Nucleus-targeted Iridium Complex Prodrugs For Type I/II Photodynamic Therapy

Iridium(?)complexes have been widely used in biomedicine due to their rich photophysical and photochemical properties,high quantum yield,adjustable emission wavelength and long triplet emission lifetime.However,the current research on iridium complexes mainly focus on the development of type II photosensitizers,type II photodynamic therapy is oxygen dependent and is not suitable for invasive and drug-resistant tumors.Type I photodynamic can operate independently of oxygen and has good therapeutic effect on hypoxic tumor microenvironment,it is necessary to develop type I photosensitizer or type I/II dual-mode photosensitizer.In addition,the biomedical application of iridium complexes remain on the planar ring metal iridium(III)complexes,Therefore,it is significance to design and synthesize three-dimensional type I/II bimodal iridium complex photosensitizers.In this work,we synthesized a three-dimensional six-nuclear cage iridium complex[(Ir(ppy)₂)₆(tcb)₄](OTf)₆(Ir6,ppy=2-phenylpyridine,tcb=1,3,5-Trinitrile,OTf=trifluoromethanesulfonate anion).When Ir6 complex interacted with 20 natural amino acids and other biomolecules,Ir6 complex only responded to histidine(his)and histidine-rich proteins(such as BSA)and emitted strong green phosphorescence.Compared with the Ir6 complex,the fluorescence lifetime and quantum yield of the product(Ir6+His)after the Ir6 complex reacted with histidine were significantly improved.Cell experiments showed that Ir6 complex specifically responded to histidine-rich protein,it was observed that the fluorescence was mainly concentrated in the nucleus,indicating that Ir6 complex could specifically light up the nucleus.This was helpful for us to study its intracellular localization and anti-cancer mechanism.Further experimental results found that after the Ir6 complex reacted with histidine and histidine-rich proteins,it could generate not only singlet oxygen but also superoxide anion under light irradiation.This indicated that the Ir6 complex was a histidine-responsive type I/type II dual-mode photosensitizer prodrug,which helped to improve the photodynamic therapy effect under hypoxia.In conclusion,Ir6 complex are promising to be developed into iridium complex anticancer prodrugs with integrated diagnosis and treatment,especially suitable for hypoxic environments.