-鼠李糖酶负责从 Rham-SN-38 中释放 SN-38，它在人体细胞中不表达，从而最大限度地减少了个体差异和副作用。将α-鼠李糖酶注射到肿瘤组织中首次实现了 Rham-SN-38 的活化。此外，α-鼠李糖酶的活性明显高于羧酸酯酶，后者是激活伊立替康的特异性酶。α-鼠李糖酶介导的 SN-38 释放在 2 小时内完成，其 kcat/Km 值约为伊立替康的 5.0 × 104 倍。Rham-SN-38 对三种癌细胞和一种正常细胞的 50% 抑制浓度（IC50）超过 4.5 × 103 nM。加入α-鼠李糖酶可显著增加细胞毒性，其 IC50 与游离 SN-38 相当。QIC50 是反映加入和不加入 α-鼠李糖酶时细胞毒性差异的指标，大约超过 1.0 × 102 倍。本研究合成的 Rham-SN-38 具有作为癌症治疗原药的巨大潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Analytical Sciences 化学-分析化学

CiteScore

2.90

自引率

18.80%

发文量

232

审稿时长

1 months

期刊介绍： Analytical Sciences is an international journal published monthly by The Japan Society for Analytical Chemistry. The journal publishes papers on all aspects of the theory and practice of analytical sciences, including fundamental and applied, inorganic and organic, wet chemical and instrumental methods. This publication is supported in part by the Grant-in-Aid for Publication of Scientific Research Result of the Japanese Ministry of Education, Culture, Sports, Science and Technology.