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

Abstract

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 <i>in vitro</i> and <i>in vivo</i>. 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.