Abstract
Economic development has raised concerns about human healthcare and disease prevention from its early stages. In that regard, the detection of biomarkers is crucial for early diagnosis of diseases, and it is an essential tool for managing various health conditions. The clinical diagnostics industry is worth hundreds of billions of dollars and has been expanding. However, the traditional methods for biomarkers detection are high-cost and time-consuming. Also, they usually require highly trained personnel and complex instrumental processes, only providing a centralized medical diagnosis system in large hospitals or specialized facilities. In contrast, a chemosensor is a smart molecular analytical device designed to sense an analyte to generate a detectable signal and to offer direct diagnosis without complex instruments or systems. Moreover, electrochemiluminescence (ECL) possesses distinct advantages such as low-costs, simplicity, and portability. ECL has become a useful technique and has been widely applied in many fields, from basic research to practical applications. Chemosensors coupled with ECL can provide compelling advantages over conventional approaches, such as rapid response time, higher sensitivity, and selectivity. This minireview aims to highlight recent representative studies on ECL-based chemosensors for clinical applications. It provides a general overview of the design and structure of ECL-based chemosensors, and also covers the general problems and challenges. The presented content may prove to be useful for discovering new sensor concepts or extension of existing biomarker detection strategies.
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Introduction
A chemosensor is a chemical molecule composed of two subparts: a recognition unit for specific binding to a molecular analyte and a signaling unit that reports the binding event in the form of a detectable signal1,2. Unlike most bioanalytical methods which exploit biological receptors such as peptides, proteins and nucleic acids (e.g. antibodies, aptamers, etc.) as their recognition element, the chemosensor relies on recognition elements of abiotic origin3,4. If the binding event between the recognition unit and the analyte is of irreversible nature (i.e. formation of covalent bonds), the sensor is termed a chemodosimeter. The fluorescent chemosensor for the detection of aluminum ion developed in 1867 by Friedrich Goppelsroder can be considered to be the first chemosensor in history, which not only pioneered the field of chemosensing in particular but also modern analytical chemistry in general. Subsequently, substantial progress was made in developing more chemosensors, primarily for metal ion sensing, by Anthony W. Czarnik5-7, A. Prasanna de Silva,8-10 Roger Tsien11,12, Lynn Sousa13 and others. At the present, applications of chemosensors can be found in various fields and industries, such as clinical analysis14-16, food analysis17-19 and environmental analysis20-22. Depending on the response produced by the signaling element, chemosensors can be further categorized into different types, including fluorescent chemosensors, chemiluminescent chemosensors, electrochemiluminescent (ECL) chemosensors, colorimetric chemosensors, electrochemical chemosensors, surface plasmon resonance chemosensors, quartz crystal microbalance chemosensors or a combination of more than one signaling method (i.e. multi-signal chemosensors)23. Nevertheless, the majority of chemosensing research has been focused on fluorescent chemosensors, due to their advantages including relative simplicity, good selectivity and high sensitivity24-27. However, the dependence of fluorescent chemosensors on an excitation light source limits their clinical point-of-care diagnostic application. Furthermore, fluorescent chemosensors also suffer from background noises (i.e. auto-fluorescence, scattered light) interfering with the desired signal and reducing the signal-to-noise ratio28.
Electrochemiluminescence (also known as electro-generated chemiluminescence) is a type of luminescence involving light emission upon relaxation of excited states produced from highly energetic electron-transfer reactions between electrochemically generated species at an electrode surface29. Since the first detailed reports on ECL in the 1960s30-32, ECL has grown to become a crucial tool for analysis across various fields such as immunosensing, aptasensing, and chemosensing. The significance of ECL is due to its unique features which combine the advantages of photoluminescence and electrochemical methods, separating ECL from other types of luminescence. Firstly, ECL does not require the use of a light source as does photoluminescence, thus simplifying the optical instrument setup and reducing luminescent interferences. And secondly, the signaling event in ECL is triggered by an applied potential, providing ECL with better spatial and temporal control as well as higher selectivity compared to chemiluminescence33. A comparison between photoluminescence, electrochemiluminescence and electrochemical methods is given in Table 1. The excited states which emit light in ECL are produced from reactive intermediates formed upon electrochemical oxidation/reduction of stable, ECL-active species. Thus, ECL can be considered a form of chemiluminescence in which the reactants are electrochemically produced on the electrode surface. Luminophores employed in ECL-chemosensors belong to one of the three categories: organic luminophores (e.g. BODIPY dyes, thiophene-based molecules)34,35; inorganic luminophores (e.g. tris(2,2’-bi-pyridine) ruthenium(II) complexes, cyclometalated iridium complexes)36,37; or nanomaterial-based luminophores (e.g. gold nanoclusters, C3N4 quantum dots)38,39.
ECL can be produced through two pathways: annihilation ECL or coreactant ECL. Annihilation ECL, or radical ion annihilation ECL, is the ECL pathway in which an oxidized form and a reduced form of the ECL-active species are sequentially produced at the surface of the electrode by rapidly alternating the potential between two values and subsequently undergo an annihilation reaction to generate the emissive excited state. The excited state 1A* in this instance is a singlet excited state. The system that is capable to directly produce a singlet excited state is called an energy-sufficient system or S-route (singlet route) owing to the fact that the energy provided by the ion radicals through the annihilation reaction is sufficient to populate the singlet excited state. The annihilation process for an energy-sufficient system is described by reactions 1–4, where A and D can represent the same, or different ECL-active species. Ru(bpy)2+ is perhaps the most well-known example of an energy sufficient system40.
In contrast, if the energy is not large enough to populate the singlet excited state, triplet excited states can be populated instead. The triplet excited states populated in this energy deficient system then undergo a triplet-triplet annihilation reaction in which the energy from two electron transfer reactions is pooled into the production of a singlet excited state41. The process is hence called the T-route or triplet route and is described by reactions 5–9.
In the case in which the cathodic radical or anodic radical of the ECL-active species is unstable or cannot be generated due to the extreme reduction or oxidation potentials required, or if one wishes to produce ECL at a single potential step, a coreactant can be incorporated into the system. A coreactant is a species which produces a strong oxidant upon reduction (hence called an oxidative-reductive coreactant, such as oxalate) or a strong reductant upon oxidation (hence called a reductive-oxidative coreactant, such as benzoyl peroxide). The reaction process for the two types of coreactant is described by reactions 1019. More coreactants are being developed, in part to provide for ECL sensors, which mainly utilize coreactant ECL.
Oxidative-reductive coreactant:
Reductive-oxidative coreactant:
Biomarkers are “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharma-cologic responses to a therapeutic intervention”42. Biomarkers have risen to become an important tool in disease detection and treatment follow-up, especially in the detection of serious health conditions such as cancer, Alzheimer’s disease and cardiovascular diseases in early phases43-47. The detection of biomarkers remains a challenging task due to them existing at exceedingly low concentrations in complex matrices that are human bodily fluids43. Recently, ECL-chemosensing has emerged as a promising method for biomarker detection because of its low costs and high sensitivity and selectivity.
Despite its relatively short history, there have been many excellent comprehensive reviews on ECL sensing and ECL in general48-53. However, a review dedicated to the application of ECL chemosensors to the important, rapidly-growing field of clinical analysis is still absent. In this mini review, we focus on ECL chemosensors aimed at detecting clinically important biomarkers and discuss the detection mechanism strategies employed therein as well as the problems and challenges faced by ECL chemosensors.
ECL Chemosensors for Clinical Applications
A typical setup for ECL detection is small-scale and compact, consisting of a sensing platform (i.e. the dark box) in which the electrodes and sample solution are placed, a detector (e.g. a PMT) for ECL signal detection, a potentiostat to control and measure electrochemical parameters and a PC to display and process the signal obtained (Figure 1A). In the sample solution, whose volume is small and can be in the range of a hundred microliters, the ECL turn-on probe reacts selectively with the analyte, turning the probe from an ECL-inactive or weakly ECL-active molecule into a strongly ECL-active product. Measurements are performed by injecting the sample solution onto the electrode surface. Upon the application of an appropriate potential, the product and coreactant undergo electrochemical oxidation-reduction reactions at the electrode surface to generate radical ions, which produce the excited species that emits light via electron-transfer reactions. On the contrary, an ECL turn-off probe is strongly ECL-active and will become ECL-inactive after reacting with the analyte (Figure 1B).
Homocysteine
Small-molecular biothiols play crucial roles in biological systems and abnormal levels of these biothiols are strongly related to various diseases. Therefore, monitoring of biothiol concentrations is of great importance in medical diagnostics. Among biothiols, homocysteine (Hcy) is an essential amino acid in human blood. An elevated level of Hcy is a risk factor for cardiovascular diseases and Alzheimer’s disease (normal Hcy range in the blood is 5 – 15 μΜ)54,55. Previous approaches utilized enzymes for selective detection of Hcy. However, this strategy requires high costs, time-consuming sample preparation, hindering their use in large-scale applications56. Kim et al. achieved a breakthrough by designing Probe 1 based on a cyclometalated iridium(III) complex37. Probe 1 incorporates a more strongly electron-withdrawing isoquinoline unit in the main ligand instead of pyridine to stabilize its the lowest-unoccupied molecular-orbital (LUMO), enabling electron transfer from the coreactant TPrA radical, which was confirmed experimentally and by density function theory calculations (Figure 2A). As a result, a turn-on ECL signal is achieved and is in good agreement with PL results. Probe 1 responded linearly to a range of 0 to 40 μΜ of Hcy concentrations, which covers the normal range of Hcy levels in the blood (Figure 2B). In the competitive binding assay, Probe 1 exhibited no significant change upon the addition of a 200-fold excess of interferences and a remarkable increase upon the addition of 100 equivalents of Hcy (Figure 2C). Probe 1 also shows selective behavior over Cys, which is a strong interference due to its similar structure to Hcy (Figure 2D).
One of the major limitations of reported chemosensors in the literature is that most studies were only conducted in buffer solution environment or deproteinized serum, which necessitate long-time pretreatment. For the first time, Stewart et al. offered a method to directly detect hyperhomocysteinemia in the blood based on the quenching effect of cathodic ECL of near-infrared quantum dots upon addition of Hcy. The quenching rate in blood is significantly lower compared to that in PBS buffer, which is possibly caused by electrostatic interactions between Hcy and biomolecules in blood. However, a linear relationship between the ECL signal and Hcy concentration was obtained in blood and not in PBS. Although the selectivity of this approach needs further optimization, it will inspire other researchers to develop novel sensors that do not require sample pretreatment57.
Cysteine
Cysteine is also an important biothiol that is involved in different biosynthetic and metabolic processes. An increase or decrease in the level of cysteine (Cys) is an indicator of a range of different health problems such as brain ischemia, slowed growth, Alzheimer’s disease or osteoporosis58-60. Xie et al. investigated the ECL properties of an organic fluorescent dye-based probe, which is designed to contain a fluorescein signaling unit and a nitroolefin binding site to interact with Cys. Cys is detected using Michael reaction, the binding adduct exhibits intense ECL signal in the presence of potassium persulfate as a reductive oxidation coreactant. This work shows a linear range of Cys from 10−9 to 10−8 M and an excellent LOD of 4.2 × 10−10 M. However, selectivity tests with other biothiols that possess similar structure to cysteine (i.e. homocysteine, glutathione) were not included61. Recently, a cyclometalated iridium(III) complex-based sensor was developed by Kim et al. which can selectively detect Cys over structurally similar compounds: Hcy and GSH. The sensing mechanism is based on phosphorescence enhancement and ECL quenching in the blue-shifted region62.
Very recently, nanomaterials have emerged to be used as the signaling unit for chemosensors. Zhu et al. demonstrated in situ sulfur-doped graphitic carbon nitride nanosheets (S-g-C3N4 NSs) for the detection of Cys in human serum using the ECL method. The ECL onset potential of S-g-C3N4 is shifted positively compared to g-C3N4 (without doped sulfur), likely because the presence of the doped sulfur atoms helps lower the potential barrier, leading to more free S-g-C3N4 \({\text{NS}}{{\text{s}}^{ \bullet - }}\) radicals and thus enhancing the electron-hole recombination efficiency. The ECL intensity of the off-on S-g-C3N4 NSs sensor is quenched by Cu2+ and is returned upon the addition of Cys due to Cu2+ and Cys having a higher coordination ability compared to Cu2+ and S-g-C3N4 NSs. This technique shows a wide linear curve from 20 nM to 0.2 mM with a LOD of 5 nM (S/N = 3)63.
Glutathione
In addition to Hcy and Cys, glutathione (GSH) is another important biothiols. GSH is a key endogenous antioxidant, the ratio of GSH (reduced form) and GSSG (oxidized form) is a marker of oxidative stress status. Abnormally high or low concentrations of GSH are closely linked to serious diseases associated with cancer, heart problems, aging and HIV64,65. Therefore, developing a portable and reliable method to quantify GSH levels is necessary. Recently, a new ECL platform was reported by Niu et al. The technique is based on the coreactant ECL of C-dots and S2O82−, amplified by Fe(CN)63−/4− redox couple, which can act as the hole-injector to convert more C-dots to \({\text{C - do}}{{\text{t}}^{ \bullet + }}\) to participate in the annihilation reaction. The system is used to detect GSH as the sulfhydryl groups of GSH can react with \(\text{SO}_4^{\bullet - }\), effectively quenching the ECL signal. Although the calibration curve is narrow (0.1–1 μΜ), the developed method demonstrated the potential application of C-dots in ECL chemosensors66.
Dopamine
Dopamine (DA) is a neurotransmitter in the central and peripheral nervous system, responsible for essential neuronal functions including emotion, movement, behavior, cognition, attention, learning, and memory67. Abnormal dopamine levels are associated with neurological disorders such as Alzheimer’s and Parkinson’s diseases68,69. Normal DA level is notably low (0.01–1 μΜ) in comparison with other interferences that exist in too high concentrations (i.e. normal range of ascorbic acid is 0.1–0.6mM). As a result, tremendous efforts have been made to develop highly sensitive, selective and reliable sensors for DA67,70.
Many authors applied new classes of luminophores to modified electrodes to detect DA based on the quenching effect via resonance energy transfer (RET) or energy transfer (ET). Wang et al. precisely doped mono-Cu+ into Cd-In-S super-tetrahedral chalcogenide nanoclusters (Cu@CdInS NCs) to introduce new Cu+/Cu2+ energy states to the system, enhancing its ECL signal. DA can interact with the negatively charged Cu@CdInS NCs and be oxidized by NC*, effectively quenching its ECL emission. Therefore, this material is immobilized on GCE via a dropcasting method to fabricate a DA sensor. The method shows a linear range from 0.5 μΜ to 100 μΜ with a LOD of 0.355 μΜ71. Another strategy was developed based on dual-stabilizers-capped CdSe quantum dots, which achieves a wide linear range of DA (from 10 nM to 3 μΜ) with a LOD of 3 nM. However, the fabrication process of this sensor is rather complex72.
Recently, ECL emission of organic nanoparticles received much attention due to their environment-friendliness, non-toxicity, diverse structures and flexible synthesis73. Feng et al. successfully synthesized silole-containing polymer nanodot (SCP dots) and proved their potential application in detecting quencher-related analytes. SCP dots were prepared by nano-precipitation method and exhibited a 100-fold enhancement of their ECL signal compared to SCP (cast on a modified GCE). SCP dots showed a linear range of dopamine levels from 0.05 to 10 μΜ with a detection limit of 50 nM74. This study shows the feasibility of using organic nanoparticles in ECL systems and ECL sensing as a substitute for toxic semiconductor quantum dots. However, challenges remain in controlling the particle size and shape of organic nanoparticles to improve their low diffusion coefficient and relatively weak ECL intensity73,75.
Tryptophan
Tryptophan (Trp) is a vital amino acid in the human body, having important functions in different biological processes. Trp is a precursor for serotonin (a neurotransmitter) and melatonin (a neurohormone). Trp is also a common antioxidant in the food industry and a biomarker in the pharmaceutical industry. Abnormalities in Trp levels could lead to serious health problems such as albinism, alkaptonuria, depression, etc76-78. Chen et al. were successful in applying the ECL technique to monitor Trp concentrations. The probe is an iridium (III) complex-based lab-on-a-molecule to detect multiple analytes (photoluminescence and UVVis for Cys/His and ECL for Trp). The concept relies on the electrochemical oxidation of indole which decreases the formation of electrogenerated excited states, thus quenching ECL emission. The developed method shows great selectivity over other interferences, but only achieved a non-linear correlation. Nevertheless, the design concept holds promising potential, especially for dealing with multianalyte detection in complex environments79.
Histidine
Histidine (His) an important α-amino acid which is involved in various important cellular functions, metabolism, and cell regulations. Abnormal levels of His are connected with various health problems such as pulmonary disease, chronic kidney disease, and psychological disorders80,81. Zhou et al. demonstrated the detection of His by synthesizing an iridium(III) solvent complex with acetonitrile ligand (Ir(ppy)2NCCH3) (Probe 2, Figure 3A). The reaction mechanism is attributed to the replacement of the solvent ligands by histidine. ECL intensity increased linearly upon addition of His from 0 to 46 μΜ with a LOD of 0.25 μΜ as shown in Figure 3B and 3C. The specificity of Probe 2 was also confirmed by testing with various amino acids such as Met, Gly, Lys, Phe, Val, Trp, and Leu (Figure 3D)82.
Hydrogen Sulfide
Hydrogen sulfide is the third member of the gas-otransmitter family and is believed to function as a neuromodulator in the brain. It is suggested that low levels of H2S may cause the dysfunction of cerebral microvasculature that results in Alzheimer’s disease83,84. Park et al. suggested a new design of a probe for detecting H2S by attaching o-(Azidomethyl)benzoate (AzMB) ester groups as the receptor unit on the main ligands (Probe 3). Sulfide selectively reacts with the ester groups of Probe 3, causing a structural change to the probe that results in an unfavorable electron transfer of tripropylamine radicals, significantly quenching the ECL intensity of Probe 3 (Figure 4A)85. Upon addition of NaHS, ECL emission was quenched and decreased linearly over the range of 40 to 140 μM (Figure 4B). The LOD achieved using ECL method is markedly lower (11 nM) compared to PL (photoluminescence) method. In addition, this probe has excellent selectivity across various anions, except for iodide ions because iodide adsorption on the electrode can hinder the oxidation process needed for ECL (Figure 4C)86.
Kim et al. designed an off-on probe by using dinitrophenyl (DNP) group as both the quencher unit and the receptor unit. The photo-induced electron transfer (PET) dinitrophenyl (DNP) moiety is either attached only on the ancillary ligand or on both the main and ancillary ligand. Both of the probes exhibit an increase of ECL signal in the presence of S2−. However, the absolute ECL intensity of (DND)2-Probe is substantially lower than that of DND-Probe, leading to a lower sensitivity, which can be rationalized by the presence of the DND moiety on the main ligand, which will form a hydroxyl group after reaction, destabilizing the HOMO level, thus impeding the electron transfer from the coreactant (tripropylamine). On the other hand, one more DND group leads to higher selectivity for (DND)2-Probe87.
Hypochlorous Acid (HOCl)
HOCl is an essential reactive oxygen species (ROS), produced from the reaction of hydrogen peroxide (H-2O2) and chloride ions (Cl−) catalyzed by myeloperoxidase enzyme (MPO). Properly controlled production of HOCl is necessary for the human body to respond to invading bacteria and pathogens. However, the overproduction of HOCl is related to diseases such as atherosclerosis, cancer, cardiovascular diseases, and rheumatoid arthritis34,88. Therefore it is necessary to monitor HOCl levels in the human body. Cao et al., for the first time, reported a ruthenium(II) complex-based chemosensor incorporating a quencher moiety (ferrocenyl moiety) with bipyridine- ruthenium(II) complex core through a reactive linker (hydrazine). Upon reaction with HOCl, the ferrocenyl quencher moiety will be released, turning on the luminescence signal of the bipyridine-ruthenium(II) complex. ECL signal is observed to increase as HOCl concentration increases in 25 mM PBS-ethanol (3:1, v/v) mixed solvent with 10 mM TPrA as coreactant89. Another chemosensor with a similar concept in which iridium is the metal core instead of ruthenium was also reported by the same research group90.
Pyrophosphate (P2O74−: PPi)
Pyrophosphate is a biologically important anion, having roles in processes such as DNA and RNA polymerization, adenosine triphosphate hydrolysis, cyclic adenosine monophosphate synthesis, etc. Abnormal PPi levels are a marker of numerous diseases such as cancer, arthritis or kidney stones91,92. Thus, quantification of PPi concentrations is of crucial importance for disease prevention. Shin et al. reported a novel probe with boron dipyrromethene as the signaling unit and a phenoxo-bridged bis(Zn2+-dipi-colylamine) as the receptor unit (Probe 4). The sensor can detect PPi based on an on-off mechanism similar to photo-induced electron transfer (PET) in which PPi forms a bridge with two Zn2+ cations, increasing the electron density on the nitrogen atoms of the two dipicolylamine moieties, allowing for electron donation from the HOMO of the (Probe 4-PPi) complex to the ground state of the excited boron dipyrromethene moiety, therefore effectively quenching the ECL emission (Figure 5A). Probe 4 shows a linear calibration curve from 6.6 to 13.3 μΜ with a LOD of 4.0 μΜ (Figure 5B, 5C). A competitive binding assay demonstrated high selectivity over other anions such as iodide, chloride or phosphate-containing anions such as adenosine-5’-triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) (Figure 5D, 5E)93.
Xu et al. reported another sensor for pyrophosphate, also employing graphite carbon nitride nano-sheets (g-C3N4 NSs). The g-C3N4 NSs show intense ECL intensity, which is quenched in the presence of Cu2+ via photo-induced electron transfer (PET). The ECL signal of the system can be recovered upon the addition of PPi anion due to the strong affinity of Cu2+ with PPi. Cathodic ECL conducted using 10mM S2O82− as co-reactant can detect PPi in the linear range of 2.0 nM to 800 nM with a LOD of 75 pM. The approach also shows good selectivity over other interferences and can quantify PPi in synovial fluid successfully94.
Vitamins
Vitamin B2 (also known as riboflavin) is an essential element required in various cellular processes, such as the metabolism of fats, carbohydrates, and proteins. Vitamin B2 is a water-soluble vitamin that cannot be produced by the human body and can only be consumed through food or medicine supplements95. The variation of vitamin B2 levels needs to be monitored to diagnose health problems such as skin rashes96. Wang et al. successfully fabricated a sensor based on graphitic carbon nitride quantum dots (g-CNQDs). ECL signal is emitted in the presence of K2S2O8 as a coreactant and can be quenched via resonance energy transfer upon the addition of riboflavin (vitamin B2). In this system, g-CNQDs act as the donor and riboflavin (the analyte) as the receptor. The sensor exhibits a linear range from 0.02 μM to 11 μM with a LOD of 0.63 nM with good selectivity. The approach also proves its potential practical application with high recovery in the human serum97.
Conclusion and Prospects
While fluorescent chemosensors or colorimetric chemosensors have been in existence for a long time, ECL chemosensors have a rather short history. However, one can still witness the rapid expansion of this particular field, not only in terms of chemosensing design concepts but also the various analytes detected using ECL chemosensors. In this review, we introduced outstanding studies on electrochemiluminescent chemosensors for clinical applications. ECL chemosensors have attracted much attention due to the high demand for novel, cutting-edge, portable and reliable sensors with high sensitivity and selectivity to detect more and more analytes in human healthcare. In the future, electrochemiluminescent chemosensors for clinical applications still have broad space for development. As novel concepts need to be developed to design new sensors that can detect more analytes. This is an important mission as more evidence for the correlations between biomarkers and biological processes are being discovered. It is also crucial to develop sensors that can accurately quantify analytes and overcome reproducibility and selectivity issues caused by various interferences in highly complex environments such as human serum or blood.
Conflict of Interests
The authors declare no competing financial interests
References
Patil, A. & Salunke-Gawali, S. Overview of the chemosensor ligands used for selective detection of anions and metal ions (Zn2+, Cu2+, Ni22+, Co2+, Fe2+, Hg2+). Inorg. Chim. Acta 482, 99–112 (2018).
Czarnik, A.W. Chemical Communication in Water Using Fluorescent Chemosensors. Acc. Chem. Res. 27, 302–308 (1994).
Czarnik, A.W. Supramolecular Chemistry, Fluorescence, and Sensing. in Fluoresc. Chemosens. Ion Mol. Recognit. (ed. Czarnik, A.W.) 1–9 (American Chemical Society, Washington, DC, 1993).
Parkesh, R., Veale, E.B. & Gunnlaugsson, T. Fluorescent Detection Principles and Strategies. in Chemosensors 229–252 (John Wiley & Sons, Inc., Hoboken, NJ, USA, 2011).
Huston, M.E., Haider, K.W. & Czarnik, A.W. Chelation enhanced fluorescence in 9,10-bis[[(2-(dimethylamino) ethyl)methylamino]methyl]anthracene. J. Am. Chem. Soc. 110, 4460–4462 (1988).
Huston, M.E., Engleman, C. & Czarnik, A.W. Chelatoselective fluorescence perturbation in anthrylazamacrocycle conjugate probes. Electrophilic aromatic cadmiation. J. Am. Chem. Soc. 112, 7054–7056 (1990).
Akkaya, E.U., Huston, M.E. & Czarnik, A.W. Chelation-Enhanced Fluorescence of Anthrylazamacrocycle Conjugate Probes in Aqueous Solution. J. Am. Chem. Soc. 112, 3590–3593 (1990).
de Silva, A.P. & de Silva, S.A. Fluorescent signalling crown ethers; ‘switching on’ of fluorescence by alkali metal ion recognition and binding in situ. J. Chem. Soc., Chem. Commun. 1709–1710 (1986).
Bryan, A.J., de Silva, A.P., De Silva, S.A., Rupasinghe, R.A.D.D. & Sandanayake, K.R.A.S. Photoinduced electron transfer as a general design logic for fluorescent molecular sensors for cations. Biosensors 4, 169–179 (1989).
de Silva, A.P., Gunaratne, H.Q.N., Gunnlaugsson, T. & Nieuwenhuizen, M. Fluorescent switches with high selectivity towards sodium ions: correlation of ion-induced conformation switching with fluorescence function. Chem. Commun. 16, 1967–1968 (1996).
Minta, A. & Tsien, R.Y. Fluorescent indicators for cytosolic sodium. J. Biol. Chem. 264, 19449–19457 (1989).
Minta, A., Kao, J.P. & Tsien, R.Y. Fluorescent indicators for cytosolic calcium based on rhodamine and fluorescein chromophores. J. Biol. Chem. 264, 8171–8178 (1989).
Sousa, L.R. & Larson, J.M. Crown ether model systems for the study of photoexcited state response to geometrically oriented perturbers. The effect of alkali metal ions on emission from naphthalene derivatives. J. Am. Chem. Soc. 99, 307–310 (1977).
Fang, H., Kaur, G. & Wang, B. Progress in Boronic Acid-Based Fluorescent Glucose Sensors. J. Fluoresc. 14, 481–489 (2004).
Dabrowski, M., Sharma, P.S., Iskierko, Z., Noworyta, K., Cieplak, M., Lisowski, W., Oborska, S., Kuhn, A. & Kutner, W. Early diagnosis of fungal infections using piezomicrogravimetric and electric chemosensors based on polymers molecularly imprinted with d-arabitol. Biosens. Bioelectron. 79, 627–635 (2016).
Peng, H., Chen, W., Cheng, Y., Hakuna, L., Strongin, R. & Wang, B. Thiol Reactive Probes and Chemosensors. Sensors 12, 15907–15946 (2012).
Pina Luis, G., Granda, M., Granda, M., Badía, R. & Díaz-García, M.E. Selective fluorescent chemosensor for fructose. Analyst 123, 155–158 (1998).
Cozzini, P., Ingletto, G., Singh, R. & Dall’Asta, C. Mycotoxin Detection Plays “Cops and Robbers”: Cyclodextrin Chemosensors as Specialized Police? Int. J. Mol. Sci. 9, 2474–2494 (2008).
Xu, Y., Niu, X., Zhang H., Xu, L., Zhao, S., Chen. H. & Chen, X. Switch-on Fluorescence Sensing of Glutathione in Food Samples Based on a Graphitic Carbon Nitride Quantum Dot (g-CNQD)-Hg2+ Chemosensor. J. Agric. Food Chem. 63, 1747–1755 (2015).
Lee, M.H., Wu, J.S., Lee, J.W., Jung, J.H. & Kim, J. S. Highly Sensitive and Selective Chemosensor for Hg2+ Based on the Rhodamine Fluorophore. Org. Lett. 9, 2501–2504 (2007).
Jung, J.H., Lee, J.H. & Shinkai, S. Functionalized magnetic nanoparticles as chemosensors and adsorbents for toxic metal ions in environmental and biological fields. Chem. Soc. Rev. 40, 4464–4474 (2011).
Guo, Z., Song, N.R., Moon, J.H., Kim, M., Jun, E.J., Choi, J., Lee, J.Y., Bielawski, C.W., Sessler, J.L. & Yoon, J. A Benzobisimidazolium-Based Fluorescent and Colorimetric Chemosensor for CO2. J. Am. Chem. Soc. 134, 17846–17849 (2012).
Wang, B. & Anslyn, E. Detection Methods in Chemosensing. in Chemosens. Princ. Strateg. Appl. 227–228 (Hoboken, NJ, USA, 2011).
de Silva, A.P., Gunaratne, H.Q., Gunnlaugsson, T., Huxley, A.J., McCoy, C.P., Rademacher, J.T. & Rice, T.E. Signaling Recognition Events with Fluorescent Sensors and Switches. Chem. Rev. 97, 1515–1566 (1997).
Kim, J.S. & Duong, T.Q. Calixarene-Derived Fluorescent Probes. Chem. Rev. 107, 3780–3799 (2007).
Rogers, C.W. & Wolf, M.O. Luminescent molecular sensors based on analyte coordination to transition-metal complexes. Coord. Chem. Rev. 233-234, 341–350 (2002).
Chen, X., Pradhan, T., Wang, F., Kim, J.S. & Yoon, J. Fluorescent Chemosensors Based on Spiroring-Opening of Xanthenes and Related Derivatives. Chem. Rev. 112, 1910–1956 (2012).
Ma, Y., Liang, H., Zeng, Y., Yang, H., Ho, C.-L., Xu, W., Zhao, Q., Huang, H. & Wong, W.-Y. Phosphorescent soft salt for ratiometric and lifetime imaging of intracellular pH variations. Chem. Sci. 7, 3338–3346 (2016).
Richter, M.M. Electrochemiluminescence (ECL). Chem. Rev. 104, 3003–3036 (2004).
Hercules, D.M. Chemiluminescence Resulting from Electrochemically Generated Species. Science 145, 808–809 (1964).
Visco, R.E. & Chandross, E.A. Electroluminescence in Solutions of Aromatic Hydrocarbons. J. Am. Chem. Soc. 86, 5350–5351 (1964).
Santhanam, K.S.V. & Bard, A.J. Chemiluminescence of Electrogenerated 9,10-Diphenylanthracene Anion Radical. J. Am. Chem. Soc. 87, 139–140 (1965).
Miao, W. Electrogenerated Chemiluminescence and Its Biorelated Applications. Chem. Rev. 108, 2506–2553 (2008).
Kim, T.I., Park, S., Choi, Y. & Kim, Y. A BODIPY-Based Probe for the Selective Detection of Hypochlorous Acid in Living Cells. Chem. Asian J. 6, 1358–1361 (2011).
Li, J., Li, X., Zhang, Y., Li, R., Wu, D., Du, B., Zhang, Y., Ma, H. & Wei, Q. Electrochemiluminescence sensor based on cationic polythiophene derivative and NH2 —graphene for dopamine detection. RSC Adv. 5, 5432–5437 (2015).
Zheng, Z.-B., Duan, Z.-M., Ma, Y.-Y. & Wang, K.-Z. Highly Sensitive and Selective Difunctional Ruthenium(II) Complex-Based Chemosensor for Dihydrogen Phosphate Anion and Ferrous Cation. Inorg. Chem. 52, 2306–2316 (2013).
Kim, H.J., Lee, K.-S., Jeon, Y.-J., Shin, I.-S. & Hong, J.-I. Electrochemiluminescent chemodosimeter based on iridium(III) complex for point-of-care detection of homocysteine levels. Biosens. Bioelectron. 91, 497–503 (2017).
Tang, Y., Xu, J., Xiong, C., Xiao, Y., Zhang, X. & Wang S. Enhanced electrochemiluminescence of gold nanoclusters via silver doping and their application for ultrasensitive detection of dopamine. Analyst 144, 2643–2648 (2019).
Zhu, X., Kou, F., Xu, H. & Yang, G.A rapid and sensitive electrochemiluminescent sensor for nitrites based on C3N4 quantum dots on C3N4 nanosheets. RSC Adv. 6, 105331–105337 (2016).
Bard, A.J. Electrogenerated chemiluminescence. (Marcel Dekker, New York, 2004).
Bard, A.J. & Faulkner, L.R. Electrochemical methods: fundamentals and applications. (Wiley, 2000).
Strimbu, K. & Tavel, J.A. What are biomarkers? Curr. Opin. HIV AIDS 5, 463–466 (2010).
Nimse, S.B., Sonawane, M.D., Song, K.-S. & Kim, T. Biomarker detection technologies and future directions. Analyst 141, 740–755 (2016).
Swierczewska, M., Liu, G., Lee, S. & Chen, X. High-sensitivity nanosensors for biomarker detection. Chem. Soc. Rev. 41, 2641–2655 (2012).
Wu, L. & Qu, X. Cancer biomarker detection: recent achievements and challenges. Chem. Soc. Rev. 44, 2963–2997 (2015).
Rezaei, B., Ghani, M., Shoushtari, A.M. & Rabiee, M. Electrochemical biosensors based on nanofibres for cardiac biomarker detection: A comprehensive review. Biosens. Bioelectron. 78, 513–523 (2016).
Shui, B., Tao, D., Florea, A., Cheng, J., Zhao, Q., Gu, Y., Li, W., Jaffrezic-Renault, N., Mei, Y. & Guo, Z. Biosensors for Alzheimer’s disease biomarker detection: A review. Biochimie 147, 13–24 (2018).
Sun, J., Sun, H. & Liang, Z. Nanomaterials in Electrochemiluminescence Sensors. ChemElectroChem 4, 1651–1662 (2017).
Xu, Y., Liu, J., Gao, C. & Wang, E. Applications of carbon quantum dots in electrochemiluminescence: A mini review. Electrochem. commun. 48, 151–154 (2014).
Wei, H. & Wang, E. Electrochemiluminescence of tris(2,2′-bipyridyl)ruthenium and its applications in bioanalysis: a review. Luminescence 26, 77–85 (2011).
LI, S.-P., GUAN, H.-M., XU, G.-B. & TONG, Y.-J. Progress in Molecular Imprinting Electrochemiluminescence Analysis. Chin. J. Anal. Chem. 43, 294–299 (2015).
Liu, Z., Qi, W. & Xu, G. Recent advances in electrochemiluminescence. Chem. Soc. Rev. 44, 3117–3142 (2015).
Li, L., Chen, Y. & Zhu, J.-J. Recent Advances in Electrochemiluminescence Analysis. Anal. Chem. 89, 358–371 (2017).
Seshadri, S., Beiser, A., Selhub, J., Jacques, P.F., Rosenberg, I.H., D’Agostino, R.B., Wilson, P.W. & Wolf, P.A. Plasma Homocysteine as a Risk Factor for Dementia and Alzheimer’s Disease. N. Engl. J. Med. 346, 476–483 (2002).
Jakubowski, H., Ambrosius, W.T. & Pratt, J.H. Genetic determinants of homocysteine thiolactonase activity in humans: implications for atherosclerosis. FEBS Lett. 491, 35–39 (2001).
Matsuyama, N., Yamaguchi, M., Toyosato, M., Takayama, M. & Mizuno, K. New enzymatic colorimetric assay for total homocysteine. Clin. Chem. 47, 2155–2157 (2001).
Stewart, A.J., Brown, K. & Dennany, L. Cathodic Quantum Dot Facilitated Electrochemiluminescent Detection in Blood. Anal. Chem. 90, 12944–12950 (2018).
Slivka, A. & Cohen, G. Brain ischemia markedly elevates levels of the neurotoxic amino acid, cysteine. Brain Res. 608, 33–37 (1993).
Choi, Y.W., Lee, J.J., You, G.R. & Kim, C. Fluorescence ’on-off-on’ chemosensor for the sequential recognition of Hg2+ and cysteine in water. RSC Adv. 5, 38308–38315 (2015).
Shahrokhian, S. Lead Phthalocyanine as a Selective Carrier for Preparation of a Cysteine-Selective Electrode. Anal. Chem. 82, 5972–5978 (2001).
Xie, H., Li, X., Zhao, L., Han, L., Zhao, W. & Chen, X. Electrochemiluminescence performance of nitroolefin-based fluorescein in different solutions and its application for the detection of cysteine. Sens. Actuators, B 222, 226–231 (2016).
Kim, T. & Hong, J.-I. Photoluminescence and Electrochemiluminescence Dual-Signaling Sensors for Selective Detection of Cysteine Based on Iridium (III) Complexes. ACS Omega 4, 12616–12625 (2019).
Zhu, R., Zhang, Y., Fang, X., Cui, X., Wang, J., Yue, C., Fang, W., Zhao, H. & Li, Z. In situ sulfur-doped graphitic carbon nitride nanosheets with enhanced electrogenerated chemiluminescence used for sensitive and selective sensing of l -cysteine. J. Mater. Chem. B 7, 2320–2329 (2019).
Townsend, D.M., Tew, K.D. & Tapiero, H. The importance of glutathione in human disease. Biomed. Pharmacother. 57, 145–155 (2003).
Niu, L.-Y., Guan, Y.-S., Chen, Y.-Z., Wu, L-Z., Tung, C.-H. & Yang, Q.-Z. BODIPY-Based Ratiometric Fluorescent Sensor for Highly Selective Detection of Glutathione over Cysteine and Homocysteine. J. Am. Chem. Soc 134, 18928–18931 (2012).
Niu, W.-J., Zhu, R.-H., Cosnier, S., Zhang, X.-J. & Shan, D. Ferrocyanide-Ferricyanide Redox Couple Induced Electrochemiluminescence Amplification of Carbon Dots for Ultrasensitive Sensing of Glutathione. Anal. Chem. 87, 11150–11156 (2015).
Salamon, J., Sathiskumar, Y., Ramachandran, K., Lee, Y.S., Yoo, D.J., Kim, A.R. & Gnana Kumar, G. One-pot synthesis of magnetite nanorods/graphene composites and its catalytic activity toward electrochemical detection of dopamine. Biosens. Bioelectron. 64, 269–276 (2015).
Martorana, A. & Koch, G. ‘Is dopamine involved in Alzheimer’s disease?’ Front. Aging Neurosci. 6, 252 (2014).
Triarhou, L.C. Dopamine and Parkinson’s Disease. (2013).
Xu, G., Jarjes, Z. A., Desprez, V., Kilmartin, P. A. & Travas-Sejdic, J. Sensitive, selective, disposable electrochemical dopamine sensor based on PEDOT-modified laser scribed graphene. Biosens. Bioelectron. 107, 184–191 (2018).
Wang, F., Lin, J., Wang, H., Yu, S., Cui, X., Ali, A., Wu, T. & Liu, Y. Precise mono-Cu+ ion doping enhanced electrogenerated chemiluminescence from Cd-In-S supertetrahedral chalcogenide nanoclusters for dopamine detection. Nanoscale 10, 15932–15937 (2018).
Liu, S., Zhang, X., Yu, Y. & Zou, G. A Monochromatic Electrochemiluminescence Sensing Strategy for Dopamine with Dual-Stabilizers-Capped CdSe Quantum Dots as Emitters. Anal. Chem. 86, 2784–2788 (2014).
Suk, J. & Bard, A.J. Electrochemistry and electrogenerated chemiluminescence of organic nanoparticles. J. Solid State Electrochem. 15, 2279–2291 (2011).
Feng, Y., Dai, C., Lei, J., Ju, H. & Cheng, Y. Silole-Containing Polymer Nanodot: An Aqueous Low-Potential Electrochemiluminescence Emitter for Biosensing. Anal. Chem. 88, 845–850 (2016).
Omer, K.M., Ku, S.-Y., Cheng, J.-Z., Chou, S.-H., Wong, K.-T. & Bard, A.J. Electrochemistry and Electrogenerated Chemiluminescence of a Spirobifluorene-Based Donor (Triphenylamine)-Acceptor (2,1,3-Benzothiadiazole) Molecule and Its Organic Nanoparticles. J. Am. Chem. Soc. 133, 5492–5499 (2011).
Li, H. Wang, Y., Ye, D., Luo, J., Su, B., Zhang, S. & Kong, J. An electrochemical sensor for simultaneous determination of ascorbic acid, dopamine, uric acid and tryptophan based on MWNTs bridged mesocellular graphene foam nanocomposite. Talanta 127, 255–261 (2014).
Keyvanfard, M., Shakeri, R., Karimi-Maleh, H. & Alizad, K. Highly selective and sensitive voltammetric sensor based on modified multiwall carbon nanotube paste electrode for simultaneous determination of ascorbic acid, acetaminophen and tryptophan. Mater. Sci. Eng. C 33, 811–816 (2013).
Yokuş, Ö.A., Kardaş, F., Akyıldırım, O., Eren, T., Atar, N. & Yola, M.L. Sensitive voltammetric sensor based on polyoxometalate/reduced graphene oxide nanomaterial: Application to the simultaneous determination of l-tyrosine and l-tryptophan. Sens. Actuators, B 233, 47–54 (2016).
Chen, K. & Schmittel, M. An iridium(iii)-based labon-a-molecule for cysteine/homocysteine and tryptophan using triple-channel interrogation. Analyst 138, 6742–6745 (2013).
Shen, R., Zou, L., Wu, S., Li, T., Wang, J., Liu, J. & Ling, L. A novel label-free fluorescent detection of histidine based upon Cu2+-specific DNAzyme and hybridization chain reaction. Spectrochim. Acta, Part A 213, 42–47 (2019).
Watanabe, M., Suliman, M.E., Qureshi, A.R., Garcica-Lopez, E., Bárány, P., Heimbürger, O., Stenvinkel, P. & Lindholm, B. Consequences of low plasma histidine in chronic kidney disease patients: associations with inflammation, oxidative stress, and mortality. Am. J. Clin. Nutr. 87, 1860–1866 (2008).
Zhou, Y., Xie, K., Kong, L., Chen, F. & Sun, D. Highly selective Electrochemiluminescent probe to histidine. J. Electroanal. Chem. 799, 122–125 (2017).
Eto, K., Asada, T., Arima, K., Makifuchi, T. & Kimura, H. Brain hydrogen sulfide is severely decreased in Alzheimer’s disease. Biochem. Biophys. Res. Commun. 293, 1485–1488 (2002).
Papapetropoulos, A., Pyriochou, A., Altaany, Z., Yang, G., Marazioti, A., Zhou, Z., Jeschke, M.G., Branski, L.K., Herndon, D.N., Wang, R. & Szabó, C. Hydrogen sulfide is an endogenous stimulator of angiogenesis. Proc. Natl. Acad. Sci. U.S.A. 106, 21972–21977 (2009).
Park, J., Kim, T., Kim, H.J. & Hong, J.-I. Iridium (iii) complex-based electrochemiluminescent probe for H2S. Dalton Trans. 48, 4565–4573 (2019).
Zu, Y. & Bard, A.J. Electrogenerated Chemiluminescence. 66. The Role of Direct Coreactant Oxidation in the Ruthenium Tris(2,2’)bipyridyl/Tripropylamine System and the Effect of Halide Ions on the Emission Intensity. Anal. Chem. 72, 3223–3232 (2000).
Kim, S.-Y., Kim, H.J. & Hong, J.-I. Electrochemiluminescent chemodosimetric probes for sulfide based on cyclometalated Ir(iii) complexes. RSC Adv. 7, 10865–10868 (2017).
Xu, Q., Lee, K.A., Lee, S., Lee, K.M., Lee, W.J. & Yoon, J. A Highly Specific Fluorescent Probe for Hypochlorous Acid and Its Application in Imaging Microbe-Induced HOCl Production. J. Am. Chem. Soc. 135, 9944–9949 (2013).
Cao, L., Zhang, R., Zhang, W., Du, Z., Lium C., Ye, Z., Song, B. & Yuan, J. A ruthenium(II) complex-based lysosome-targetable multisignal chemosensor for in vivo detection of hypochlorous acid. Biomaterials 68, 21–31 (2015).
Zhang, F., Liang, X., Zhang, W., Wang, Y.L., Wang, H., Mohammed, Y.H., Song, B., Zhang, R. & Yuan, J. A unique iridium(III) complex-based chemosensor for multi-signal detection and multi-channel imaging of hypochlorous acid in liver injury. Biosens. Bioelectron. 87, 1005–1011 (2017).
Long, B.M., Pfeffer, F.M. & Barrow, C.J. Colorimetric semi-quantitative measurement of pyrophosphate by functionalised SPPS resin in biological media. Sens Actuators, B 243, 761–764 (2017).
Yang, J., Acharya, R., Zhu, X., Köse, M.E. & Schanze, K.S. Pyrophosphate Sensor Based on Principal Component Analysis of Conjugated Polyelectrolyte Fluorescence. ACS Omega 1, 648–655 (2016).
Shin, I.-S., Bae, S.W., Kim, H. & Hong, J.-I. Electrogenerated Chemiluminescent Anion Sensing: Selective Recognition and Sensing of Pyrophosphate. Anal. Chem. 82, 8259–8265 (2010).
Xu, H., Zhu, X., Dong, Y., Wu, H., Chen, Y. & Chi, Y. Highly sensitive electrochemiluminescent sensing platform based on graphite carbon nitride nanosheets for detection of pyrophosphate ion in the synovial fluid. Sens Actuators, B 236, 8–15 (2016).
Kundu, A., Nandi, S., Layek, R.K. & Nandi, A.K. Fluorescence Resonance Energy Transfer from Sulfonated Graphene to Riboflavin: A Simple Way to Detect Vitamin B2. ACS Appl. Mater. Interfaces 5, 7392–7399 (2013).
Powers, H.J. Riboflavin (vitamin B-2) and health. Am. J. Clin. Nutr. 77, 1352–1360 (2003).
Wang, H. Ma, Q., Wang, Y., Wang, C., Qin, D., Shan, D., Chen, J. & Lu, X. Resonance energy transfer based electrochemiluminescence and fluorescence sensing of riboflavin using graphitic carbon nitride quantum dots. Anal. Chim. Acta 973, 34–42 (2017).
Fähnrich, K.A., Pravda, M. & Guilbault, G.G. Recent applications of electrogenerated chemiluminescence in chemical analysis. Talanta 54, 531–559 (2001).
Acknowledgements
This work was supported by the Technology Innovation Program (10077599 and 1007 7648) funded by the Ministry of Trade, Industry & Energy, Korea. It was also supported by the Basic Science Research Program (NRF-2017R1D1A1B03028668) through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (MOE), and by Original Technology Research Program for Brain Science (NRF-2017M3A9D8029943) funded by Ministry of Science, ICT & Future Planning (MSIP).
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Truong, C.K.P., Nguyen, T.D.D. & Shin, IS. Electrochemiluminescent Chemosensors for Clinical Applications: A Review. BioChip J 13, 203–216 (2019). https://doi.org/10.1007/s13206-019-3301-9
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DOI: https://doi.org/10.1007/s13206-019-3301-9