Probing the impact of sulfur/selenium/carbon linkages on prodrug nanoassemblies for cancer therapy

Tumor cells are characterized as redox-heterogeneous intracellular microenvironment due to the simultaneous overproduction of reactive oxygen species and glutathione. Rational design of redox-responsive drug delivery systems is a promising prospect for efficient cancer therapy. Herein, six paclitaxel-citronellol conjugates are synthesized using either thioether bond, disulfide bond, selenoether bond, diselenide bond, carbon bond or carbon-carbon bond as linkages. These prodrugs can self-assemble into uniform nanoparticles with ultrahigh drug-loading capacity. Interestingly, sulfur/selenium/carbon bonds significantly affect the efficiency of prodrug nanoassemblies. The bond angles/dihedral angles impact the self-assembly, stability and pharmacokinetics. The redox-responsivity of sulfur/selenium/carbon bonds has remarkable influence on drug release and cytotoxicity. Moreover, selenoether/diselenide bond possess unique ability to produce reactive oxygen species, which further improve the cytotoxicity of these prodrugs. Our findings give deep insight into the impact of chemical linkages on prodrug nanoassemblies and provide strategies to the rational design of redox-responsive drug delivery systems for cancer therapy.