Photothermal-Hypoxia Sequential Activatable Phase-Change Nanoagent for Mitochondria-Targeting Tumor Synergistic Therapy

To enhance anti-tumor therapies with high specificity and efficiency, we design a multifunctional nanoplatform for photochemotherapy under fluorescence (FL) and photoacoustic (PA) imaging guidance. Nanoparticles (NP) composed of a eutectic mixture of natural fatty acids that undergo solid–liquid phase transition at 39 ℃ are used as encapsulating materials for rapid and uniform release of hypoxia-activated prodrug tirapazamine (TPZ) and photosensitizer IR780. IR780 can target the mitochondria of tumor cells and kill these cells by photodynamic therapy (PDT) and photothermal therapy (PTT). Mitochondrial-targeted phototherapy can improve the effectiveness of phototherapy. And TPZ, which can be activated as a cytotoxic drug by hypoxia produced by photodynamic therapy, makes up for the deficiency of phototherapy and can reduce the side effects of traditional chemotherapy. In vitro, the NPs exhibit conspicuous cell uptake and NIR laser triggered drug release. In vivo, photochemotherapy of NPs achieve the best antitumor efficacy under photoacoustic (PA) and fluorescence (FL) imaging guidance and monitoring. This study demonstrates a new intracellular photochemotherapy nanosystem that co-encapsulates photosensitizers and hypoxia-activated drugs to enhance the overall anticancer effect precisely and efficiently, thus holding great promise for cancer treatments in the future.