Multimodal Imaging Guided Synergistically Therapy in Hypoxic Tumor based on α-NaYbF4:Tm@Cu2– x Se@ZnFe2O4-DOX Nanoplatforms Mediated by NIR Light

The aberrant vascularization and uneven vascular distribution stemming from rapid tumor cell proliferation culminate arouse intra-tumoral hypoxia, which substantially compromises the therapeutic response to conventional chemotherapy, as well as photothermal therapy (PTT) and photodynamic therapy (PDT). In this work, we present an innovative α-NaYbF4:Tm@Cu2-xSe@ZnFe2O4-DOX nanoplatform that synergistically integrates PTT, Fenton reaction-enhanced chemodynamic therapy, PDT, and doxorubicin (DOX)-based chemotherapy under 980 nm near-infrared (NIR) light activation and weakly acidic environment-initiation. The 10 nm cubic-phase α-NaYbF4:Tm up-conversion cores were initially synthesized. Subsequently, low atomic number (Z) Cu2-xSe nanocrystal grown as photo-thermal conversion agent demonstrated significantly stronger X-radiation (X-ray) attenuation capabilities and enhanced computed tomography (CT) imaging performance compared to clinically used iopromide. Furthermore, zinc ferrite (ZnFe2O4) shell was obtained in hydrothermal synthesis manner. The 980 nm NIR-excited α-NaYbF4:Tm nanoparticles undergo efficient energy down-conversion, emitting photons that perfectly match the absorption spectrum of ZnFe2O4, thereby maximizing reactive oxygen species (ROS) generation through bandgap-engineered photoconversion. The tumor's glycolytic activity creates a hydrogen peroxide (H2O2)-rich microenvironment, enabling ZnFe2O4-mediated Fenton-like reactions that produce hydroxyl radicals (•OH) radicals, ultimately triggering oxidative damage and apoptotic cell death. It is noted that dual-mode photothermal therapeutic efficacy was achieved by Cu2-xSe and ZnFe2O4 as photothermal nanocrystal with up-conversion luminescence (UCL), magnetic resonance imaging (MRI) and CT multimodal imaging. DOX as anticancer chemotherapeutics was conjugated to form α-NaYbF4:Tm@Cu2-xSe@ZnFe2O4-DOX nanoplatforms. It remains effectively release of large quantities of DOX at tumor part conferred response to excessive lactic and carbonic acids generated in cancer cells. Our research may provide an insight for generalizing enhanced synergetic performance by NIR light-mediated PTT, Fenton reaction, PDT and chemotherapy. It is not a simple assembly of known components, but rather a multi-functional synergistic system constructed through ingenious core-shell structural design, capable of responding to near-infrared light and the tumor microenvironment. For the first time, this system seamlessly integrates up-conversion luminescence-mediated PDT, dual photothermal agent-enhanced PTT, self-supplying H2O2 Fenton reactions, and acid/heat dual-responsive chemotherapy into a single nanoplatform. Additionally, it incorporates multimodal imaging capabilities, providing an innovative and comprehensive solution to overcome the clinical challenge of tumor hypoxia.