A Hydrogen Peroxide Activatable Gemcitabine Prodrug for the Selective Treatment of Pancreatic Ductal Adenocarcinoma

Abstract The main concern in the use of anticancer chemotherapeutic drugs is host toxicity. Patients need to interrupt or change chemotherapy due to adverse effects. In this study, we aimed to decrease adverse events with gemcitabine (GEM) in the treatment of pancreatic ductal adenocarcinoma and focused on the difference of hydrogen peroxide levels in normal versus cancer cells. We designed and synthesized a novel boronate‐ester‐caged prodrug that is activated by the high H 2 O 2 concentrations found in cancer cells to release GEM. An H 2 O 2 ‐activatable GEM (A‐GEM) has higher selectivity for H 2 O 2 over other reactive oxygen species (ROS) and cytotoxic effects corresponding to the H 2 O 2 concentration in vitro. A xenograft model of immunodeficient mice indicated that the effect of A‐GEM was not inferior to that of GEM when administered in vivo. In particular, myelosuppression was significantly decreased following A‐GEM treatment compared with that following GEM treatment.