Design of diselenide-containing polyprodrug and its pH/redox co-triggered degradation and slow drug release for tumor-specific chemotherapy

Abstract

Polyprodrugs have attracted intense interest for tumor-specific chemotherapy, by conjugating chemotherapeutic drugs via two dynamic covalent bonds in the polymer main chains. Here, pH/redox co-triggered degradable diselenide-containing polyprodrug with a high doxorubicin (DOX) content of 1.42×10−3 mmol/g was designed by linking diselenide-containing dimer of doxorubicin (D-DOXSeSe) with adipic dihydrazide. The polyprodrug could be triggered to degrade and release drug only when the hydrazone and diselenide conjugations on both sides of the drug units were cleaved, triggered by the higher acidity and higher GSH or ROS levels. Slow drug release was achieved in the simulated tumor intracellular microenvironment due to the lower solubility of the release drugs (DOX derivatives), with cumulative release of 10.3 % and 7.4 % in 96 h co-triggered with 10 mM GSH or 0.5 mM H2O2, without obvious drug mis-release in the simulated intracellular environment of the normal cells. It might provide a safe and efficient tumor-specific chemotherapy avoiding the toxic and side effects on the normal cells.