3‑Bromopyruvate-Conjugated\nNanoplatform-Induced\nPro-Death Autophagy for Enhanced Photodynamic Therapy against Hypoxic\nTumor

Abstract

Autophagy\ntriggered by reactive oxygen species (ROS) in photodynamic\ntherapy (PDT) generally exhibits an anti-apoptotic effect to promote\ncell survival. Herein, an innovative supramolecular nanoplatform was\nfabricated for enhanced PDT by converting the role of autophagy from\npro-survival to pro-death. The respiration inhibitor 3-bromopyruvate\n(3BP), which can act as an autophagy promoter and hypoxia ameliorator,\nwas integrated into photosensitizer chlorin e6 (Ce6)-encapsulated\nnanoparticles to combat hypoxic tumor. 3BP could inhibit respiration\nby down-regulating HK-II and GAPDH expression to significantly reduce\nintracellular oxygen consumption rate, which could relieve tumor hypoxia\nfor enhanced photodynamic cancer therapy. More importantly, the autophagy\nlevel was significantly elevated by the combination of 3BP and PDT\ndetermined by Western blot, immunofluorescent imaging, and transmission\nelectron microscopy. It was very surprising that excessively activated\nautophagy promoted cell apoptosis, leading to the changeover of autophagy\nfrom pro-survival to pro-death. Therefore, PDT combined with 3BP could\nachieve efficient cell proliferation inhibition and tumor regression.\nFurthermore, hypoxia-inducible factor-1α (HIF-1α) could\nbe down-regulated after tumor hypoxia was relieved by 3BP. Tumor metastasis\ncould then be effectively inhibited by eliminating primary tumors\nand down-regulating HIF-1α expression. These results provide\nan inspiration for future innovative approaches of cancer therapy\nby triggering pro-death autophagy.