A Mitochondrion-Localized Two-Photon Photosensitizer Generating Carbon Radicals against Hypoxic Tumors.

The efficacy of photodynamic therapy is typically reliant on the local concentration and diffusion of oxygen. Due to the hypoxic microenvironment found in solid tumors, oxygen-independent photosensitizers are in great demand for cancer therapy. We herein report an iridium(III) anthraquinone complex (Ir4) as a mitochondrion-localized carbon radical initiator. The emission of Ir4 is turned-on under hypoxic conditions after reduction by reductase. Furthermore, the two-photon excitation properties of Ir4 (λex = 730 nm) are highly desirable for imaging. Upon irradiation, the reduced form of Ir4 (Ir4-red) generates carbon radicals leading to loss of mitochondrial membrane potential and cell death (IC50light = 2.1 μM, IC50dark = 58.2 μM, PI = 27.7). The efficacy of Ir4 as a PDT agent was also demonstrated under hypoxic conditions in vivo. To the best of our knowledge, Ir4 is the first metal complex-based theranostic agent which can generate carbon radicals for oxygen-independent two-photon photodynamic therapy.