title: Mitochondria-targeting cyclometalated iridium(III)-PEG complexes with tunable photodynamic activity.
abstract: We present a new class of phosphorescent cyclometalated iridium(III) polypyridine poly(ethylene glycol) (PEG) complexes [Ir(N(^)C)2(bpy-CONH-PEG)](PF6) (bpy-CONH-PEG = 4-(N-(2-(ω-methoxypoly-(1-oxapropyl))ethyl)aminocarbonyl)-4'-methyl-2,2'-bipyridine, number average molecular weight (Mn) = 5272.23, weight average molecular weight (Mw) = 5317.38, polydispersity index (PDI) = 1.009; HN(^)C = 2-phenylpyridine, Hppy (1a), 2-((1,1'-biphenyl)-4-yl)pyridine, Hpppy (2a), 2-phenylquinoline, Hpq (3a), 2-phenylbenzothiazole, Hbt (4a), 2-(1-naphthyl)benzothiazole, Hbsn (5a)). The photophysical, photochemical, and biological properties of these complexes have been compared with those of their PEG-free counterparts [Ir(N(^)C)2(bpy-CONH-Et)](PF6) (bpy-CONH-Et = 4-(N-ethylaminocarbonyl)-4'-methyl-2,2'-bipyridine; HN(^)C = Hppy (1b), Hpppy (2b), Hpq (3b), Hbt (4b), Hbsn (5b)). Upon irradiation, all the complexes exhibited intense and long-lived green to orange-red emission under ambient conditions. The emission was phosphorescence in nature and can be quenched by O2 with the generation of singlet oxygen ((1)O2). The quantum yields for (1)O2 production of the complexes in aerated DMSO (0.24-0.83) were found to be dependent on the excited-state lifetimes of the complexes, which can be altered using different cyclometalating ligands (N(^)C). Cell-based assays indicated that the PEG complexes were noncytotoxic in the dark (IC50 > 300 μM); however, most of them became significantly cytotoxic upon irradiation (IC50 = 3.4 - 23.2 μM). Laser-scanning confocal microscopy images revealed localization of complex 3a in the mitochondrial region of HeLa cells and the induction of rapid necrotic cell death upon light activation. Additionally, the lack of dark toxicity and potential application of the PEG complexes as a visualizing reagent have been demonstrated using zebrafish (Danio rerio) as an animal model.
authors.affiliation: Department of Biology and Chemistry, City University of Hong Kong, Kowloon, Hong Kong, PR China.
authors.forename: Steve Po-Yam
authors.initials: SP
authors.lastname: Li
authors.forename: Chris Tsan-Shing
authors.initials: CT
authors.lastname: Lau
authors.forename: Man-Wai
authors.initials: MW
authors.lastname: Louie
authors.forename: Yun-Wah
authors.initials: YW
authors.lastname: Lam
authors.forename: Shuk Han
authors.initials: SH
authors.lastname: Cheng
authors.forename: Kenneth Kam-Wing
authors.initials: KK
authors.lastname: Lo
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007495:Iridium / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010641:Phenotype; D010778:Photochemotherapy; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013050:Spectrometry, Fluorescence; D014018:Tissue Distribution / Q000187:drug effects; D015027:Zebrafish
chemical_list: D056831:Coordination Complexes; D008055:Lipids; D011092:Polyethylene Glycols; D007495:Iridium; D007770:L-Lactate Dehydrogenase; D002945:Cisplatin
keywords: Biocompatibility; Iridium; Molecular imaging; Photocytotoxicity; Singlet oxygen