Fenton Reaction-Assisted Photodynamic Therapy for Cancer with Multifunctional Magnetic Nanoparticles

Tumor hypoxia and the short half-life of reactive oxygen species (ROS) with small diffusion distance have greatly limited the therapeutic effect of photodynamic therapy (PDT). Here, a multifunctional nanoplatform is developed to enhance the PDT effect through increasing the oxygen concentration in tumor cells by the Fenton reaction and reducing the distance between the ROS and the target site by mitochondrial targeting. Fe₃O₄@Dex-TPP nanoparticles are first prepared by coprecipitation in the presence of triphenylphosphine (TPP)-grafted dextran (Dex-TPP) and Fe²⁺/Fe³⁺, which have a magnetic resonance imaging effect. Next, the photosensitizers of protoporphyrin IX (PpIX) and glutathione-responsive mPEG-ss-COOH are grafted on Fe₃O₄@Dex-TPP to form Fe₃O₄@Dex/TPP/PpIX/ss-mPEG nanoparticles. After the nanoparticles are internalized, part of Fe₃O₄ are decomposed into Fe²⁺/Fe³⁺ in the acidic lysosome and then Fe²⁺/Fe³⁺ diffused into the cytoplasm, and subsequently, Fe²⁺ reacted with the overproduced H₂O₂ to produce O₂ and •OH. The undecomposed nanoparticles enter the cytoplasm by photoinduced internalization and targeted to the mitochondria, leading to ROS direct generation around the mitochondria. Simultaneously, the produced O₂ by the Fenton reaction can serve as a raw material for PDT to continuously exert PDT effect. As a result, the Fenton reaction-assisted PDT can significantly improve the therapeutic efficacy of tumors.