Tumor Microenvironment-Responsive Theranostic Nanoplatform for Guided Molecular Dynamic/Photodynamic Synergistic Therapy

The integration of reactive oxygen species (ROS)-involved molecular dynamic therapy (MDT) and photodynamic therapy (PDT) holds great promise for enhanced anticancer effects. Herein, we report a biodegradable tumor microenvironment-responsive nanoplatform composed of sinoporphyrin sodium (SPS) photosensitizer-loaded zinc peroxide nanoparticles (SPS@ZnO2 NPs), which can enhance the action of ROS through the production of hydrogen peroxide (H2O2) and singlet oxygen (1O2) for MDT and PDT, respectively, and the depletion of glutathione (GSH). Under these conditions, SPS@ZnO2 NPs show excellent MDT/PDT synergistic therapeutic effects. We demonstrate that the SPS@ZnO2 NPs quickly degrade to H2O2 and endogenous Zn2+ in an acidic tumor environment and produce toxic 1O2 with 630 nm laser irradiation both in vitro and in vivo. Anticancer mechanistic studies show that excessive production of ROS damages lysosomes and mitochondria and induces cellular apoptosis. We show that SPS@ZnO2 NPs increase the uptake and penetration depth of photosensitizers in cells. In addition, the fluorescence of SPS is a powerful diagnostic tool for the treatment of tumors. The depletion of intracellular GSH through H2O2 production and the release of cathepsin B enhance the effectiveness of PDT. This theranostic nanoplatform provides a new avenue for tumor microenvironment-responsive and ROS-involved therapeutic strategies with synergistic enhancement of antitumor activity.