Hypoxia Exacerbation-Triggered Doxorubicin Prodrug Activation for Sequential Photodynamic/Chemotherapy

Hypoxia, which can promote tumor invasiveness and metastasis, is a major obstacle to various cancer therapies. At the same time, the hypoxic tumor microenvironment provides a great target for achieving precise treatment. Here, we report a nanoprodrug consisting of a hypoxia-responsive doxorubicin prodrug and a pH-responsive photosensitizer-containing amphiphilic polymer. When the nanoprodrug accumulates in tumor cells, the acidic environment promotes the disintegration of the nanoprodrug, which is beneficial for improving the generation efficiency of singlet oxygen and activating prodrugs. Under 660 nm laser irradiation, the photodynamic therapy process consumes oxygen and produces toxic singlet oxygen. The hypoxia exacerbation further promotes activation of the doxorubicin prodrug. Therefore, this study provides a promising approach to achieve great therapeutic efficacy by sequential photodynamic/chemotherapy.