A Mitochondrion‐Localized Two‐Photon Photosensitizer Generating Carbon Radicals Against Hypoxic Tumors

Abstract

The efficacy of photodynamic therapyi st ypically 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 as am itochondrion-localized carbon-radical initiator.I ts emission is turned on under hypoxic conditions after reduction by reductase.F urthermore,i ts two-photon excitation properties (l ex = 730 nm) are highly desirable for imaging.U pon irradiation, the reduced form of the complex generates carbon radicals,l eading to al oss of mitochondrial membrane potential and cell death (IC 50 light = 2.1 mm,IC 50 dark = 58.2 mm,P I= 27.7). The efficacy of the complex as aP DT agent was also demonstrated under hypoxic conditions in vivo. To the best of our knowledge,i ti st he first metal-complexbased theranostic agent which can generate carbon radicals for oxygen-independent two-photon photodynamic therapy.

Fine‐Feature Modifications to Strained Ruthenium Complexes Radically Alter Their Hypoxic Anticancer Activity†

“…Importantly, PCT mechanisms do not necessarily rely on oxygen, a feature that could be exploited in hypoxic tumors. While few compounds to date have been shown to present good hypoxic activity (26–32), efforts are actively underway to design improved PCT agents with high photocytotoxicity in low‐oxygen conditions.…”

A mitochondria-localized iridium(iii)–chlorin E6 conjugate for synergistic sonodynamic and two-photon photodynamic therapy against melanoma

“…20,21 Two-photon excitations with deeper penetration and high spectral resolution allow for selective excitation in the tissue and avoid interferences from endogenous chromophores. [22][23][24] As an alternative approach, over the last few years, attention has been devoted toward sonodynamic therapy (SDT) as a noninvasive therapeutic modality. 25 SDT relies on the generation of ROS upon exposure to low-intensity ultrasound waves.…”

A pH-responsive iridium(iii) two-photon photosensitizer loaded CaCO3 nanoplatform for combined Ca2+ overload and photodynamic therapy

“…[22][23][24] To overcome these drawbacks, much atten-tion has been devoted to ruthenium and iridium coordination complexes based on their high chemical and photophysical stability, strong luminescence, production of reactive oxygen species, large Stokes shift, and cellular organelle targeting properties. 25,26 Capitalizing on these promising properties, iridium(III) coordination complexes have been investigated as two-photon near-infrared excited photosensitizers for photodynamic therapy, [27][28][29][30][31] luminescent probes for the detection of specific cellular processes, [32][33][34][35][36] or cellular dyes. 37,38 However, due to the poor tumor selectivity of the molecular iridium(III) complexes upon intravenous injection into the bloodstream, these compounds could only find an application by local intratumoral injection, thus limiting their application.…”