Nii_2024_Anal.Sci__

This study introduces the alpha-rhamnose (Rham)-conjugated prodrug of SN-38 (Rham-SN-38) as a promising alternative to irinotecan. alpha-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 alpha-rhamnosidase into the tumor tissues makes it possible, for the first time, to activate the Rham-SN-38. Furthermore, alpha-rhamnosidase demonstrates significantly higher activity than carboxylesterase, the specific enzyme activating irinotecan. SN-38 release mediated by alpha-rhamnosidase completes within 2 h, with a k(cat)/K(m) value approximately 5.0 x 10(4)-fold higher than that of irinotecan. The 50% inhibition concentration (IC(50)) of Rham-SN-38 against three types of cancer cells and one normal cell exceeds 4.5 x 10(3) nM. The addition of alpha-rhamnosidase significantly increases cytotoxicity, with IC(50) comparable to free SN-38. The QIC(50), an index reflecting the difference in cytotoxicity with and without alpha-rhamnosidase, exceeds approximately 1.0 x 10(2)-fold. Rham-SN-38, synthesized in this study, demonstrates significant potential as a prodrug for cancer therapy.