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Ir(III) Complexes with AIE Characteristics for Biological Applications: History
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Contributor: Yu Pei ,
Yan Sun
,
Meijia Huang
, Zhijun Zhang , Dingyuan Yan ,
Jie Cui
, Dongxia Zhu , Zebing Zeng , Dong Wang , Benzhong Tang

Both biological process detection and disease diagnosis on the basis of luminescence technology can provide comprehensive insights into the mechanisms of life and disease pathogenesis and also accurately guide therapeutics. As a family of prominent luminescent materials, Ir(III) complexes with aggregation-induced emission (AIE) tendency have been recently explored at a tremendous pace for biological applications, by virtue of their various distinct advantages, such as great stability in biological media, excellent fluorescence properties and distinctive photosensitizing features. Significant breakthroughs of AIE-active Ir(III) complexes have been achieved and great progress has been witnessed in the construction of novel AIE-active Ir(III) complexes and their applications in organelle-specific targeting imaging, multiphoton imaging, biomarker-responsive bioimaging, as well as theranostics.

  • aggregation-induced emission (AIE)
  • Ir(III) complexes
  • PDT

1. Introduction

Iridium(III) complexes have attracted significant scientific interest in various fields, ranging from photoelectric devices, catalysis and chemical sensing to biological applications, benefitting from their prominent photophysical properties. Ir(III) has a higher spin-orbit coupling (SOC) constant (4430 cm−1) than other transition metals (Ru(II): 990 cm−1, Rh(III): 1425 cm−1, Os(II): 3531 cm−1, Pt(II): 4000 cm−1) and the strong SOC effect can accelerate the intersystem crossing (ISC) process [1][2]. Moreover, Ir(III) can easily form multiple coordination compounds. The structures of auxiliary ligands that coordinate with the metal center are rich and diverse, resulting in efficient metal to ligand charge transfer (MLCT), ligand-centered (LC) and ligand to ligand charge transfer (LLCT) [3][4][5], which causes strong phosphorescent emission and long excited-state lifetimes [6]. Meanwhile, Ir(III) complexes possess tunable photophysical properties, satisfactory photostability and large Stokes shifts. On the basis of those features, in particular, Ir(III) complexes are receiving great attention as promising candidates for optical bioimaging and phototherapy [7][8][9].
Photodynamic therapy (PDT) has accurately eradicated tumors and reduced side effects in healthy tissues by controlling the area of light irradiation. In general, the tumor apoptosis caused by PDT goes through photochemical reactions between excited triplet states of photosensitizers (PSs) and cellular substrates or oxygen to generate cytotoxic reactive oxygen species (ROS). Typically, the activated PSs may migrate to their triplet excited state via ISC. After that, the triple-activated PSs further react with oxygen to afford ROS via electron transfer (type I) or energy transfer (type II) processes [10]. Of particular interest is the heavy atom effect of Ir atoms, which plays an important role in efficiently enhancing the ability of ISC and effectively improving the generation efficiency of ROS [11][12][13]. However, the aggregation-caused quenching (ACQ) effect caused by the aggregation of Ir(III) complexes in an aqueous physiological environment leads to a reduction in luminescence emission and the generation capacity of ROS, which further limits their practical applications in the biomedical field [14][15].
Fortunately, aggregation-induced emission (AIE) was proposed in 2001 to solve the problem of unsatisfactory emission of luminescent materials in the aggregated state [16]. The main mechanism of the AIE phenomenon is the restricted intramolecular motion (RIM), thereby blocking the nonradiative energy decay pathway and boosting the radiative channel [17]. In recent years, AIE luminogens (AIEgens) have attracted extensive attention in the field of bioimaging, sensing and therapy applications, thanks to their distinct properties, including excellent photobleaching resistance and reliable output signal in an aggregated state [18][19][20]. In particular, AIEgens have unique aggregation-enhanced theranostics (AET) properties, referring to the advantages of enhancements in ROS generation, nonlinear optical effects under aggregation-induced effects [21][22]. On the other hand, many cases of Ir(III) complexes with AIE properties have been reported to date [23][24][25][26] and the following design strategies are generally recommended: (i) introducing active units with AIE properties into Ir(III) complexes and (ii) restricting intramolecular motion of flexible rotating units (such as imine bonds of Schiff bases) through coordination with the central metal iridium. Ir(III) complexes are potential phosphorescent molecules for the construction of AIE materials via strategic modification of ligands [27]. Therefore, constructing AIE phosphorescent materials based on Ir(III) complexes is one of the most promising candidates in the field of photo-triggered theranostics.

2. Improving Photophysical Property of Ir(III) Complexes with AIE Activity

2.1. Red-Shift Emission

Making the emission red shift is a good way to reduce the interference of background antofluorescence and increase the depth of penetration [28]. Compared with red emission, near-infrared (NIR) emission has better performance in overcoming autofluorescence interference, minimizing photodamage to cells and improving the signal-to-noise ratio (SNR) of imaging [29][30].

2.2. Enhancing Molar Absorption Coefficient

In general, the upper limit of the output signal depends on the absorption capacity of the PSs. Actually, high brightness can be achieved by increasing the molar absorption coefficients. Therefore, improving absorptive capacity has been the focus of many efforts [31].

2.3. With the UCNPs

Upconversion nanoparticles (UCNPs) are desirable photoconversion materials for biosensing and biomedicine on account of their capability to transform the NIR photons to UV/visible photons [32][33]. Therefore, the conjugation of PSs to UCNPs presents an alternative to achieve NIR light-triggered generation of ROS.

2.4. Two-Photon Absorption (TPA)

In recent years, two-photon absorption (TPA) has emerged as an attractive protocol in bioimaging and PDT. Two-photon photodynamic therapy (TP-PDT) activates PSs by contemporaneously absorbing two photons [34][35][36][37]. It provides photodamage and phototoxicity as well as deeper penetration, weaker autofluorescence and lower photobleaching [38][39]. Developing Ir(III) complexes with TPA is a new strategy to enhance the efficiency of Ir-PSs. However, conventional PSs suffer from ACQ and reduced photocytotoxicity, resulting in inferior imaging and PDT efficacy.

2.5. Multiphoton Absorption (MPA)

Compared with TPA, multiphoton absorption (MPA) improves the conversion efficiency through simultaneously absorbing several infrared photons. The two primary benefits of MPA have attracted attention: excitation wavelengths are in the near infrared (NIR) (700–900 nm) and the relationship between multiphoton absorption activity and excitation intensity is nonlinear [36]. Nevertheless, Ir(III) complexes activated by MPA are still very rare.

3. Accurate Targeting of Ir(III) Complexes with AIE Activity

3.1. Targeting Mitochondria

It is well known that mitochondria are one of the most essential organelles. As the power workshop of cells, mitochondria provide most of the cellular ATP through pathways, such as pyruvate oxidation, fatty acid oxidation, tricarboxylic acid cycle (TCA cycle), and so on. On the other hand, mitochondria are the key to the apoptotic pathway. For instance, in extrinsic apoptosis, the mitochondrial outer membrane opens after signals, including intracellular Ca2+ overload and oxidation, which leads to the release of pro-apoptotic factors [40]. PSs act on mitochondria and make mitochondrial ROS burst, so mitochondria will be destroyed and then Cytochrome C, kinds of pro-apoptotic factors, will release, resulting in cancer cell death [41]. As a result, mitochondria-targeted PDT becomes an effective method to improve the treatment of cancer. The agents with delocalized positive charge are preferable to go through the mitochondrial lipid bilayer membrane due to the highly negative inner-membrane potential of mitochondria. Ir(III) complexes are demonstrated as mitochondrial targeting molecules applied in PDT, due to their lipophilic cationic properties.

3.2. Targeting Nucleolus

Ribonucleic acid (RNA) exists in biological cells and some viruses, as a viroid genetic information carrier. As the basis of life, RNA takes part in biological processes, such as gene transcription, post-transcriptional regulation of gene expression, protein synthesis based on gene information, etc. Thereinto, rRNA is responsible for protein synthesizing. rRNA gathers in the nucleolar region, which is a dark region under fluorescence microscopy. In recent years, the exploration of rRNA-selective probes for the nucleolar region becomes a meaningful topic. Holding more intense interaction with DNA than rRNA, small molecules are difficult to make use of as rRNA-selective probes. Ir(III) complexes have potential to construct a kind of rRNA-selective probe due to their greater interaction with intra-nuclear proteins [9].

4. Specific Response of Ir(III) Complexes with AIE Activity

In recent years, Ir(III) complexes with AIE properties have attracted more attention as photoluminescent probes in bioimaging, owing to their high photophysical performance (such as large Stokes shifts, tunable photophysical properties, long excited-states lifetime, satisfactory photostability, etc.). So far, several specific responsive probes based on Ir(III) complexes with AIE activity have been reported for bioimaging applications.

4.1. Perchlorate (ClO4−)

Perchlorate (ClO4−) salts are widespread and relatively stable in foods and water samples [42]. ClO4− competitively disrupts thyroid uptake of iodine and accumulates in the human body due to its similar ionic radius with iodide, resulting in adverse consequences, such as iodide deficiency and goiter, even brain impairment [43]. Hence, it is necessary to detect ClO4− in water and monitor it in cells. An AIE-active complex based on the Ir(III) complex for specific sensing of ClO4− in cells reported by Chao et al. in 2016 was rationally designed by introducing the thioacetal group [44].

4.2. BSA

BSA is a globular protein and has an important effect on biophysical functions, such as blood circulation and drug binding [45][46].

4.3. Drug-Resistant Bacteria

Antimicrobial resistance (AMR) has developed rapidly due to the overuse of medicines, leading to contaminating water bodies and posing a serious threat to public health [47][48]. Therefore, there is an urgent need for monitoring and eliminating drug-resistant bacteria to control waterborne diseases [49]. The work of Sasmal et al. is a good example of developing Ir(III) complexes with AIE properties for detecting and inhibiting drug-resistant bacteria [50].

5. Conclusions

By introducing various ligands into Ir(III) complexes, the photophysical properties could be improved to enhance the effect of bioimaging and therapeutics. These results are of great importance and promote the development of AIE materials based on Ir(III) complexes for biomedical applications.

This entry is adapted from the peer-reviewed paper 10.3390/bios12121104

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