Resorufin Enters the Photodynamic Therapy Arena: A Monoamine Oxidase Activatable Agent for Selective Cytotoxicity

Abstract

A red-absorbing, water-soluble, and iodinated resorufin derivative (<b>R1</b>) that can be selectively activated with a monoamine oxidase (MAO) enzyme was synthesized, and its potential as a photodynamic therapy (PDT) agent was evaluated. <b>R1</b> showed high ¹O₂ generation yields in aqueous solutions upon addition of MAO isoforms, and it was further tested in cell culture studies. <b>R1</b> induced photocytotoxicity after being triggered by endogenous MAO enzyme in cancer cells with a much higher efficiency in SH-SY5Y neuroblastoma cells with high MAO-A expression. Additionally, <b>R1</b> displayed differential cytotoxicity between cancer and normal cells, without any considerable dark toxicity. To the best of our knowledge, <b>R1</b> marks the first example of a resorufin-based photosensitizer (PS) as well as the first anticancer drug that is activated by a MAO enzyme. Remarkably, the target PDT agent was obtained only in three steps as a result of versatile resorufin chemistry.