N-Phenyl-2-Pyridone-Derived Endoperoxide Exhibiting Dual Activity by Suppressing both Lung Cancer and Idiopathic Pulmonary Fibrosis

Abstract

Conventional light-driven photodynamic therapy (PDT) to generate toxic singlet oxygen are potential for cancer therapeutics but limited by the light penetrability and hypoxia tumor. PDT-involved combinational therapy could enhance overall therapeutic effects and reduce drug resistance, while disadvantages such as diverse pharmacokinetics among different ingredients, low active-ingredient loading, inevitably utilization of non-functional components need to be addressed. Here we report an endoperoxide E5 synthesized via ‘in vitro’ PDT could spontaneously deliver singlet oxygen, triplet oxygen and 3-methyl-N-phenyl-2-pyridone as an analogue of pirfenidone (Approved drug for treatment of idiopathic pulmonary fibrosis), showing great potential for treating non-small cell lung cancer and idiopathic pulmonary fibrosis. In aqueous solution, E5 could undergo a clear cycloreversion to afford three components with a half-life time of 8.3 hours and it efficiently suppress the migration and invasion of lung cancer cell as well as the TGF-b1 induced fibrosis in vitro. In vivo experiments suggest that E5 not only efficiently inhibits tumor growth, decreases the HIF-1α protein levels, relieves idiopathic pulmonary fibrosis, but shows good biocompatibility. Many evidence reveal that both singlet oxygen and 3-methyl-N-phenyl-2-pyridone are therapeutic ingredients, and triplet oxygen could relieve tumor hypoxia which is an inevitable issue in conventional PDT. Our study validates that endoperoxides as single active components containing multiple ingredients including singlet oxygen are of exceptionally therapeutic potential.