A pH/Redox Dual‐Responsive Nanocarrier for Hypoxia‐Activated Prodrug and Anticancer Prodrug in Cancer Treatment

Abstract

AbstractTumor microenvironment heterogeneity (TMH) remains a challenge in cancer treatment. Nanocarrier prodrugs based on small‐molecular drug or macromolecular drug conjugates emerge as an efficient approach for multidrug delivery at tumor sites and activating the prodrugs by endogenous stimuli resulting from TMH. Herein, a redox/pH dual‐sensitive micelle conjugated is developed via disulfide linkage with naphthalimide‐based prodrug (PNA), assigned as PDM to encapsulate hypoxia‐activated prodrug, banoxantrone (AQ4N), for combination therapy. These micelles have several interesting features, including sufficiently stable with less drug release under physiological conditions and dual stimuli‐triggered intracellular release, high drug loading content, and negligible cytotoxicity. More importantly, in vitro cytotoxicity of AQ4N‐loaded PDM micelles exhibits a combinational anticancer efficacy between chemotherapy of PNA and hypoxia‐activated chemotherapy of AQ4N under hypoxic conditions. Moreover, the developed PNA as a new chemotherapeutic drug displays good therapeutic efficiency and fluorescent properties, which can be used for monitoring drug release in real time. This study not only offers an attractive strategy for an effective combination of traditional chemotherapy and hypoxia‐activated chemotherapy, but also provides an important concept to develop dual stimuli‐sensitive prodrug nanoplatform targeting for endogenous TMH.