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@ZnO 2 NPs), which can enhance the action of ROS through the production of hydrogen peroxide (H 2 O 2 ) and singlet oxygen ( 1 O 2 ) for MDT and PDT, respectively, and the depletion of glutathione (GSH). Under these conditions, SPS@ZnO 2 NPs show excellent MDT/PDT synergistic therapeutic effects. We demonstrate that the SPS@ZnO 2 NPs quickly degrade to H 2 O 2 and endogenous Zn 2+ in an acidic tumor environment and produce toxic 1 O 2 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@ZnO 2 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 H 2 O 2 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.