Abstract
Luminescence chemosensors are one of the most useful tools for the determination and imaging of small biomolecules and ions in situ in real time. Based on the unique photo-physical/-chemical properties of ruthenium(II) (Ru(II)) complexes, the development of Ru(II) complex-based chemosensors has attracted increasing attention in recent years, and thus many Ru(II) complexes have been designed and synthesized for the detection of ions and small biomolecules in biological and environmental samples. In this work, we summarize the research advances in the development of Ru(II) complex-based chemosensors for the determination of ions and small biomolecules, including anions, metal ions, reactive biomolecules and amino acids, with a particular focus on binding/reaction-based chemosensors for the investigation of intracellular analytes’ evolution through luminescence analysis and imaging. The advances, challenges and future research directions in the development of Ru(II) complex-based chemosensors are also discussed.
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1 Introduction
Small biomolecules and ions are building blocks of living organisms and play indispensable roles in all biological processes, such as enzymatic reactions, metabolism, growth, adaptation, and various disease developments and progressions [1, 2]. Determination and monitoring of the levels of these biomolecules and ions in situ are essential for better understanding their biological roles in biomedical systems, thus contributing to early diagnosis and treatment assessment of various diseases [3,4,5]. The most common and typical methods, such as high-performance liquid chromatography (HPLC) and inductively coupled plasma-optical emission spectroscopy/mass spectrometry (ICP-OES/MS), have been developed for the determination of small biomolecules and ions in vitro [6,7,8]. Onsite determination of these analytes in situ and in vivo, using these techniques, is not possible because the sample preparation in solution is an essential step to ensure performing successful analysis [9]. Imaging technologies, such as computerized tomography (CT) [10], magnetic resonance imaging (MRI) [11] and positron emission tomography (PET), have been widely used in clinical diagnosis [12], while these technologies cannot be directly used for the determination of the concentration and/or activity of these analytes in biological samples [13, 14]. This is mainly because the contrast agents (CAs) used in these technologies are generally nonspecific; more importantly, these CAs hardly respond to small biomolecules and ions at molecular level because of their resolution and sensitivity limitations [15]. Other approaches to optical detection, such as fluorescence and phosphorescence measurements, have also been successfully developed and adopted in biomedical research and clinical diagnosis [16]. In contrast to conventional bioassay and imaging technologies, luminescence bioassay and imaging using advanced optical spectroscopic and imaging instruments are featured with high sensitivity and selectivity, fast response time and low cost, enabling their use in biological and biomedical investigations involving in vitro bioassay and in vivo luminescence bioimaging [17,18,19,20].
Chemosensors are one of the most important tools for luminescence bioassay and imaging of small biomolecules and ions in situ in real time [21,22,23]. Luminescent chemosensors are normally designed as chemical compounds that can respond to targeted analytes through a unique binding/reaction (Fig. 1) [24, 25]. Generally, the chemosensors with reaction-based sensing mechanisms have higher selectivity, and the chemosensors with binding-based sensing mechanisms feature excellent reversibility for monitoring the targeted analyte in situ. As a result of these response processes, the luminescence signals can be switched “ON” (Fig. 1A) or “OFF” (Fig. 1B). Of the luminescence switch “OFF” and “ON” responses, the emission switch “ON” chemosensors are preferable for imaging analysis because the enhancement of the luminescence intensity can be easily observed by microscopy. The emission wavelengths of the chemosensors can also be shifted after the response processes (Fig. 1C) [25,26,27], allowing ratiometric luminescence detection and imaging of targeted analytes with the potential for precise and quantitative analyses. The changes of emission signals generally correspond to the concentrations of the targeted analyte and thus can be recorded for the analyte’s determination of abundance by luminescence spectroscopes and/or microscopes. Because of the unique advantages of luminescence bioassays and imaging, enormous efforts have been devoted to the development of luminescent chemosensors for the detection of a variety of analytes in complicated biological and environmental systems in the past few decades.
As shown in Fig. 1, luminescence chemosensors generally consist of three parts, including the luminophore, response unit and spacer, which links the luminophore and response unit. Of all luminophores that are being used for the development of chemosensors, fluorescent organic dyes are most widely investigated because of their high quantum yields (ϕ) and easy modification of chemical structures [28]. Lanthanide chelates are another family of luminophores that have been successfully employed in the development of chemosensors [29, 30]. Compared with fluorescent organic dyes, lanthanide chelate luminescence has high photostability, large Stokes shift and unique line-like emissions [29]. The prolonged lifetime of lanthanide chelates (microseconds to milliseconds) enables a background-free bioassay and imaging of targeted analytes through time-gated luminescence (TGL) measurement [28, 31]. Transition metal complexes, particularly the luminescent ruthenium(II) (Ru(II)) [32], iridium(III) (Ir(III)) [33], platinum(II) (Pt(II)), gold(I) (Au(I)) [34], rhenium(I) (Re(I)) [35] and osmium(II) (Os(II)) complexes with d6, d8 and d10 electron structures, have also been studied when develo** chemosensors for biomolecule and ion detection and imaging [36,37,38,39,40]. Different from the fluorescent organic dyes that emit from excited singlet state, phosphorescence of transition metal complexes is derived from excited triplet states [41]. The excited states of these transition metal complexes are more complicated than those of fluorescent dyes and mainly include metal-to-ligand charge transfer (MLCT), intraligand charge transfer (ILCT), ligand-to-ligand charge transfer (LLCT), metal–metal-to-ligand charge transfer (MMLCT), ligand-to-metal charge transfer (LMCT), metal-to-ligand-ligand charge transfer (MLLCT) and ligand-to-metal–metal charge transfer (LMMCT) [41,42,43]. The excited state-mediated emission properties of transition metal complexes are varied upon the changes of the metal center, local environment and particularly chemical structure of ligands, enabling transition metal complexes to be designed as the chemosensors through modulating these parameters [43].
Of all transition metal complex-based luminophores, Ru(II) polypyridine complex, particularly the prototype of the Ru complex ([Ru(bpy)3]2+ (bpy: 2,2′-bipyridine)) (Fig. 2A), has been one of the most popular molecules and widely investigated in the past few decades [44]. Ru(II) polypyridine complexes have octahedral symmetry with three kinds of electronic transitions, including metal centered (MC), ligand centered (LC) and MLCT [41]. As shown in Fig. 2B, in this octahedral symmetry of Ru(II) complex, MC excited states are obtained for an electron transition from πM to σ*M orbitals, LC excited states are formed through an electron transition from πL to π*L, and MLCT excited states are produced by promotion of an electron from πM metal orbital to π*L ligand orbitals [45]. The lowest excited state MC can decay to the ground state through a fast radiationless process. In contrast, the lowest excited states LC and MLCT undergo radiative deactivation to the ground state, thus exhibiting intense luminescence at room temperature in a rigid matrix and fluid solution, respectively [41]. Consequently, the lowest excited state is 3MLCT for most luminescent Ru(II) polypyridine complexes in solution. Upon the excitation at about 450 nm (spin-allowed 1MLCT), the lowest spin-forbidden 3MLCT excited state is obtained after a fast intersystem crossing process and then emits orange to near infrared emission [46]. The 3MLCT-based emission of Ru(II) polypyridine complexes displays unique photochemical and photophysical properties, including large Stokes shift (about 150 nm), prolonged luminescence lifetime (hundreds of nanoseconds to microseconds level), high photostability and brightness by visible light excitation [41, 47].
The emission of Ru(II) complexes, including luminescence intensity and lifetime, can be fine-modulated by modifying the chemical structure of ligands, allowing the Ru(II) complexes to be used for the development of chemosensors for biomolecule and ion detection. As described in early review articles [42, 43, 48, 49], the response mechanisms of luminescent Ru(II) complex chemosensors for target analytes mainly include (1) photo-induced electron transfer (PeT), in which the Ru(II) polypyridine complexes are ideal electron donors and acceptors, (2) Förster resonance energy transfer (FRET), in which the Ru(II) complexes can serve as the energy donor and acceptor [50,51,52,53] for the energy transfer (ET), (3) distortion of ligand and the octahedral symmetry after binding/reaction with the target analyte and (4) changes of the local environment upon the analyte’s binding. In addition to the luminescence response of Ru(II) complex-based chemosensors to the analyte [40, 54, 55], other prerequisites for this family of chemosensors to be applied in bioassay and imaging include (1) capability of analyte determination in aqueous solution, (2) high sensitivity and selectivity, which allow the chemosensors to be used for targeted analyte detection even at extremely low concentration without non-specific binding of interference species, (3) low cytotoxicity, enabling targeted analyte determination and imaging with minimum perturbation to the native micro-environment and (4) high cell membrane permeability to ensure the chemosensors are easily internalized into biological tissues.
The last few years have witnessed a huge leap forward in the development of Ru(II) complexes as the chemosensors for the detection of various analytes. Based on the above-described response mechanisms, hundreds of Ru(II) complex chemosensors for colorimetric and luminescent determination of anions, metal ions, small biomolecules and biomacromolecule have been available [42, 43]. For example, the triplet nature of the emission state with long lifetime of Ru(II) complexes allows them to be used for oxygen sensing by monitoring the changes of their luminescence intensity and lifetime [56,57,58]. Some of the Ru(II) complexes have also been revealed to be nucleic acid sensitive [59, 60], thus serving as a “light switch” for DNA detection [61]. The Ru(II) complexes with dipyridophenazine (dppz) ligands (e.g., complex 1 ([Ru(phen)2(dppz)]2+) are particularly interesting (Fig. 3A) [61]. These complexes are non-luminescent (undetectably small quantum yield) in water, while the emission intensity is significantly increased when bound to DNA [62, 63], which allows the Ru(II) complexes (e.g., complex 2) to be used for imaging of DNA structure and related mitosis progression (Fig. 3A). Subsequent research has also revealed that Ru(II) complexes (e.g., complex 3) can be used for the determination of DNA mismatches and RNA (Fig. 3B) [64,65,66,67]. Since the investigation of cellular uptake and imaging of the Ru(II) complex by Barton’s group [68, 69], the application of Ru(II) complex chemosensors for sensing and imaging of intracellular biomolecules and ions has increasingly attracted interest in recent years.
In this chapter, we wish to summarize recent examples of Ru(II) complex chemosensors for the detection of small biomolecules and ions in aqueous solution, with a particular focus on binding/reaction-based chemosensors for the investigation of intracellular analytes’ evolution through luminescence imaging. Specifically, the chemosensors for the determination of reactive oxygen/nitrogen/carbonyl species (ROS/RNS/RCS), biothiols, amino acids, pH, metal ions and anions are summarized, followed by the discussion of these chemosensors for luminescence bioimaging. The advances, challenges and future research directions in the development of Ru(II) complex-based chemosensors will also be discussed.
2 Ru(II) Complex Chemosensors for Anions
In various chemical and biological processes, anions play important roles in the body, such as blood pressure stabilization, blood purification, sugar level reduction, respiration and fatigue recovery. For anion sensing, the development of Ru(II) complex-based chemosensors has attracted enormous attention in the past few decades [70,71,72]. By virtue of their abundant photo-physical and chemical properties, hundreds of Ru(II) complexes have been designed and synthesized for the detection of various anions, such as fluoride (F−) [73,74,75,76], acetate (CH3COO−) [77], cyanide (CN−)[78], phosphate (H2PO4−) [79,80,81], chloride (Cl−) and bromide (Br−). Similar to the design of other anion receptors [82], most Ru(II) complex-based chemosensors are designed using the following three response mechanisms, including (1) the binding of the Ru(II) complex’s recognition unit with anions via hydrogen bonding and deprotonation [83], electrostatic and Lewis acid–base interactions [84], (2) specific reactions of the Ru(II) complex’s recognition unit with anions [85] and (3) displacement of metal ions from heterobimetallic Ru(II) complex [86]. In the following section, the Ru(II) complex-based chemosensors for anions will be discussed according to their different response mechanisms.
2.1 Response Based on Hydrogen Bonding, Electrostatic and Lewis Acid-Base Interactions
Although most Ru(II) complex-based anion chemosensors are developed through the mechanism of hydrogen bonding and electrostatic and Lewis acid-base interactions, the colorimetric and luminescent response of these Ru(II) complexes to anions can only be obtained in organic solvents, including acetonitrile (CH3CN) and dimethyl sulfoxide (DMSO) [87, 88]. This is mainly because the hydrogen bonding, electrostatic and Lewis acid-base interactions are significantly inhibited by the water molecules and other anions in the buffer solution [89]. This sub-section will discuss some examples of Ru(II) complex chemosensors for determination of anions in aqueous solution [90,91,92].
Through modification of the [Ru(bpy)3]2+ with amide containing a calixarene moiety (binding site), Maity et al. reported a Ru(II) complex (4) for CN− and CH3COO− determination (Fig. 4) [93]. Titration of complex 4 with CN− and CH3COO− in H2O–CH3CN (95:5) resulted in a remarkable luminescence quenching and enhancement, respectively. The different response mechanisms of complex 4 to CN− and CH3COO− were investigated by 1H NMR spectra. The CN− can bind to each amide N–H and leads to the deprotonation to form HCN. The electron density on the bpy ligand increased, and thus the intramolecular quenching was enhanced. In contrast, the weak interaction of bidentate CH3COO− with two N–H protons led to the formation of electron delocalization, in which the CH3COO− pulls the electron density to itself and thus decreases the intramolecular quenching. The luminescence response of complex 4 to CN− showed a LoD of 70 ppb.
Mardanya and co-workers described a Ru(II) complex (5) with pyrene-biimidazole ligand as a chemosensor for highly selective CN− detection in both CH3CN and aqueous media (Fig. 5) [94]. The imidazole N–H protons of the coordinated ligand were found to be highly acidic with pKa1 = 5.09 and pKa2 = 8.95. Deprotonation of these two N–Hs was found through hydrogen bonding interaction with CN−, leading to the increase of electron density of the metal center. As a result, red shift of absorption and quenching of emission were obtained for complex 5 after CN− binding. Detection limit of complex 5 to CN− was determined to be 5.24 × 10–9 and 4.67 × 10–9 M for colorimetric and luminescent analyses, respectively. A similar hydrogen bonding-based interaction has been employed for the development of Ru(II) complex 6 for selective detection of thiocyanate (SCN−) (Fig. 5) [95]. In complex 6, the SCN− interacts with N–H through a 1:1 binding mode, which hinders the photo-induced electron transfer (PeT) between the long pair electron of the N atom and the Ru(II) complex. The increase of luminescence intensity was thus recorded for SCN− detection in CH3CN-HEPES buffer solution (1:1, v/v, pH = 7.2).
In an early study, Lin et al. reported a Ru(II) complex (7) for highly selective detection of F− in water by naked eye and luminescence (Fig. 6) [96]. Complex 7 was developed by incorporating a Schiff-base ligand with two bpy ligands. In the presence of F−, the conversion of quinonehydrazone moiety to azophenol could occur, resulting in a remarkable red shift of absorption spectra from 475 to 580 nm and a solution color change from orange to blue-violet. The binding of F− also led to the increase of luminescence intensity at 630 nm. Although the spectrometric responses were measured in CH3CN, the test paper prepared by staining of complex 7 also showed color changes in aqueous solution. In a later study, the same group modified the 1,10-phenanthroline-5,6-dione ligand to produce complex 8 for F− detection (Fig. 6) [97]. In the presence of F−, a similar red shift of absorption spectra (from 467 to 580 nm), color change (from yellow to magenta) and luminescence enhancement were obtained, which were attributed to the F−-mediated hydrogen bonding and deprotonation of N–H. The test papers were also prepared for F− detection in aqueous solution with ten times higher sensitivity (LoD = 1 ppm) than complex 7.
2.2 Response Based on Specific Reactions
Compared with the above-discussed response mechanism of hydrogen bonding and Lewis acid-base interactions, the chemosensors developed by the mechanism of chemical reaction have high sensitivity and selectivity [78, 98, 99]. The interference from water is also minimized because specific chemical reactions are involved in the sensing mechanism of these chemosenosors. Aldehyde is a strong electron-withdrawing group that can quench the MLCT emission of Ru(II) complex. In a previous study, a Ru(II) complex (9, [Ru(CHO-bpy)3]2+) with three aldehyde functionalized bpy ligands was designed and synthesized by Zhang et al. as the chemosensor for biothiol (cysteine-Cys and homocysteine-Hcy) detection in DMSO-HEPES buffer [100]. In a later study, Zhang et al. found that the nucleophilic addition of aldehyde can also be triggered by hydrogen sulfite (HSO3−) in acidic buffer [24], thus allowing complex 9 to be used as a chemosensor for HSO3− detection in phosphate-buffered saline (PBS) buffer (50 mM, pH = 5) (Fig. 7) [101]. The reaction of HSO3− and complex 9 led to the formation of 9-SO, accompanied by an increase of luminescence at 620 nm. The result of HSO3− detection in wine and sugar samples showed that complex 9 has good precision and accuracy for HSO3− in food samples. Using 5-formyl-2,2′-bipyridine as the ligand, Zhu et al. prepared a Ru(II) complex (10) as the luminescence chemosensor for CN− detection (Fig. 7) [102]. Similar to [Ru(CHO-bpy)3]2+, complex 10 in CH3CN-H2O (6:4) showed weak emission at 700 nm. The nucleophilic attack by CN− led to the formation of 10-CN, accompanied by a blue shift and increase of emission at 618 nm. Complex 10 with a detection limit of 0.75 μM was then used for the preparation of a test paper for naked eye CN− detection.
In addition to aldehyde, nucleophilic addition between the azo (N = N) group and HSO3− has recently been exploited for the development of chemosensors for HSO3− detection (Fig. 8A) [24, 85]. Owing to the PeT from the Ru(II) center to the attached azo-2,4-dinitrobenzene (DNB), Ru(II) complex 11 (Ru-azo) exhibited weak emission in 25 mM PBS buffer of pH 7.4. The HSO3− triggered reaction with the azo group led to the formation of 11-SO3 (Ru-SO3), accompanied by an enhancement in luminescence at 635 nm. More interestingly, complex 11 has a long emission lifetime of 258 ns, which enabled its use for background-free luminescence detection of HSO3− through a TGL mode. In a wine sample containing rhodamine (spiked as the artificial background signal), steady-state luminescence analysis of HSO3− failed (Fig. 8B). TGL analysis eliminated the background signals and allowed for HSO3− detection with high accuracy and precision (Fig. 8C).
2.3 Response Based on Displacement of Metal Ions
By modifying the ligands with additional coordination sites, the produced Ru(II) complexes are capable of binding to other metal ions, such as Cu2+, Co2+, Zn2+ and Hg2+, to form heterobimetallic complexes. The heterobimetallic Ru(II) complexes thus can be used as chemosensors for anion sensing through a displacement approach. Different from the hydrogen bonding-based anion sensing approach, the displacement-based response mechanism also allowed the chemosensors to be used for anion detection in water because the water molecules are not involved in the displacement processes. Among various heterobimetallic Ru(II) complexes, the one with Cu2+ (Ru(II)–Cu(II)) has been widely studied because Ru(II) complex luminescence can be quenched by Cu2+ binding through electron and energy transfers. Then, Cu2+ can be displaced in the presence of several anions, including sulfide (S2−), CN− and pyrophosphate (PPi) (Fig. 9A).
By coupling di(2-picolyl)amine (DPA) to one bpy ligand, Zhang et al. synthesized a Ru(II) complex (12) and then demonstrated the corresponding heterobimetallic Ru(II)–Cu(II) complex as the chemosensor for S2− detection (Fig. 9B) [86]. Complex 12 showed high luminescence (ϕ = 3.07%) in HEPES buffer (pH 7.2), while the luminescence was completely quenched upon binding to Cu2+ through a 1:1 coordination stoichiometry. In the presence of S2−, Cu2+ was then displaced to form the original complex 12, which was accompanied by the recovery of luminescence. This heterobimetallic Ru(II)–Cu(II) complex showed high sensitivity to S2− (LoD = 20.7 nM), allowing its use for S2− detection in three wastewater samples. In a similar work, Li et al. modified the bpy ligand with a Cu2+ receptor, 1,4,7,10-tetraazacyclododecane (cyclen), and then demonstrated the Ru(II) complex (13) for sequential Cu2+ and S2− detection (Fig. 9B) [103]. Compared with complex 12, complex 13 has better selectivity to Cu2+ binding, while the formed 13-Cu is not as sensitive as 12-Cu for S2− sensing.
The displacement approach has also been employed for the development of Ru(II) complex chemosensors for CN−. In 2017, two Ru(II) complexes (14 and 15) were synthesized by Zheng and co-workers, and the corresponding heterobimetallic Ru(II)–Cu(II) complexes were used for CN− detection in 20 mM HEPES buffer (pH 7.2) (Fig. 9B) [104]. A recovery of luminescence was observed after the displacement of Cu2+ from 14-Cu to 15-Cu to form [Cu(CN−)X]n− and complexes 14 and 15. The LoD for CN− was then determined to be 0.36 and 0.87 μM using 14-Cu and 15-Cu as the chemosensors, respectively. Similarly, Zhang et al. reported a Ru(II) complex (16) for PPi detection in 2018 (Fig. 9B) [105], in which one Cu2+ from the 16-Cu was displaced by the addition of two PPi. The chemosensor 16-Cu showed high sensitivity (LoD = 0.58 nM) for PPi detection in 10 mM HEPES buffer (pH 7.4).
3 Ru(II) Complex Chemosensors for pH
Similar to most pH sensors, Ru(II) complex chemosensors for pH have mainly been developed through the mechanism of protonation and deprotonation of several functional groups, such as imidazole [106, 107], hydroxyl (–OH) [108,109,110], carboxyl (–COOH) [111], pyridine [112, 113] and others [114]. As a result of the protonation-deprotonation process, the molecular structures and the electron density distribution of Ru(II) complex are changed, leading to the variations of absorption and emission intensity/wavelength. In this section, the progress in the development of Ru(II) complex chemosensors for pH will be briefly discussed.
As described above, deprotonation of N–H of Ru(II) complex 5’s 2,2′-biimidazole ligand occurs under basic conditions or binding with CN− [94]. In 2020, Tormo et al. also reported the use of imidazole-based ligand for the development of Ru(II) complex chemosensors for pH [115]. In later research, deprotonation of imidazole N–H under neutral and basic conditions was exploited by Yu et al. for the development of Ru(II) complex 17 ([Ru(bim)2(pip)]2+) for pH sensing and imaging (Fig. 10A) [116]. The increase of pH led to the deprotonation of all imidazole N–H from both bim and pip ligands, resulting in red shift of absorption spectra and decrease of MLCT emission. Complex 17 has a pKa of 4.49 and low cytotoxicity, enabling lysosome imaging in U251 cells. Luminescence images of U251 cells with complex 17 and LysoTracker Red showed good co-localization (Fig. 10B), and then the application of complex 17 in monitoring of intracellular pH changes was demonstrated by treating the U251 cells with lysosomal acidification inhibitor (bafilomycin A1).
In 2015, Zheng and coworkers synthesized two Ru(II) complexes (18 and 19) and investigated their absorption and luminescence responses to pH (Fig. 11A) [112]. Protonation-deprotonation process occurs on the imidazole N–H and both imidazole N–H and pyridine for complexes 18 and 19, respectively. The two-step protonation-deprotonation processes resulted in complex 18 with pKa1 = 0.98 ± 0.04 and pKa2 = 8.34 ± 0.03, while the three-step protonation-deprotonation processes of complex 19 exhibited pKa1 = 1.86 ± 0.02, pKa2 = 3.43 ± 0.04 and pKa3 = 9.07 ± 0.08. Coordination of the terpyridine (tpy) ligand of complex 19 with Re(I), a heterobimetallic Ru(II)–Re(I) complex 20, was developed by Zheng et al. in 2014 (Fig. 11A) [113]. The coordination of the tpy ligand blocked the protonation-deprotonation of one pyridine; thus, a two-step protonation-deprotonation process was obtained. The pKa1 and pKa2 value of complex 20 was 1.38 ± 0.03 and 6.84 ± 0.04, respectively. Interestingly, the coordination with Re(I) significantly improved the biocompatibility, allowing complex 20 to be used for luminescence imaging in HeLa cells.
Dinuclear Ru(II) complex 21 was then synthesized by Meng and co-workers in 2017 (Fig. 11A) [117]. Ru(II) complex 21 showed NIR emission at 760 nm with a large Stokes shift of 254 nm and lifetime (τ) 108.3 ± 0.4 ns. Different from complex 20, a three-step protonation-deprotonation process was observed on imidazole N–H at the second ligand. pKa values of complex 21 changed to pKa1 = 1.36 ± 0.02, pKa2 = 5.76 ± 0.05 and pKa3 = 9.01 ± 0.14. Through modification of the second ligand, the same group recently reported a Ru(II) complex (22) as a chemosensor for pH imaging and cancer cell discrimination (Fig. 11A) [118]. Compared with complex 20, similar photophysical properties, including intense NIR emission (~ 700 nm) and large Stokes shift (~ 200 nm) were obtained for complex 22. More importantly, the pKa2 value of complex 22 was determined to be 7.87, which is closer to the physiological value (i.e., 7.0–7.4). This allowed complex 22 to be used for luminescence imaging of intracellular pH in lysosomes (Fig. 11B). Moreover, imaging of HeLa cells showed about 13-fold higher intensity than HEK293 cells (Fig. 11C), demonstrating the “distinguishing” ability of complex 22 to identify the tumor and healthy cells.
4 Ru(II) Complex Chemosensors for Metal Ions
In addition to the anions, metal ions also play important roles in biological and environmental systems. Some metal ions, such as Cu2+, Fe3+ and Zn2+, are essential elements in the human body, while the metal ions, such as Hg2+, Cd2+ and Cr3+, are highly toxic, causing several problems for biological and environmental systems [119]. To detect these metal ions in biological and environmental systems, a number of Ru(II) complex chemosensors have been developed in the past few decades. In this section, the progress in the development of chemosensors for Cu2+, Hg2+ [120] and others will be discussed according to the types of ions.
4.1 Ru(II) Complex Chemosensors for Cu2+
As described above, the binding of Ru(II) complexes with Cu2+ could lead to the quenching of their luminescence through an excited-state electron transfer or energy transfer mechanism [86, 104, 105]. By virtue of this mechanism, a series of Ru(II) complexes have been developed as luminescence “ON–OFF” chemosensors for Cu2+ determination and imaging (Fig. 12). Complex 17 with biimidazole ligands showed good performance in pH sensing with the protonation-deprotonation mechanism [116]. In a recent study, the biimidazole-coupled phen ligand was employed as the binding site for the development of Ru(II) complex chemosensor (23) for Cu2+ detection by Li and co-workers [121]. The coordination (1:1 bonding ratio) of Cu2+ with complex 23’s biimidazole led to the formation of a stable cyclic structure. The quenched emission of complex 23 showed a linearity with Cu2+ concentration in the range of 0.25–12 μM, and the LoD was 83.3 nM. The application of complex 23 was then demonstrated by Cu2+ detection in tap and lake water samples and imaging in A549 cells. For simple modification of imidazole to pyrazol, Cu2+ “ON–OFF” Ru(II) complex 24 was then reported by **a and colleagues [122]. Different from complex 23, complex 24 coordinated with Cu2+ through a 1:2 stoichiometry. This complex showed higher sensitivity to Cu2+ (LoD = 17.8 nM) compared with complex 23. The test paper was then prepared for Cu2+ detection in river water samples. Interestingly, complex 25 with quinoline substitution showed a 1:1 stoichiometry when binding to Cu2+ in HEPES buffer (LoD = 50.67 nM) [123]. The test paper was also prepared using complex 25 as the chemosensor for Cu2+ detection. In another study, Zhang et al. reported a Ru(II) complex 26 for Cu2+ detection in aqueous solution and imaging in live pea aphids (LoD = 244 nM) [124]. Complex 26 was developed through coordination with two phen ligands and one 2-(2-hydroxyphenyl) imidazo[4,5-f][1,10]phenanthroline. The Cu2+ binding with 2-hydroxyphenyl imidazo through a 1:1 stoichiometry quenched complex 26’s emission. Similar to Cu2+-coordinated complexes 23 and 25, the Cu2+ can be displaced by the addition of EDTA (ethylene diamine tetraacetic acid), which allows the reset of the chemosensors for further detection of Cu2+.
In addition to imidazole, some other groups, such as DPA [86, 125,126,127,128], 1,8-naphthyridine [129], 1,3-benzothiazole [130], carboxyl [131] and others [132], have also been utilized as the response units for the development of Ru(II) complex chemosensors for Cu2+. For example, complex 27 reported by Ramachandran and colleagues was capable of detecting phosphate anions through C–H-anion interaction and Cu2+ through coordination with triazole, benzothiazole and the “O” linker, respectively [130] (Fig. 12). The application of this chemosensor (27) for Cu2+ detection (LoD = 700 nM) and imaging was also demonstrated by luminescence Cu2+ imaging in MCF-7 cells.
Similar to complex 15, the pyridine “linker” of dinuclear Ru(II) complex 28 has also been developed as the chemosensor for Cu2+ detection in H2O/CH3CN (1:1, v/v) [133], in HEPES buffer solution (10 mM, pH 7.4) (Fig. 13A) [134]. Complex 28 showed high luminescence (ϕ = 0.06) at 600 nm, while the Ru(II) complex’s MLCT emission was quenched after coordination of Cu2+ with imidazole and pyridine. This chemosensor showed high sensitivity (LoD = 33.3 nM) and selectivity, reversibility (in the presence of EDTA) and good biocompatibility and cell membrane permeability, enabling it to be used for luminescence imaging. In addition, the Ru(II) complex’s large two-photon absorption (TPA) cross-section enabled complex 28 to be used for TP imaging of Cu2+ in HeLa cells and zebrafish (Fig. 13B).
Although “OFF–ON” luminescence response chemosensors feature high sensitivity and selectivity, and excellent performance in luminescent bioimaging, the development of turn “ON” response chemosensors remains a challenge due to the intrinsic luminescence quenching property of Cu2+. In 2009, a phenothiazine-coupled Ru(II) complex 29 was developed by Ajayakumar as the luminescence turn “ON” chemosensor for Cu2+ detection (Fig. 14A) [135]. Complex 29 was almost non-luminescent (ϕ = 0.0035 in CH3CN) because of the PeT from electron-rich phenothiazine to the Ru(II) center. In the presence of Cu2+, the oxidation of phenothiazine to phenothiazine-5-oxide inhibited the PeT process, and thus the emission of complex 29 was switched “ON.” In another research, Zhang et al. reported a Ru(II) complex “OFF–ON” luminescence chemosensor 30 for Cu2+ detection and imaging (Fig. 14A) [136]. Complex 30 with an o-(phenylazo)aniline structure showed weak luminescence in HEPES buffer solution (20 mM, pH 7.4). Cu2+-mediated oxidative cyclization led to > 80-fold enhancement in luminescence at 599 nm. The large enhancement in luminescence allowed complex 30 for highly sensitive (LoD = 4.42 nM) and selective detection of Cu2+ in buffer and imaging of Cu2+ in pea aphids (Fig. 14B).
Despite the quenching of most Ru(II) complexes’ emission by Cu2+ binding, the heterobimetallic Ru(II)–Cu(II) complexes provided an excellent platform for further development of “OFF–ON” response chemosensors for the detection of various analytes, such as anions [137], adenosine triphosphate (ATP) [138], amino acids [139, 140], redox biology [128] and other metal ions [141]. For example, in 2012, Wang et al. reported a Ru(II) complex for sequential detection of Cu2+ and Cr3+ in aqueous solution [141]. The coordination of a complex with Cu2+ produced the non-luminescent Ru(II)–Cu(II) complex, and this heterobimetallic complex showed high selectivity to Cr3+ in NaOAc-HOAc buffer (pH 5.6). A high sensitivity of this chemosensor to Cr3+ was also obtained with a LoD 66 nM.
4.2 Ru(II) Complex Chemosensors for Hg2+
Because of the high binding affinity of S atom with Hg2+, a series of S atom-bearing Ru(II) complexes have been developed as the chemosensors for Hg2+ detection. Previous research has revealed the colorimetric response of N-719 to Hg2+, in which the absorption spectra of N-719 were blue-shifted after binding of Hg2+ [142, 143]. The N-719 functionalized upconversion nanoparticles (UCNPs) were then prepared, and the application of the ratiometric upconversion luminescence (UCL) nanosensor for Hg2+ detection and imaging was also demonstrated [142]. In 2015, the N-719 derivative Ru(II) complex 31 was prepared by Fan and co-workers for colorimetric and luminescent determination of Hg2+ [144]. Similar to N-719, the response of complex 31 to Hg2+ was ascribed to the binding of electron-deficient Hg2+ to the electron-rich sulfur atom of NCS (thiocyante) groups. A 40-nm blue shift (from 525 to 485 nm) of absorption and a remarkable increase of luminescence at 720 nm were observed upon binding of complex 31 to Hg2+. In another study, Li et al. reported that a cyclometallated Ru(II) complex functionalized UCNPs for Hg2+ detection in water [145]. By modifying the cyclometallated Ru(II) complex with a propylsulfonate-coupled hemi-cyanine, Ru(II) complex 32 was then produced as the chemosensor for Hg2+ colorimetric analysis [194] and environmental samples [173]. Recent research found that the Ru(II) complexes’ 4,5-diamino-1,10-phenanthroline ligand can respond to RCS [200], particularly the MGO to form 2-methylpyrazino-1,10-phenanthroline ligand coordinated products [201]. Based on this reaction, Zhang et al. investigated the capability of the Ru(II) complex chemosensor for MGO determination and imaging in RAW 264.7 macrophages and flea. Recently, Zhang et al. reported a “dual-key-and-lock” Ru(II) complex chemosensor 49 for lysosomal FA determination in cancer cells and tumors (Fig. 23A) [202]. Complex 49 was designed by coupling of Ru(II) complex with a DNP quencher through an FA-responsive linker. Interestingly, the response reaction of complex 49 can only take place in the presence of FA (first “key”) under acidic conditions (second “key”), which allow FA detection specifically in lysosomes. Complex 49 has a long lifetime (τ = 330.4 ns), which facilitates the application of background-free TGL analysis in human serum samples and mouse organs. Luminescence imaging results clearly showed that complex 49 could be used for lysosomal FA detection in HeLa cells (Fig. 23B). With this FA-responsive Ru(II) complex, in vivo and ex vivo imaging results confirmed the much higher FA levels in tumor cells and tissues (Fig. 23C).
5.4 Ru(II) Complex Chemosensors for RSS
Hydrogen sulfide (H2S) is one of the major RSS in the human body and is involved in various biological processes. This endogenous gaseous molecule is produced by CBS (cystathionine β-synthase) and CSE (cystathionine γ-lyase) catalyzed reaction with thiol-containing biomolecules [203]. Recent research has also revealed that the H2S is a gasotransmitter and a regulator of critical biological processes [204, 205]. The metabolites of H2S, such as polysulfides and persulfides, are also important RSS that may have similar or divergent regulatory roles in living systems [206, 222]. In 2017, Gao et al. reported on Ru(II) complex 53 for luminescence detection of biothiols (Fig. 25) [223]. In this Ru(II) complex, two DNP quenchers were linked to two bpy ligands through a sulfonate ester bond, which enabled the quenching of MLCT emission and the “OFF–ON” response to biothiols. A morpholine moiety was conjugated to the third bpy ligand, allowing complex 53 with lysosome targeting ability. The capability of complex 53 for background-free TGL detection of biothiols was also demonstrated.
Although a number of biothiol-sensitive chemosensors have been reported, the measurement of total biothiols and determination the level of each one remains a challenge. In 2020, Liu et al. reported a “Two Birds with One Stone” Ru(II) complex 54 for the detection and discrimination of biothiols in vitro and in vivo (Fig. 26A) [224]. Complex 54 was developed through coupling of two different signaling units (Ru(II) complex and NBD) through a “luminophore-responsive linker-luminophore” approach. In the presence of GSH, the cleavage of “O” ether bond led to the formation of a luminescent Ru(II) complex and non-fluorescent NBD-SR1. In contrast, the reaction of complex 54 with Cys and Hcy led to the formation of a red-emitting Ru(II) complex and NBD-SR2 that can further undergo a five- or six-member cyclic intermediate-associated rearrangement to form corresponding green-emitting NBD-NR. This allowed for discrimination of GSH from Cys and Hcy under steady-state luminescence measurements. Moreover, under the TGL measurement model, the total biothiol concentration was obtained as elimination of the emission from NBD-NR. The GSH and Cys/Hcy concentrations were thus determined by measuring the same sample with both steady-state and TGL models. The time-gated luminescence imaging of intracellular biothiols was then demonstrated, showing that the NBD emission was eliminated after a 4-ns delay (τNBD-NR = 0.8 ns) (Fig. 26B).
6.2 Ru(II) Complex Chemosensors for Other Amino Acids
Ru(II) complexes have also been developed for the detection of other amino acids, such as methionine (Met) and histidine (His), through the response mechanism of amino acid-dominated binding of metal ions (e.g., Cu2+ and Ni2+) [56]. Therefore, development of the Ru(II) complex chemosensors with minimal quenching from the surrounding environments, particularly the levels of oxygen, is also demanded. With intense background autofluorescence in biological systems limiting the use of other probes, recent research has confirmed that indeed Ru(II) complexes with prolonged emission lifetime can be used for TGL bioassays and imaging [28, 31, 202]. Such a background-free bioassay and imaging approach allow the determination of target analytes in living cells with higher sensitivity and signal-to-noise (S/N) ratio, which can be further investigated for biomolecule detection in vivo in future studies.
In summary, taking together with the unique photo-physical/-chemical properties of Ru(II) complexes and the potential applications of chemosensors, ongoing research is expected to develop robust Ru(II) complex chemosensors for the determination and imaging of ions and biomolecules in the future. We hope that this review will provide a knowledge base for the Ru(II) complex chemosensor area and inspire the readers to contribute to this promising research field in the future.
Abbreviations
- Ru(II):
-
Ruthenium(II)
- HPLC:
-
High-performance liquid chromatography
- ICP-OES/MS:
-
Inductively coupled plasma-optical emission spectroscopy/mass spectrometry
- bpy:
-
2,2′-Bipyridine
- CT:
-
Computerized tomography
- MRI:
-
Magnetic resonance imaging
- PET:
-
Positron emission tomography
- CA:
-
Contrast agent
- LoD:
-
Limit of detection
- ϕ:
-
Quantum yields
- TGL:
-
Time-gated luminescence
- Ir(III):
-
Iridium(III)
- Pt(II):
-
Platinum(II)
- Au(I):
-
Gold(I)
- Re(I):
-
Rhenium(I)
- Os(II):
-
Osmium(II)
- MLCT:
-
Metal-to-ligand charge transfer
- ILCT:
-
Intraligand charge transfer
- LLCT:
-
Ligand-to-ligand charge transfer
- MMLCT:
-
Metal–metal-to-ligand charge transfer
- LMCT:
-
Ligand-to-metal charge transfer
- MLLCT:
-
Metal-to-ligand-ligand charge transfer
- LMMCT:
-
Ligand-to-metal–metal charge transfer
- MC:
-
Metal centered
- LC:
-
Ligand centered
- FRET:
-
Förster resonance energy transfer
- PeT:
-
Photo-induced electron transfer
- dppz:
-
Dipyridophenazine
- ROS:
-
Reactive oxygen species
- RNS:
-
Reactive nitrogen species
- RCS:
-
Reactive carbonyl species
- RSS:
-
Reactive sulfur species
- F− :
-
Fluoride
- CH3COO− :
-
Acetate
- CN− :
-
Cyanide
- H2PO4 − :
-
Phosphate
- Cl− :
-
Chloride
- Br− :
-
Bromide
- CH3CN:
-
Acetonitrile
- DMSO:
-
Dimethyl sulfoxide
- SCN− :
-
Thiocyanate
- Cys:
-
Cysteine
- Hcy:
-
Homocysteine
- GSH:
-
Glutathione
- HSO3 − :
-
Hydrogen sulfite
- S2 − :
-
Sulfide
- PPi:
-
Pyrophosphate
- DPA:
-
Di(2-picolyl)amine
- ATP:
-
Adenosine triphosphate
- UCNP:
-
Upconversion nanoparticle
- UCL:
-
Upconversion luminescence
- NO:
-
Nitric oxide
- ONOO− :
-
Peroxynitrite
- HNO:
-
Nitroxyl
- O2 • − :
-
Superoxide
- Cy5:
-
Cyanine 5
- •OH:
-
Hydroxyl radicals
- H2O2 :
-
Hydrogen peroxide
- 1O2 :
-
Singlet oxygen
- HOCl:
-
Hypochlorous acid
- DNP:
-
2,4-Dinitrophenyl
- BFO:
-
Benzofurazan-1-oxide
- GO:
-
Glyoxal
- CO:
-
Carbon monoxide
- MGO:
-
Methylglyoxal
- FA:
-
Formaldehyde
- CBS:
-
Cystathionine β-synthase
- CSE:
-
Cystathionine γ-lyase
- H2S:
-
Hydrogen sulfide
- NBD:
-
7-Nitro-2,1,3-benzoxadiazoles
- His:
-
Histidine
- S/N:
-
Signal-to-noise
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The authors gratefully acknowledge the financial support from Australian Research Council (DE170100092) and National Health and Medical Research Council (APP1175808).
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This article is part of the Topical Collection “Metal Legand Chromophores for Bioassays,” edited by Kenneth Kam-Wing Lo and Peter Kam-Keung Leung.
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Wu, M., Zhang, Z., Yong, J. et al. Determination and Imaging of Small Biomolecules and Ions Using Ruthenium(II) Complex-Based Chemosensors. Top Curr Chem (Z) 380, 29 (2022). https://doi.org/10.1007/s41061-022-00392-8
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DOI: https://doi.org/10.1007/s41061-022-00392-8