Teruki Nii, Shoichi Hijii, Ryosuke Kaneko, Kenta Tanito, Kota Yamanaka, Akihiro Kishimura, Takeshi Mori, Yoshiki Katayama
{"title":"体外评估由外源酶的α-鼠李糖酶激活的新型 SN-38 原药。","authors":"Teruki Nii, Shoichi Hijii, Ryosuke Kaneko, Kenta Tanito, Kota Yamanaka, Akihiro Kishimura, Takeshi Mori, Yoshiki Katayama","doi":"10.1007/s44211-024-00593-9","DOIUrl":null,"url":null,"abstract":"<div><p>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 <i>k</i><sub><i>cat</i></sub>/K<sub>m</sub> value approximately 5.0 × 10<sup>4</sup>-fold higher than that of irinotecan. The 50% inhibition concentration (IC<sub>50</sub>) of Rham-SN-38 against three types of cancer cells and one normal cell exceeds 4.5 × 10<sup>3</sup> nM. The addition of α-rhamnosidase significantly increases cytotoxicity, with IC<sub>50</sub> comparable to free SN-38. The QIC<sub>50</sub>, an index reflecting the difference in cytotoxicity with and without α-rhamnosidase, exceeds approximately 1.0 × 10<sup>2</sup>-fold. Rham-SN-38, synthesized in this study, demonstrates significant potential as a prodrug for cancer therapy.</p><h3>Graphical abstract</h3>\n<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":7802,"journal":{"name":"Analytical Sciences","volume":null,"pages":null},"PeriodicalIF":1.8000,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"In vitro evaluation of novel SN-38 prodrug activated by α-rhamnosidase of exogenous enzyme\",\"authors\":\"Teruki Nii, Shoichi Hijii, Ryosuke Kaneko, Kenta Tanito, Kota Yamanaka, Akihiro Kishimura, Takeshi Mori, Yoshiki Katayama\",\"doi\":\"10.1007/s44211-024-00593-9\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>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 <i>k</i><sub><i>cat</i></sub>/K<sub>m</sub> value approximately 5.0 × 10<sup>4</sup>-fold higher than that of irinotecan. The 50% inhibition concentration (IC<sub>50</sub>) of Rham-SN-38 against three types of cancer cells and one normal cell exceeds 4.5 × 10<sup>3</sup> nM. The addition of α-rhamnosidase significantly increases cytotoxicity, with IC<sub>50</sub> comparable to free SN-38. The QIC<sub>50</sub>, an index reflecting the difference in cytotoxicity with and without α-rhamnosidase, exceeds approximately 1.0 × 10<sup>2</sup>-fold. Rham-SN-38, synthesized in this study, demonstrates significant potential as a prodrug for cancer therapy.</p><h3>Graphical abstract</h3>\\n<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>\",\"PeriodicalId\":7802,\"journal\":{\"name\":\"Analytical Sciences\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.8000,\"publicationDate\":\"2024-05-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Analytical Sciences\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://link.springer.com/article/10.1007/s44211-024-00593-9\",\"RegionNum\":4,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CHEMISTRY, ANALYTICAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Analytical Sciences","FirstCategoryId":"92","ListUrlMain":"https://link.springer.com/article/10.1007/s44211-024-00593-9","RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, ANALYTICAL","Score":null,"Total":0}
In vitro evaluation of novel SN-38 prodrug activated by α-rhamnosidase of exogenous enzyme
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 kcat/Km 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.
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.
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