Redox responsive paclitaxel dimer for programmed drug release and selectively killing cancer cells

Redox stimulus responsive drug delivery systems have been widely investigated and proved to be promising prospects for efficient cancer therapy due to the abnormal high level of reactive oxygen species and glutathione in tumor microenvironment. Herein, three paclitaxel dimers (named as PTX₂-R, R = S, Se and Te) bridged with alkyl sulfide, selenide or telluride are synthesized. These dimers can self-assemble into stable uniform nanoparticles (named as PTX₂-R NPs, R = S, Se and Te) with impressively high drug loading. As expected, sulfur/selenium/tellurium bonds exhibit different redox responsiveness, thereby affecting the drug release and cytotoxicity. Of note, tellurium bridged paclitaxel dimer shows ultra-sensitivity to hydrogen peroxide, which rapidly cleaves into two paclitaxel under the subsequent dithiothreitol stimulation. Our findings provide deep insight into the redox sensitivity of chalcogenide elements and offer the rational design strategies to biologically redox condition for programmed drug release.