Design of the tumor microenvironment-multiresponsive nanoplatform for dual-targeting and photothermal imaging guided photothermal/photodynamic/chemodynamic cancer therapies with hypoxia improvement and GSH depletion

Due to the inherent defects of complex tumor microenvironment (TME), such as hypoxia and high glutathione (GSH) content, reactive oxygen species (ROS) mediated therapies, including photodynamic therapy (PDT) and chemodynamic therapy (CDT) are greatly limited. Ingenious design of a novel nanoplatform by improving and utilizing the TME to achieve effective antitumor effects has been a significant challenge. Herein, a TME-multiresponsive nanoplatform containing innovative photosensitizer (gold nanoclusters (Au NCs) protected by L-cysteine-polyacrylamide (LCPAA) hydrogels, magnetically targeted ferric oxide (Fe 3 O 4 ) and mitochondrial localized triphenylphosphine derivatives (TPP) for cancer diagnosis and treatment is reported. The combination of Fe 3 O 4 with Au NCs@LCPAA can broaden and enhance the near-infrared (NIR) absorption of the nanoplatform so that the considerable photothermal therapy (PTT)/PDT and photothermal imaging are achieved during NIR (808 nm) laser irradiation. More importantly, because Fe 3 O 4 responds to acid TME and continuously decomposes into iron ions (Fe 2+ & Fe 3+ ), the Fenton reaction induced by Fe 2+ ions and the production of oxygen (O 2 ) from hydrogen peroxide (H 2 O 2 ) catalyzed by Fe 3+ ions as well as the depletion of GSH led by the oxidation of Fe 3+ ions all can be triggered by TME rich in H 2 O 2 and GSH, which reduce the hypoxia and antioxidant capacity of tumor so as to enhance the O 2 and/or ROS-dependent PDT/CDT of Fe 3 O 4 /Au NCs@LCPAA-TPP nanoplatform. A series of in vitro and in vivo experiments have proved that through multiple regulation of TME, the as-prepared nanoplatform integrates the potential of dual-targeting, photothermal imaging as well as synergetic improved CDT/PDT/PTT.