Tumor\nMicroenvironment-Responsive Theranostic Nanoplatform\nfor Guided Molecular Dynamic/Photodynamic Synergistic Therapy

Abstract

The\nintegration of reactive oxygen species (ROS)-involved molecular\ndynamic therapy (MDT) and photodynamic therapy (PDT) holds great promise\nfor enhanced anticancer effects. Herein, we report a biodegradable\ntumor microenvironment-responsive nanoplatform composed of sinoporphyrin\nsodium (SPS) photosensitizer-loaded zinc peroxide nanoparticles (SPS@ZnO₂ NPs), which can enhance the action of ROS through the production\nof hydrogen peroxide (H₂O₂) and singlet oxygen\n(¹O₂) for MDT and PDT, respectively, and the\ndepletion of glutathione (GSH). Under these conditions, SPS@ZnO₂ NPs show excellent MDT/PDT synergistic therapeutic effects.\nWe demonstrate that the SPS@ZnO₂ NPs quickly degrade to\nH₂O₂ and endogenous Zn²⁺ in an acidic\ntumor environment and produce toxic ¹O₂ with\n630 nm laser irradiation both <i>in vitro</i> and <i>in vivo</i>. Anticancer mechanistic studies show that excessive\nproduction of ROS damages lysosomes and mitochondria and induces cellular\napoptosis. We show that SPS@ZnO₂ NPs increase the uptake\nand penetration depth of photosensitizers in cells. In addition, the\nfluorescence of SPS is a powerful diagnostic tool for the treatment\nof tumors. The depletion of intracellular GSH through H₂O₂ production and the release of cathepsin B enhance the\neffectiveness of PDT. This theranostic nanoplatform provides a new\navenue for tumor microenvironment-responsive and ROS-involved therapeutic\nstrategies with synergistic enhancement of antitumor activity.