Luminescent Neutral Cyclometalated Iridium(III) Complexes Featuring a Cubic Polyhedral Oligomeric Silsesquioxane for Lipid Droplet Imaging and Photocytotoxic Applications

Abstract

New neutral iridium(III) complexes featuring a cubic polyhedral oligomeric silsesquioxane (POSS) unit, [Ir-(N ∧ C) 2 (L1-POSS)] [HN ∧ C = 2-phenylpyridine (Hppy; 1), 2phenylbenzothioazole (Hbt; 2), and 2-(1-naphthyl)benzothiazole (Hbsn; 3); L1-POSS = (E)-4-[(2-hydroxybenzylidene)amino]benzyl 3-heptakis(isobutyl)POSS-propyl carbamate], were designed and synthesized. Their POSS-free counterparts, [Ir-(N ∧ C) 2 (L1)] [L1 = (E)-N-(4-hydroxymethylphenyl)-1-(2hydroxyphenyl)methanimine; HN ∧ C = Hppy (1a), Hbt (2a), and Hbsn (3a)], and the poly(ethylene glycol) Hbt (2b), and Hbsn (3b)] were also prepared. The photophysical, photochemical, and biological properties of the POSS complexes were compared with those of their POSS-free and PEG-modified counterparts. Upon irradiation, all of these complexes displayed orange-to-red emission and long emission lifetimes under ambient conditions. The bsn complexes 3, 3a, and 3b exhibited the highest singlet oxygen ( 1 O 2 ) generation quantum yields (Φ Δ = 0.85−0.86) in aerated CH 3 CN. Laser-scanning confocal microscopy images revealed that complexes 1−3 and 1a−3a showed exclusive lipid-droplet staining upon cellular uptake, while the PEG derivatives 1b−3b displayed lysosomal localization. Complex 3 was utilized to study various lipid-droplet-related biological events including lipid-droplet accumulation under oleic acid stimulation, the movement of lipid droplets, and preadipocyte differentiation. Notably, 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays indicated that the ppy complexes 1 and 1b and the bt complexes 2 and 2b were noncytotoxic both in the dark and upon irradiation at 450 nm for 5 min (IC 50 > 200 μM), while the bsn complexes 3, 3a, and 3b showed low dark cytotoxicity (IC 50 = 52.9 to >200 μM) and high photocytotoxicity (IC 50 = 1.1−5.3 μM). The cellular uptake, internalization mechanisms, and cell death pathways of these complexes were also investigated. This work not only offers promising luminescent probes for lipid droplets through the structural modification of iridium(III) complexes but also paves the way to the construction of new reagents for theranostics.

Luminescent Metal Complexes as Emerging Tools for Lipid Imaging

“…Probe 4 is another example of a neutral cyclometalated Ir(III) complex that is specific to LDs (Fig. 3 ) [ 104 ]. The probe features a bulky polyhedral oligomeric silsesquioxane (POSS) cage, which, when compared to the POSS-free counterpart, has a higher lipophilicity (experimentally determined log P = 1.08 and 0.63, respectively).…”

“…Scale bar: 25 μm. Reprinted (adapted) with permission from Zhu et al [ 104 ]. Copyright 2021 American Chemical Society …”

Luminescent metal complexes as emerging tools for lipid imaging

“…Probe 4 is another example of a neutral cyclometalated Ir(III) complex that is specific to LDs (Fig. 3) [104]. The probe features a bulky polyhedral oligomeric silsesquioxane (POSS) cage, which, when compared to the POSS-free counterpart, has a higher lipophilicity (experimentally determined logP = 1.08 and 0.63, respectively).…”

Novel Pyrazine-Bridged D-A-D Type Charge Neutral Probe for Membrane Permeable Long-Term Live Cell Imaging

“…Using fluorescent probes for long-term monitoring of live cells is the key to understanding and modulating molecular events happening within organelles, unraveling the physiological dynamics. Recently reported fluorogenic probes involve the D-A (donor–acceptor) type platforms such as substituted acetylnaphthalene derivatives ( Tang and Jiang, 2017 ; Zhang et al, 2021a ; Gao et al, 2021 ), BODIPYs ( Tian et al, 2018 ; Bai et al, 2019 ; Liu et al, 2019 ; Zhang et al, 2021b ; Li et al, 2021 ), AIEgens ( Shi et al, 2019 ; Xu et al, 2021 ; Zheng et al, 2021 ), and organometallic compounds ( Jin et al, 2021 ; Zhu et al, 2021 ; Ünlüer, 2021 ). However, tuning the bandgaps for predictable photophysical properties of D-A type molecules was limited by synthetic approaches.…”