New Class of Homoleptic and Heteroleptic Bis(terpyridine) Iridium(III) Complexes with Strong Photodynamic Therapy Effects

Abstract

Six homo- or heteroleptic tricationic Ir(R₁-tpy)(R₂-tpy)³⁺ complexes (<b>Ir1</b>-<b>Ir6</b>, R₁/R₂ = Ph, 4'-N(CH₃)₂Ph, pyren-1-yl, or 4'-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}Ph, tpy = 2,2';6',2"-terpyridine) were synthesized and tested for photodynamic therapy (PDT) effects. The ground- and excited-state characteristics of these complexes were studied systematically <i>via</i> spectroscopic methods and quantum chemistry calculations. All complexes possessed intraligand charge transfer (¹ILCT) / metal-to-ligand charge transfer (¹MLCT) dominated transition(s) in their low-energy absorption bands, which red-shifted with the increased electron-releasing strength of the R₁/R₂ substituent. Five of the complexes exhibited ligand-centered ³ <i>π,π</i>*/³ILCT/³MLCT emission. With a stronger electron-releasing R₁/R₂ substituent, the degree of charge transfer contribution increased, leading to a decrease of the emission quantum yield. When the 4'-N(CH₃)₂Ph substituent was introduced on both tpy ligands, the emission of <b>Ir3</b> was completely quenched. Our study on the transient absorption of these complexes demonstrated that they all possessed broadband triplet excited-state absorption in the 400-800 nm region. Pyrenyl substitution of one or more tpy ligands, as in <b>Ir4</b> and <b>Ir5</b>, increased the lifetimes of the lowest triplet excited state and the singlet oxygen (¹O₂) production efficiencies. <b>Ir1</b>-<b>Ir5</b> were nontoxic toward SK-MEL-28 cells, with photocytotoxicities that varied from 0.18 to 153 <i>µ</i>M. Among them, <b>Ir4</b> had the highest ¹O₂ quantum yield (0.81) in cell-free conditions, showing the largest photocytotoxicity against SK-MEL-28 cells for Ir(III) PSs to date, and was the most efficient generator of reactive oxygen species (ROS) <i>in vitro</i>. <b>Ir4</b> possessed a very large phototherapeutic index (PI = dark EC₅₀ / light EC₅₀) of >1657, the largest reported for an Ir(III) complex photosensitizer upon broadband visible light (400-700 nm) activation. <b>Ir4</b> also exhibited a very strong PDT effect toward MCF-7 breast cancer cells and its xenograft tumor model. Upon 450-nm light activation, <b>Ir4</b> dramatically inhibited the xenograft tumor growth and exhibited negligible side effects upon PDT treatment.