Design of a Thiol-Responsive, Traceless Prodrug with Rapid Self-Immolation for Cancer Chemotherapy

Prodrugs can be formed by chemical modification of the existing active pharmaceutical ingredients (APIs); however, this often sacrifices their functional efficacy. Self-immolative linkers have recently attracted attention, as they can be designed to release pristine APIs. Herein, we report a strategy to generate a self-immolative prodrug (SIP) that can release pristine doxorubicin (DOX). Compared to conventional linkers, the key SIP DOX (KSIP-DOX) developed here can rapidly and quantitatively release the API due to its strong leaving group after reduction by thiol groups, which are present in tumors. KSIP-DOX has enhanced cellular uptake and improved anticancer efficacy, demonstrating its utility for cancer treatment.