Recent advances in chemiluminescence for reactive oxygen species sensing and imaging analysis

Microchemical Journal 146 (2019) 83–97

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Review article

Recent advances in chemiluminescence for reactive oxygen species sensing and imaging analysis Yingying Sua, Hongjie Songb, Yi Lva,b, a b

T

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Analytical & Testing Center, Sichuan University, Chengdu, Sichuan 610064, China College of Chemistry, Sichuan University, Chengdu, Sichuan 610064, China

ARTICLE INFO

ABSTRACT

Keywords: Chemiluminescence Reactive oxygen species Strategies Sensing Imaging

In this article, we reviewed the current state of chemiluminescence in reactive oxygen species (ROS) sensing and imaging with 132 references. The review is divided into three main sections. The first focuses on the various strategies used in ROS sensing and imaging; the second is organized by a series of detections and applications for five ROS, including hydrogen peroxide, hydroxyl radical, superoxide radical, singlet oxygen and peroxynitrite; and the last covers two individual ROS (hydrogen peroxide and superoxide radical) imaging and multiplex imaging (hydrogen peroxide and adenosine triphosphate, peroxynitrite or β-galactosidase) not only in vitro but also in vivo. Finally, the future trend is discussed.

1. Introduction Reactive oxygen species (ROS) are defined as relatively short-lived molecules that contain oxygen atoms, and their half-lives (t1/2) are in the range of nanoseconds to hours [1–3]. They are produced as molecules, ions and radials in many chemical and biological processes, such as hydrogen peroxide (H2O2), singlet oxygen (1O2), hypochlorite ion (ClO−), peroxynitrite (ONOO−), hydroxyl radical (·OH), hydroperoxyl radical ((HOO·), and the superoxide radical (O2%−). The roles they play differ significantly, depending on the types of ROS, the reactions they participate in, and the target molecules with which they react. In chemical processes, since ROS are highly reactive, they have been used widely, for instance, decomposing hazardous chemicals. In biological processes, ROS is a natural by-product of oxygen metabolism and plays an important role in cell signal transduction and homeostasis [4–7]. However, under environmental pressure (e.g., ionizing radiation), ROS levels can increase dramatically to cause oxidative stress, leading to cellular damages and various diseases including neurological disorders, cardiovascular diseases, lung diseases, various kinds of inflammation and cancer [8–12]. Therefore, identification, quantification, and kinetics evaluation of ROS in complex samples even in cells and in vivo are one of the most important issues in the chemical, biological, and medical fields. Due to the significance of ROS in chemical and biological processes, many approaches have been developed for detecting ROS. Electron spin resonance (ESR) is acknowledged as a traditional technique for

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measurement of ROS [13–15]. But its practical application is limited by the lack of spin trapping specificity, instability of the probes and high cost of ESR spectrometers. With high selectivity, simplicity of operation, temporal and spatial information about target molecules in complicate systems, fluorescence (FL) has become one mainly used mode of photoluminescence for the detection of ROS in biological analysis [16–18]. However, photobleaching of the fuorophores, photo-damage to the living organisms, background interference, and auto-fluorescence limit its application in long-term and dynamic monitoring. Chemiluminescence (CL), the light emission accompanied by chemical reactions, has been exploited in different fields such as food, pharmaceutical, biological and environmental industry and so on [19,20]. Since CL does not require light excitation and all CL reactions are based on redox reactions, CL analysis is especially applied for the detection of ROS. CL reagents such as luminol and luminol derivatives, imidazopyrazinone derivatives, lophine derivatives, lucigenin (Luc) and acridinium ester derivatives [21] have been used for determination of different ROS. Among them, luminol was selected as the standard CL reagent, and then twenty CL reagents for six types of ROS were comprehensively studied by Yamaguchi et al. [22]. Recently, since antioxidants in foods have received special attention due to their role in scavenging ROS, bis(2,4,6-trichlorophenyl) oxalate-Mn(II) CL system [23] and luminol‑potassium permanganate CL system [24] have been successfully used to monitor the antioxidant activity of oils and wine, respectively. In addition to the CL systems based on traditional CL reagents, the weak CL systems (e.g. peroxymonocarbonate (HCO4−) [25]

Corresponding author at: Analytical & Testing Center, Sichuan University, Chengdu, Sichuan 610064, China. E-mail address: [email protected] (Y. Lv).

https://doi.org/10.1016/j.microc.2018.12.056 Received 17 July 2018; Received in revised form 25 December 2018; Accepted 26 December 2018 Available online 29 December 2018 0026-265X/ © 2018 Elsevier B.V. All rights reserved.

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Fig. 1. CL mechanisms of luminol catalyzed by a) traditional catalyst and b) GO [43].

have also been developed for the determination of ROS. Recently, in order to enhance the intensity of CL, improve the selectivity of the methods and further expand new applications in ROS sensing and imaging, various materials acted as catalysts or luminophor have been employed. Up to now, nanoparticles (NPs), nanocluster (Au NCs, Cu NCs, Ag NCs and Zn/Cu NCs [25]), quantum dots (QD), metal–organic framework (MOF) have acted as catalysts in different CL systems for ROS. Meanwhile, luminescent materials which act as luminophor have also been designed and synthesized for ROS sensing. For instance, based on radiative recombination of %OH -injected holes and electrons in luminescent nanomaterials, CdTe QDs [26] and SiC NPs [27] were designed for the selective determination of %OH. Additionally, another two ways to obtain luminescent material as probes have been designed. One is polymer-based, allowing for encapsulation of the detector and signal transducer compounds, such as ROS-sensitive dyes; and the other is that the materials are functionalized by using CL regent, such as N-aminobutyl-N-ethylisoluminol (ABEI). In addition to these materials, some chemical reagents and some other strategies, such as self-immolation, conjugation and substituent effect and aggregationinduced emission (AIE) have been applied in the sensitive and selective detection of ROS in the recent years. For ROS imaging in vivo, many existing CL systems are not suitable. Take luminol for example, the highest reactivity of luminol must be obtained under basic conditions which are not available in vivo. In addition, the emission maximum of luminol is at a 425 nm wavelength that cannot offer deep depth imaging of ROS in organs. As a result, luminescent materials such as NPs based on QDs and luminol derivative (L012) with high enough CL intensity in physiological conditions [28], horseradish peroxidase (HRP) -SiO2@FFLuc NPs [29] and peroxalate NPs [30] that can produce near-infrared (NIR) light have developed rapidly. Among them, due to tunable wavelength emission and excellent specificity for H2O2 over other ROS, the peroxalate NPs have become the most excellent material for in vivo imaging of H2O2 since 2007 [30]. Very recently, peroxalate has been used as a chemical fuel to generate electronic excitation energy for H2O2, semiconducting polymers [31] instead of dye molecule [32] acting as bright NIR emitters have been adopted for H2O2 imaging in vivo. Based on chemiluminescence resonance energy transfer (CRET) between imidazopyrazinone (CLA) and conjugated polymers, a supersensitive imaging nanoprobe PCLA-O2%− for O2%− was proposed by Tang and coworkers [33]. The attractive probe was applied in mice to selectively visualize O2%− in normal/inflammation tissues. Although researches on the aspects of CL for ROS develop rapidly and more and more related literatures have been reported, a few related literature reviews especially on CL analysis for ROS have been

published. One of the excellent reviews was reported in 2006 by Lu et al. [34]. They extensively summarized CL systems for superoxide radical, singlet oxygen, hydroxyl radical, hydrogen peroxide and peroxynitrite, respectively. Several years later, although the detection of singlet oxygen [35] and the imaging of hydrogen peroxide [36] with CL probes were briefly mentioned in the reviews, it is essential to comprehensively summarize the latest developments in ROS sensing and imaging with CL. Therefore, this review summarized the recent advances of three aspects of CL for ROS, including the strategies (e.g. the introducing of materials), sensing of five ROS ((hydrogen peroxide, hydroxyl radical, singlet oxygen, superoxide radical and peroxynitrite) and two individual ROS (hydrogen peroxide and superoxide radical) imaging and multiplex imaging. The future prospects in this field are also discussed. 2. Strategies 2.1. Materials 2.1.1. Catalyst Recently, much attention has been extended to using different nanomaterials as new catalysts to enhance the inherent sensitivity and expand new applications [37,38], including the CL detection of ROS. The catalytic activity of water-soluble fluorescent Zn/Cu NCs [25] in NaHCO3-H2O2 CL system, and cubiform Co3O4 NPs [39], Ag NCs [40], MOFs Fe–MIL–88NH2 [41] and MIL-101(Fe)/Fe3O4 composites [42] in the luminol-H2O2 CL system were studied and developed as sensitive CL probes for H2O2, respectively. In NaHCO3-H2O2 CL system, HCO4– formed from the reaction of H2O2 and NaHCO3, and Zn/Cu@BSA NCs acted as catalysts facilitate the decomposition of HCO4– to generate the intermediate radicals, (% OH and %CO3−), then they react with H2O2 to form emitter intermediate 1O2. Simultaneously, %OH will react with excess HCO3−, forming emitter intermediate (CO2)2*, which decomposes to CO2, releasing energy to generate light. In luminol–H2O2 system, the decomposition of H2O2 is slow and the CL signal from the reaction of luminol and the decomposition product (%OH and O2%−) of H2O2 is weak. While when these nanomaterials acted as catalysts were introduced to the reaction, the decomposition of H2O2 is accelerated, producing more amounts of %OH and then O2%− to oxidized luminol and the enhancement CL was obtained (Fig. 1a). However, the enhancement mechanism is be entirely different when GO acted as catalyst [43]. In this work, 1O2 rather than %OH and O2%− that directly led to the CL generation and enhancement of luminol. As shown in Fig. 1b, GO catalyze the decomposition of H2O2 to yield OH· 84

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and O2%−. The recombination reaction of OH% and O2%− would take place to form a high yield of 1O2 on the surface of GO, then the produced 1O2 reacted with luminol anion, generating an unstable endoperoxide. The endoperoxide decomposed to the 3-APA*, which returned to the ground-state accompanied by an enhanced emission. The CL intensity with GO is six times higher than that without GO. Notably, not only the morphology and size of nanomaterials but also uniformity were found to have a great influence on their catalytic properties toward CL systems [44]. The study indicated that layered double hydroxides (LDHs) with the higher uniformity possess the more catalytic active sites, which are conductive to stimulate the generation of excited-stated intermediates and results in the CL enhancement. In a word, nanomaterials which possess more catalytic active sites is conductive to the enhancement of CL and the catalytic decomposition of H2O2 or HCO4– is a key step in the reaction process.

and coworkers designed SPNs-based H2O2 probe via CRET [31]. Afterwards, the mechanism of the SPNs-based CL process was studied by Zhen et al. [57]. They believed the CL of SPNs can be amplified by chemically initiated electron exchange luminescence (CIEEL). In order to prove the conclusion, five polyfluorene-based SPs with different molecular orbitals were respectively paired with peroxalate and transformed into CL SPNs. Among them, SPN-P14 had the highest chemiluminescence quantum yield and was successfully used to detect H2O2 in vitro. Same as peroxalate for H2O2, CLA is usually used to recognize O2%− [58,59]. Recently, a new polymer nanoprobe based on CRET for imaging of O2%− in mice has been reported by Tang and coworkers [60]. In this work, imidazopyrazinone acts as both recognition unit of O2%− and the energy donor, while conjugated polymers (CPs) act as both the energy acceptor and signal amplification matrix. Based on well-established response of CLA to O2%− and superior turn-on properties of tetraphenylethene (TPE), this group then developed a conjugated TPE-CLA probe as an example of FL/CL dual sensing platform, expecting simultaneous turn-on FL/CL signals specifically modulated by O2%− [61]. This double-signal probe was successfully used in real-time monitoring of O2%− in live cells.

2.1.2. Luminophor In the recent years, various materials also have been explored as luminophor for ROS sensing. Take QDs as an example, it is highly luminescence materials in a wide emission wavelength range from UV to NIR. QD–ROS interactions play a pivotal role in a wide variety of QD CL processes [45–47]. Interestingly, Lu and his coworkers found the special interaction between QDs and the radical pair from ONOO− could produce the CL emissions [48]. Their investigation showed that oxidized QDs (QDs%+) can be obtained when %OH from ONOOH inject a hole into the valence band (VB) of the CdTe QDs. Then the electrontransfer annihilation between QDs%+ and O2%− from ONOO− to form the excited QDs, which could emit light when they returned to the ground states. More importantly, other ROS cannot initiate the CL of CdTe QDs. So a probe for ONOO− with high selectivity has been designed. Additionally, there are two methods to design and synthesize the materials with CL property. One is that the material is functionalized by using CL regent, such as ABEI [49] and luminol [50]. The other is polymer-based, allowing for encapsulation of the detector and signal transducer compounds, such as ROS-sensitive dyes or incorporating a chemiluminescent substrate, peroxalate into the semiconducting polymers (SPs) which act as an emitting component. MOFs have broad application prospects in many areas, such as gas storage, electronics, catalysis and sensing. Fe-MIL-88NH2 has been used as a CL metalloimmunoassay labeling agent [51] or a catalyst [41] for luminol CL system. They are also excellent candidates for the preparation of materials as CL agent. Based on the interactions between the unsaturated metal sites of MIL-101(Cr) and the amino groups of luminol, luminol was loaded in the pores of MIL-101(Cr) and then a highly chemiluminescent MOF was obtained [50]. The first example of direct chemiluminescent MOFs (MOF 1) has been synthesized by Xie and Shao's group [52]. The side and the perspective views of MOF 1 were shown in Fig. 2a and b, respectively. In order to design the luminescent MOFs, (2E, 2′ E)-3,3′-(anthracene-9,10diyl) diacrylic acid (H2L, Fig. 2c) was selected as a ligand, and an anthracene moiety was incorporated into the framework. The emission spectrum of MOF 1 and H2L was shown in Fig. 2c. No light emission can be obtained for H2L. Covering MOF 1 with peroxalate CL (POCL) reaction solution, the photographs under ambient light and in the dark was taken (Fig. 2d). Bright light can be seen directly. Based on this, a selective visual sensor for hydrogen peroxide was developed. Semiconducting polymer nanoparticles (SPNs) have become a relatively new “family” of nanomaterials for the design and synthesis of optical probes [53]. Its fluorescence intensity is several orders of magnitude higher than that of small molecular clusters, and ten times more than that of QDs [54]. The major components of SPNs are SPs, which are polymers with π-electron backbones [55]. Therefore, the optical characteristics of SPNs are mostly determined by the molecular structure of SPs [56]. Incorporating a chemiluminescent substrate, peroxalate into the semiconducting polymer matrix of the SPNs, Rao

2.1.3. Support Owing to large specific surface area and high catalytic activity, layered nanomaterial has attracted wide publicity, and layered-nanomaterial-based CL detection systems have been summarized in the past years [62]. Among these materials, LDH, an important member of hostguest materials, has been widely used as a support in design of CL probes for various ROS. For instance, CoeFe layered double hydroxides (CoeFe LDHs) [63] and organic dye–LDH hybrids [64] have been used for sensitive determination of H2O2 and peroxynitrite, respectively. The role of LDHs as a support is accelerating the reaction or reducing the self-adsorption and nonradiative emission to amplify the CL signal. The other two layered-nanomaterials, GO and MMT acted as supports to design H2O2 [49,65] and %OH [66] probes have also been reported, respectively. Due to their various special charterers, layerednanomaterials have great potential in improving the sensitivity and selectivity of CL probes for ROS. 2.2. Chemical reagents Recently, some chemical reagents have also been used as catalysts in the CL reactions. Take iodophenol blue as an example. The catalytic activity on luminol-H2O2 CL reaction of the chemical indicator was found and employed to detect H2O2 and glucose [67]. Interaction between CuII and imidazolium rings of the cationic cores of Ionic liquids (ILs) leads to the enhancement of the catalytic activity of the complex [68]. In CL reactions, the catalytic activity of the complex is obviously higher than that of IL–free metal systems [69]. Based on this, CuII-ILs act as reaction media and catalyst for Luc-CL reaction was carried out and a new CL method for the detection of H2O2 and glucose was employed [70]. More importantly, the adding of ILs makes Luc-CL reaction be performed under near-neutral conditions. 2.3. Other strategies 2.3.1. Self-immolation and self-catalyzing Self-immolation enables the fragmentation of large molecules leading to the formation of multiple excited state anions which can trigger the CL process of 1, 2-dioxetanes with signal amplification. As a result, 1, 2-dioxetane based self immolative chemiluminogenic probe for H2O2 has been designed and synthesized recently [71]. With the addition of H2O2, boronate ester was deprotected. The self-immolation subsequently triggers the decomposition of 1, 2-dioxetane ring via CIEEL mechanism to emit light. Very recently, luminol-diazonium ion (N2+-luminol) has been found to have the peroxidase-like activity to catalyze the cleavage of 85

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Fig. 2. a) A side view of MOF 1; b) A perspective view of MOF 1; c) Chemiluminescence emission spectrum of MOF 1 and (2 E, 2′ E)-3,3′-(anthracene-9,10-diyl) diacrylic acid (H2L); d) Photographs of MOF 1 fixed on a watch glass by double-faced tape covered with the POCL reaction solution under ambient light (left) and in the dark(right), showing the direct CL emission [52].

H2O2. Using self-catalyzing CL, an attractive catalyst-free CL probe for ROS has been successfully designed [72]. The studies based on selfimmolation and self-catalyzing provide new insights into the CL probe for ROS.

electronically excited benzoate ester. In this design, the role of the acrylic acid substituent at the ortho position of the phenol is to form a donor–acceptor pair that increases the emissive nature of the benzoate intermediate. The addition of the chlorine substituent at the other ortho position reduces the pKa of the phenol and thus enriches the percentage of the phenoxy ion under physiological conditions. Consequently, the chemiexcitation kinetics of the phenoldioxetane is accelerated. The structure of CL probe (SOCL) and its chemiexcitation pathway upon reaction with 1O2 is shown in Fig.3.

2.3.2. Conjugation and substituent effect Generally, the direct CL generated by emission of the corresponding dioxetane probe in water is very weak. In order to search for new strategies besides self-immolation to amplify its CL emission that would enable biological use, Shabat and his coworkers conducted a series of outstanding work on designing of chemiluminescent dioxetane probes. They first designed a practical synthetic route to adamantylidene-dioxetane conjugated with fluorescent dyes [73]. Through the energy transfer from the typical excited benzoate to the attached fluorophore yielding a highly emissive intermediate, the chemiluminescent emission of such conjugates was significantly amplified under physiological conditions. In addition to the indirect CL pathway, they also achieved direct CL amplification by a striking substituent effect. In this strategy, an electron-withdrawing group (EWG) was introduced at the orthoposition of the phenol to the phenolate donor of benzoate ester III and such a donor−acceptor pair design increased the emissive nature of the benzoate species. This work is the first demonstration of cell-imaging achieved by a nonluciferin small-molecule probe with a direct CL mode of emission [74]. It is intriguing that they extended their methodology to develop the first NIR chemiluminescence turn-on probe that the CL luminophores with direct mode of NIR light emission was successfully designed and used detection and imaging of β-galactosidase and hydrogen peroxide in vivo [75]. It is based on incorporation of a substituent with an extended π-electron system on the excited species obtained during the chemiexcitation pathway of Schaap's adamantylidene− dioxetane probe. Since dicyano-methylchromone (DCMC)-based push-pull chromophores are known to produce NIR emissive dyes with decent fluorescence quantum yield and high photostability, the DCMC acceptor was chosen as substituent at the para position of the phenol. Based on substituent effect, they also designed a highly selective and sensitive CL probe (SOCL-CPP) for the detection of 1 O2 in living cells [76]. The probe reacts with 1O2 to generate a phenoldioxetane species, and then the species spontaneously decomposes in water through a chemiexcitation process to produce the corresponding

2.3.3. Aggregation-induced emission (AIE) The phenomenon of AIE was observed by Tang's group in 2001. For AIE molecules, no or weak light emission can be obtained in diluted solution, while high light emission can be obtained in concentrated solution. It is believed to be based on a mechanism of the restriction of intramolecular rotation [77]. Based on this concept, Lu's group used gold nanocluster aggregates to strongly enhance CL emission of bis (2,4,6-trichlorophenyl) oxalate (TCPO)−H2O2 CL system [78]. The new CL probe for H2O2 is quite sensitive even without any catalyst. Moreover, based on the nanoscopic coaggregation of a dye exhibiting AIE with a H2O2-responsive peroxalate, highly sensitive detection and visualization of H2O2 in vivo can be obtained and stage inflammation associated with H2O2 can be studied [32]. AIE was also employed to develop a novel organic platform TPECLA with simultaneous turn-on FL/CL signals specifically modulated by O2%− in cells, which can be attributed to the activation of AIE resulted from the decreasing solubility after recognition [61]. The strategy utilizing AIE to accomplish the FL/CL dual detection is expected to extend the application of AIE as reaction-activated biosensors. The low-bandgap polymeric structure is believed to be valid for the AIE activity. It has been skillfully used to fabricate a POCL nanoprobe for sensitive in vivo imaging of inflammation in murine models of arthritis and peritonitis [79]. In this work, CPPO, BODIPY and DPA-CNPPV were encased together to act chemical fuel and relay molecule and NIR emitter, respectively. Among them, DPA-CN-PPV was also used as the low-bandgap conjugated polymer, which showed a typical AIE behavior in the NIR with a maximum emission peaking at ~700 nm. The boosted NIR CL from energy-relayed CLNP-PPV/BDP is a key to realize the high sensitivity for H2O2 and a fairly high tissue penetration depth 86

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Fig. 3. Structure of 1O2 chemiluminescent probe SOCL and its chemiexcitation pathway upon reaction with 1O2 [76].

Fig. 4. (a) Schematic representation of the energy-relayed POCL NPs (CLNP-PPV/BDP) and intraparticle energy-relay between the encased molecules therein. Solid and dashed arrows indicate efficient and inefficient energy transfers, respectively; (b) CL signals of CLNP-PPV and CLNP-PPV/BDP through biological tissues of different thickness (stacked slices of ~3.0 mm-thick pork ham) [79].

(> 12 mm). The schematic of the energy-relayed POCL NPs (CLNPPPV/BDP) and intraparticle energy-relay between the encased molecules therein is shown in Fig. 4.

liquid samples [80]. This approach makes H2O2 measurements in near real time possible. However, a pretreatment step is necessary due to samples with high viscosity and narrow connectors and tubes. Recently, Moßhammer et al. introduced microdialysis probes (MDPs) to the FI AE-H2O2 CL system to overcome the restrictions [81]. The combined FIA-MDP approach was successfully used to continuously monitor H2O2 concentrations in different media and systems. It is also believed to have more potential applications in chemiluminescent reaction-based

2.3.4. Flow injection (FI) and continuous flow chemiluminescence (CFCL) system Flow injection (FI) combined with H2O2-acridinium esters (AE) CL reaction is frequently and well used for the determination of H2O2 in 87

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quantification of other ROS. ROS play very important roles in the photocatalytic reactions of semiconductors. Therefore, identification, quantification, and kinetics evaluation of ROS are of great significance to understanding the photodegradation mechanisms, improving degradation efficiency, and eventually utilizing the technology in practical applications. In previous research, a separate step is necessary to detect different ROS generated in semiconductor photocatalysis. As well known, some ROS can be produced during ultraviolet (UV) irradiation of semiconductor nanomaterials. Based on this, Wang et al. developed a CFCL system to develop CL methods for sensitive and online detection of O2%−, %OH, and H2O2 [82]. In this work, the irradiated TiO2 suspension and luminol were pumped continuously into a detection cell to detect O2%−. If the irradiated TiO2 suspension was kept in darkness for 30 min, it can be used to react with luminol/K3Fe(CN)6 to produce CL for the detection of H2O2. For %OH, it was captured by phthalhydrazide, and then mixed with H2O2/K5Cu(HIO6)2 to produce CL. The unique features of the new methods is the almost-real-time detection of O2%− and %OH radicals. This may provide a very convenient and low-cost tool for the studies of ROS generation kinetics in photocatalytic reactions.

hybrids exhibited excellent CL activity over a wide range of pH from 6.1 to 13.0 when reacted with H2O2. Besides HRP immobilization, new luminescent material which emits light under physiological conditions opens a window to design of new bioassays and biosensors. Carbon dots (CDs) has been widely used as new luminescent material in the recent years. The possible CL mechanism is believed from the production of excited-state CDs (CD*) which induced by the energy transfer from a reactive oxygen radical to CDs. However, oxidative agents or alkalines is needed. Co3O4 nanomaterial has been the excellent catalyst of decomposition of H2O2 to % OH radicals (a strong oxidative agent) at neutral pH. Based on this, Co3O4-cored carbon dots (CDs) was prepared subtly to act as a new type of luminescent probe for H2O2 in biological field [87]. Due to the good cellular permeability and low cytotoxicity of Co3O4-cored CDs and the high sensitivity (10 μM), the NPs was successfully used for the analysis of intracellular H2O2. In recent years, nonenzymatic POCL and self-catalyzing CL of N2+luminol [72] have been applied for sensitive detection or in vivo imaging of H2O2. These studies are introduced in section 4.1. 3.2. %OH

3. Sensing

%OH has a very strong oxidation capacity that can directly oxidize a lot of biological species [88]. To fully understand the roles of %OH in biology, the study of high selective and sensitive probes in biological systems has attracted much attention. Over the last few decades, a number of CL probes for %OH have been established based on its strong oxidation capacity [89,90]. However, because of the non specific redox reaction, many CL probes reported have low selectivity to OH. Fabricating new CL probes with high selectivity for %OH is a great challenge. A novel RhB–MMT composite material has been constructed to improve CL selectivity for %OH [66]. By π–π stacking interactions, π-electron density of aromatic ring of RhB aggregated on the surface of MMT can be increased, which promotes the attack of electrophilic %OH toward RhB to give strong light emission. The proposed method has been successfully used for the detection of %OH in untreated and gentamicin treated mouse fresh plasma samples. QDs-based optical probes for biorecognition and biosensing have been studied widely [91,92]. However, it is an enormous challenge to develop QD-based optical probe for a single ROS because all ROS can change the fluorescence or photoluminescence of QDs. Excitingly, among all ROS, only %OH can inject holes into the HOMO of the QDs and a novel QD-based CL probe for the specific detection of %OH was designed [26]. This CL probe for %OH was selective and validated by monitoring %OH in living cells. In environmental filed, %OH is an important atmospheric oxidant. It is produced by the reaction or decay of an energized carbonyl oxide and another atmospheric species [93]. Due to a close relationship between health effects and %OH in PM2.5, it is necessary to explore the sensitive and selective methods to directly determine %OH generation of PM2.5 from the environment. In recent years, our group did a series of work focused on selective and sensitive CL probes based on various nanomaterials, such as carbon nitride QDs [94–96], black phosphorus QDs [97] and Co MOF [98]. Very recently, SiC NPs has been synthesized by a one-step hydrothermal approach and a new CL probe for selective and sensitive detecting of %OH in PM2.5 was developed [27]. In our work, % OH injects holes into SiC NPs to form excited-state SiC NPs to emit light. In order to prove that %OH played a major role in the reaction, DMSO and ethanol, two different %OH scavengers were added in the system. As shown in Fig. 5a, the CL intensities were quenched remarkably, and DMSO exhibited better %OH scavenging ability than ethanol. It is in good agreement with the known reaction rate constants for the reaction of %OH with them [99]. Different ROS were investigated. As the results in Fig. 5b, no obvious CL can be observed by adding either ClO−, H2O2, 1O2, RO– or O2−, whereas a very strong CL was obtained in the presence of H2O2.

3.1. H2O2 Hydrogen peroxide, as a chemical and biological active oxidant, plays a crucial role in the oxidation and reduction processes in many environmental and biological fields. Thus, the accurate estimation of H2O2 in various chemical and biological samples is an important issue for environmental, food and clinical analysis. Of all the methods established, CL-based methods have been among the simplest and sensitive ones [34]. H2O2 widely exists in various environments and is the key substance to understand the mechanism of atmospheric photochemical pollution and the formation mechanism of acid [83]. In order to monitor the trace amounts of H2O2 in environmental samples, such as snow water, river water and lake water, several CL methods have been developed in recent years [25,84,85]. By the CL amplification of Co(II)-EDTA-intercalated MgeAl LDHs for luminol-H2O2 CL system [84], CTAB–CNS for Co(II)–H2O2–OH– CL system [85] and Zn/Cu NC capped with BSA for the weak NaHCO3 CL system [25], three different CL sensors have been designed for H2O2 in natural water with a detection limit of s 0.14 μM, 2.6 μM and s 0.3 nM, respectively. Among all the CL systems which are employed for the sensing of H2O2, luminol-H2O2 CL system plays an important role and a number of catalysts have been used in the system. For example, cubiform Co3O4 NPs [39] which act as a catalyst has been introduced to luminol-H2O2 CL reaction for the determination of H2O2 in exhaled breath condensate (EBC). The analysis of H2O2 in EBC is a new promising noninvasive technique in the early diagnosis and monitoring of inflammatory diseases [86]. In this work, the study of H2O2 concentration in EBC from feverish subjects, rheum subjects, and healthy subjects suggested that the average H2O2 concentration of EBC from feverish subjects was significantly high. Besides cubiform Co3O4 NPs [39] and Co(II)-EDTAintercalated MgeAl LDHs [84] mentioned above, Fe–MIL–88NH2 [41] and CoeFe LDHs [63] with effective peroxidase mimetic activity have been designed to amplified the CL signal of luminol–H2O2 reaction for the analysisH2O2 in milk samples. All of them acted as catalysts to promote the decomposition of H2O2 to generate O2%− and %OH radicals which were responsible for the luminol CL reaction. However, the alkaline media of luminol-H2O2 CL system seriously hinder its application in biological field. To overcome the weakness, HRP immobilization has become an efficient way. By synthesizing a bifunctionalized GO hybrids (ABEI-GO@HRP) with excellent CL property, enzyme specificity, solubility, and biocompatibility, a sensitive CL sensor for the quantification of H2O2 in urine was fabricated [49]. The 88

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Fig. 5. a) Effects of ethanol and dimethyl sulfoxide (DMSO) on the SiC NPs-%OH system.; b) ROS selectivity of the CL method. All data were expressed is CL intensity ratio of all ROS to %OH; c) Schematic illustration of CL mechanism in the SiC NPs-%OH CL system [27].

The study indicated that the SiC NPs exhibited highly selective CL response to %OH than other ROS. This CL probe can be used to monitor % OH generated from PM2.5 suspension. The CL mechanism of SiC NPs-% OH CL system is illustrated in Fig. 5c. From the recent research on %OH CL probes mentioned above, we can conclude that the property of %OH that the %OH/OH– couple displays the highest standard redox potential of all ROS is a key to improve the selectivity of %OH CL probes.

surfactant. The study helps to design new luminescence platforms for the rapid screening of photosensitizers during photodynamic therapy. In order to design CL probes for the detection of 1O2 with high sensitivity and selectivity, substituent effect was introduced [76]. The design of CL probe (SOCL) and the CL mechanism has been described before (Fig. 3). Furthermore, to increase the cell permeability of the probe, a cell-penetrating peptide (CPP) was covalently attached to the acrylic acid moiety of SOCL. SOCL-CPP demonstrated a promising ability to detect intracellular 1O2 produced by a photosensitizer in HeLa cells during the PDT mode of action. Compared to the previously known CL probes for 1O2, the probe exhibited significant advantages and superiority due to aqueous solubility and high emission intensity in water. Inspired by the study on CL luminophores with direct mode of NIR light emission for H2O2 [75], a new type of CL probe with NIR light emission for 1O2 sensing and imaging is expected.

3.3. Singlet oxygen In chemical and biochemical reactions, singlet oxygen is one of the most active intermediates involved. Studying it's the concentration is urgent in different fields. Due to the low level and the short lifetime (about 3 s) of 1O2, analytical methods have largely been based on fluorescence. However, its application is limited by background fluorescence and light scattering. As a result, CL has been studied to circumvent the limitations. 2-methyl-6-phenyl-3,7-dihydroimidazo(1,2α) pyrazin-3-one(CLA), 2-methyl-6-(p- methoxyphenyl)-3,7-dihydroimidazo(1,2α) pyrazin-3one(MCLA) and ABEI-bound microspheres have been widely used to construct CL probes for 1O2 [100–103]. However, these probes lack selectivity. Owing to a low electronegativity, tetrathiafulvalenem (TTF) and an anthracene luminophore has shown more selectivity for singlet oxygen [104–106]. Unfortunately, it is still developing slowly due to poor water solubility. Thus, stable dioxetane has been studied [107–109]. In these work, a trap-and-trigger detection method is employed. Singlet oxygen reacts with a probe to form the corresponding thermally stable dioxetane. By adding a chemical trigger, stable dioxetane can be decomposed to give off light. Not only CL regents mentioned above, materials and surfactants have been introduced to the studies of singlet oxygen involved CL [43,110]. Among them, a high yield of 1O2 has been found to be produced on the surface of GO [43] which acts a catalyst to decompose H2O2. It indicates that some materials such as GO have great potential to be new CL probes with high sensitivity and environmentally friendly nature. Except for GO, a surfactant, tetraphenylethene‑sodium dodecyl sulfonate has been found to amplify the intrinsic CL emission from 1O2 [110]. This was brought about mainly by AIE characteristics of the

3.4. Superoxide anion In biological systems, lucigenin and a luminol analog (L-012) have been used for the determination of superoxide anion [111]. However, they are limited by the restriction to the extracellular space or its propensity to enhance superoxide anion formation. Coelenterazine is known to react with superoxide anion in chemical systems and acts as a CL probe for superoxide anion [112]. Recently, it has been successfully used to quantify the dynamic changes of superoxide anion levels in vitro and in vivo [113]. CLA have been selected to recognize O2%− in biological analysis [58,114,115]. Recently, Tang's group has studied the CL system in detail. Based on CRET between CLA and CPs, a supersensitive nanoprobe was designed to detect O2%− with LOD down to picomole level [33]. Afterwards, an integrated sensing platform, which can be simultaneously turned on in signals of both FL and CL by O2%−, was developed by covalently linking TPE which acts as the prototypical AIE motif and CLA [61]. The LOD was estimated to be 0.21 nM for FL and 0.38 nM for CL. The FL/CL probe for O2%− is sensitive and selective enough and can be used for imaging O2%− in vitro and in vivo. From the two independent modes (FL and CL), more complementary information can be obtained simultaneously. As a result, the false results can be reduced and accuracy can be increased. 89

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3.5. Peroxynitrite

They did a series of outstanding work in this field. Firstly, they synthesized colloidal POCL nanoprobes filled with a highly reactive peroxalate (CPPO) and a typical NIR-emissive cyanine dye (Cy5). Due to NIR signal window and nanometer size, the POCL nanoprobe was successfully used for sensing and imaging H2O2 in vivo [123]. However, they found Cy5 with self-quenching of fluorescence will result in limited emission output. Therefore, they utilized a special dye (BLSA) that emits solid-state fluorescence (SSF) without typical self-quenching of fluorescence to replace Cy5, the CL intensity could be simply enhanced by one order of magnitude [32]. An intriguing aspect of the SSF-induced enhanced POCL (SSF-CL) is that the achieved detection limit is far below the normal physiological level of H2O2. Recently, based on their previous studies, a nanoreactor called “biolighted luminescent nanotorch (BioNT)” has been proposed by them [124]. SSF-CL is lighted and sustained by the reaction between nanoscopically confined fuels (peroxalates) and endogenous biological H2O2 and then extinguished after complete fuel consumption. BioNT and its constituents are shown in Fig. 6a. To construct SSF-incorporated POCL nanoreactors, an aqueous dispersion of dye/peroxalate coaggregates was formulated by excess loading of BDSA and CPPO within micellar NPs of a polymeric surfactant, Pluronic F-127. From the TEM and dynamic light-scattering (DLS) measurements, the average diameter and the number weighted hydrodynamic size of BioNT were estimated (Fig. 6b), respectively. The colloidal size was suitably engineered to be small enough for long systemic circulation. To control the duration of torchlight to be long enough for imaging a disease, they devised a simple way of tailoring the luminescence kinetics by loading the nanotorch with antioxidants. CL spectrum of water-dispersed BioNT was shown in Fig. 6c. After intravenous injection into a normal mouse, strong CL torchlight throughout the whole body was obtained. In order to further improve the stability of peroxalate in vivo environment and avoid rapid reduction of CL signals after in vivo administration, the multifunctional micelles [125] prepared by using Pluronic F-127 copolymers to form micelles and CL nanodroplets [126] fabricated by using a microemulsion method were introduced, respectively. The CL nanodroplets are made of soybean oil and a mixture of NIR BODIPY dye, Pluronic F-127 and CPPO. The better CL properties were obtained than those of oil-free NPs in detection of endogenous H2O2. In addition to the replacing common NIR dye with a special dye that emits SSF and the designing of multifunctional micelles or a microemulsion, SPs with the superior optical characteristics in NIR and photostablity has been introduced to design POCL probes for H2O2 imaging. Five polyfluorene-based SPs with different optoelectronic properties were chosen to fabricate SPNs by combining peroxalate TCPO and the mechanism of CIEEL was proposed [57]. In CIEEL, TCPO reacts with H2O2 to produce the intermediate (HEI), 1, 2-dioxetanedione. The intermediate obtains an electron from the SP and SP radical cations and the carbon dioxide radical anions are formed. Then, the excited SPs obtained by the combination of the cations and the anions give out light. By doping the SPNs with NIR775, the CL wavelength was red-shifted to the NIR region, and in vivo imaging of LPS was carried out. The reduced signals by remediation of GSH show the ability of the SPN-P14 probe to monitor the level of H2O2 in real-time. According to the mechanism of CIEEL, one important factor that improves the POCL intensity is the efficiency of energy transfer from the excited energy donor to the emitting component. Recently, a theoretical study has shown that CL efficiencies in POCL reaction are determined by the dye structure [127]. Based on these results, another interesting work on POCL in vivo imaging of H2O2 was reported by Kim's group [79]. As shown in Fig. 4, low-bandgap conjugated polymers and AIE-active dyes were combined to transform to a new non-conventional bright emitter. The energy gap between the new emitter and peroxalates was bridged by a co-doped ‘relay molecule’. It can effectively accept and relay the energy by AIE effects. Without complex chemical tuning of the emitter structure, this method was successfully

ONOO− from the diffusion-controlled reaction between nitric oxide and superoxide radicals can easily react with different biomolecules to produce highly reactive secondary radicals (e.g., hydroxyl radical and carbonate radicals), potentially leading to a lot of diseases, such as neurodegenerative, cardiovascular, and inflammatory disorders [116–118]. Therefore, accurate quantitation of ONOO− in living cells is vital. There are two reviews summarized the detection methods for ONOO− in 2001 [119] and 2006 [34], respectively. In CL methods for ONOO−, coelenterazine CL system and luminol CL system are initially introduced [120,121]. However, the selectivity is poor. Afterwards, although the new CL probe based on fluorescent CDs has been used for the determination of ONOO− in natural water and milk, it is still interfered with %OH [122]. To solve the problem, Lu and his coworkers have introduced fluorescence dye-LDH nanocomposite for ONOO– sensing [64]. The probe was fabricated by embedding trace calcein molecules on the LDH surfaces. A strong CL emission can be produced owing to CRET process between ONOOH* donor and calcein acceptor. The probe has been successfully used to detect ONOO− in cancer mouse plasma samples and monitor ONOO− generated from 3-morpholinosydnonimine (SIN−1). Since the interaction between QDs and the radical pair from ONOO− could produce the CL emissions by electrontransfer annihilation, the group developed another novel CL probe for ONOO− [48]. It also has been used to detect ONOO− generated from SIN−1 in living cells. These results indicate the materials provide a promising platform for the detection of ONOO− in biological systems. The summary of the analytical performance and application of various ROS CL probes reported in the review was shown in Table 1. 4. Imaging 4.1. H2O2 The development of numerous diseases such as cancer or cardiovascular disease will result in the overproduction of H2O2. Therefore, there is currently great interest in imaging H2O2 both in vitro and in vivo. Luminol is the most frequently CL reagent for detecting H2O2. However, the emission maximum of luminol is at a 425 nm wavelength that severely limited the offering of deep depth imaging in organs. As a result, luminescent materials such as NPs based on quantum dots with the maximum emission wavelength at about 800 nm and L012 with enough high CL intensity in physiological conditions was were designed for in vivo CL imaging of H2O2 [28]. In the work, PEGylated QDs (PEGQDs) was used as an acceptor, and L012 as a CRET donor. Based on the CRET, noninvasive in vivo NIR imaging of H2O2 in disease lesions was performed. Compare with luminol CL reaction, the POCL reaction also have high selectivity to H2O2. In the POCL reaction, H2O2 selectively oxidizes peroxalate to produce an intermediate (1, 2- dioxetanedione). Then the intermediate is used as CRET donor to transfer its high energy to nearby fluorescent molecules to produce luminescence. Thus, NPs which employ the characteristics of POCL reaction have great potential in imaging H2O2. The first work using peroxalate based CL probe as a contrast agent for imaging H2O2 in vivo was reported in 2007 [30]. It is formulated from the peroxalate polymer contained peroxalate ester and a fluorescent dye, pentacene with emission wavelength at 630 nm. A high-energy dioxetanedione intermediate within the NPs was produced by the action of peroxalate ester and H2O2. Then it chemically excites the encapsulated dye through the CIEEL mechanism to give light emission. Using the CL probe, imaging H2O2 generated by activated macrophages and neutrophils, in a lipopolysaccharide (LPS) model of acute inflammation was investigated in detail. Afterwards, POCL reaction has been further applied to in vivo imaging of inflammation by Kim's group [32,123]. 90

Co3O4@CDs acts as luminophor Co3O4 NPs acts as catalyst HRP acts as catalyst GO acts as support CTAB–CNS acts as catalyst Co(II) acts as catalyst; EDTA acts as remover for metal cations; MgeAl LDHs acts as support Zn/Cu NC @ BSA acts as catalyst Iodophenol blue acts as catalyst CuII-ILs acts as catalyst Fe-MIL-88NH2 acts as catalyst Co-Fe acts as catalyst; LDHs acts as support Catalyst-free

Co3O4@CDs-H2O2 Luminol-H2O2 ABEI-H2O2

91

CdT QD acts as luminophor

SiC NPs acts as Luminophor CRET(CLA-O2%− acts as a donor; TPE-SDS with AIE characteristics acts as an acceptor)

SOCL-CPP synthetizede by substituent effect (direct NIR emission mode) NP CRET (CLA-O2%− acts as a donor; CPs acts as an acceptor and signal amplification matrix) AIE; FL/CL platforms

Dialysis membrane sample CDs acts as luminophor CRET (ONOOH* donor acts as a donor; calcein acts as an acceptor; LDH acts as signal amplification matrix) CdTe QD acts as luminophor

CdT QD-%OH

SiC NPs-%OH NaIO4-H2O2

Dioxetane Coelenterazine-O2%− PCLA-O2%− TPE-CLA-O2%−

Luminol-ONOO− CDs-NaNO2-H2O2 Calcein@SDS-LDH- ONOO−

NP means no reported.

CdTe QD-ONOO−

POCL NPs-H2O2 RhB–MMT-%OH

Substituent effect (direct NIR emission mode) CRET (L012-H2O2 acts as a donor; PEGQDs acts as an acceptor.) CRET (CPPO-H2O2 acts as a donor; BDSA which shows strong reddish SSF acts as an acceptor) CRET (CPPO-H2O2 acts as a donor; Cy5 acts as an acceptor) CRET (CPPO-H2O2 acts as a donor; AEF active dyes acts as an acceptor) CRET (HPOX micelles-H2O2 acts as a donor; rubrene acts as an acceptor) CRET (CPPO-H2O2 acts as a donor; BODIPY dye acts as an efficient relay molecule and acts as an acceptor; NIR AIE polymer acts as an emitter) AIE; CRET (CPPO-H2O2 acts as a donor; NIR BODIPY dye acts as an acceptor) RhB acts as luminophor; MMT acts as support

Dioxetane L012-H2O2 POCL NPs-H2O2 POCL NPs-H2O2 POCL NPs-H2O2 POCL NPs-H2O2 POCL NPs-H2O2

Co(II)-H2O2-OH− Luminol-H2O2 NaHCO3-H2O2 Luminol-H2O2 Luc- H2O2 Luminol-H2O2 Luminol-H2O2 N2+-luminol-H2O2

Strategy

CL system

Table 1 Summary of the analytical performance and application of various CL probes for ROS.

ONOO−

ONOO− ONOO− ONOO−

0.46–46 μM

NP NP NP 0–55 μM (CL); 0–60 μM (FL) 80 fM–0.1 μM 0.1–10.0 μM 1.0–20.0 μM

1 O2 O2%− O2%− O2%−

%OH O2 1

%OH

1–500 nΜ 0.1–10.0 μΜ; 30–100 μΜ 0.1–3.0 μM; 5–50 μM 0.27–0.90 μΜ 1.0–100 μM

5–1000 μΜ 0.5–50 μΜ 5.0 nΜ–1.0 μΜ 0.025–10 μΜ 0.4 μΜ–10.0 mΜ 0.1–10.0 μΜ 10 nΜ–3.0 μΜ 0.1–2.0 μΜ 2.0–8.0 μΜ NP NP NP 0.5 nΜ–10 μΜ 0.1–10 μΜ 0.1–1 μΜ NP

NP 1.0–1000 nM 0.1 pM–10 nM

Linear range

H2O2 %OH

H2O2 H2O2 H2O2 H2O2 H2O2 H2O2 H2O2

H2O2 H2O2 H2O2 H2O2 H2O2 H2O2 H2O2 H2O2

H2O2 H2O2 H2O2

Species

0.1 μM

500 nM NP pM 0.38 nM (CL); 0.21 nM (FL) 10 fM 53 nM 0.3 μM

263.6 nM NP

35 nM

∼1 nM 31 nM

NP NP NP 0.5 nM ∼0.1 μΜ < 0.1 μΜ < 0.1 μΜ

2.6 μΜ 0.14 μΜ 0.3 nM 14 nM 0.1 μM 0.025 μM 9 nM 30 nM

10 μM 0.3 nM 47 fM

LOD

Good

Poor Interference: %OH Good

Good NP Good Good

Good Good

Good

Good Good

Good Good Good Good Good Good Good

Good Good Good Poor Poor Good Good Good

NP NP Good

Selectivity

vivo vivo vivo vivo vivo vivo vivo

imaging imaging imaging imaging imaging imaging imaging

Living cells

NP Natural water and milk Mouse plasma

PM2.5 Study the behaviors of photosensitizers NP Ex vivo and in vivo imaging In vivo imaging In vivo imaging

Living cells

In vivo imaging Mouse fresh plasma

In In In In In In In

Natural water Natural water Natural water Diluted serum Human serum and urine Milk Milk In vivo imaging

MCF 7 cells and HeLa cells Exhaled breath condensate Urine

Sample/Application

[48]

[121] [122] [64]

[76] [113] [33] [61]

[27] [110]

[26]

[79] [66]

[75] [28] [124] [123] [32] [125] [126]

[85] [84] [25] [67] [70] [41] [63] [72]

[87] [39] [49]

Ref.

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Fig. 6. (a) Schematic representation of BioNT. (b) Number averaged hydrodynamic size distribution and TEM image (inset) of BioNT. (c) CL spectrum of waterdispersed BioNT, taken at 10 s after addition of H2O2 (0.17 M). The inset shows photographs of the generated CL under room light (i) and in the dark (ii) [124].

used to sensitive image deep inflammation even in an unshaved murine model. A probe based on energy transfer is structurally based on a conjugate of two separated entities while a probe with a direct emission mode is a single entity, which results in the smaller in size. As a result, a probe with direct NIR emission mode will benefit for in vivo imaging. For this goal, the first CL dioxetane luminophores with direct mode of NIR light emission was designed as an excellent probe for in vivo imaging of endogenous H2O2 [75]. Based on this work, more probes with direct NIR emission mode are expected to image biologically relevant analytes in small animal models.

the energy receptors of CRET process. Based on CRET between imidazopyrazinone and CPs, a supersensitive imaging nanoprobe PCLA- O2%− for O2%− was designed [33]. The NPs preparation by “nanoprecipitation” and O2%− sensing of PCLA- O2%− and the structure of PCLA- O2%− was illustrated in Fig.7a. The CL signals showed good linearity with the concentration of O2%− from 0 to 950 pM (Fig. 7b). O2%− generated in both LPS-induced inflammation model and tumor model was successfully detected by the nanoprobe. Three-fold higher CL signals were obtained from tumor tissues after injecting the nanoprobe both in tumor and normal tissues. With the adding of a typical superoxide scavenger Tiron, CL signals were reduced, which indicated the decreasing of O2%− (Fig. 7c, d). It is the first time visualization of the O2%− native variance without stimulation in small animals. Very recently, an integrated sensing platform which can be simultaneously turned on in signals of both FL and CL by O2%− has been successfully by the same research group [61]. CLA is still used for response to O2%− and TPE act as the prototypical AIE motif. They covalently linked TPE and CLA to develop a conjugated TPE-CLA probe as an example of FL/CL dual sensing platform, expecting simultaneous turnon FL/CL signals specifically modulated by O2%−. TPE-CLA is composed of two CLA units for specific recognition and a TPE skeleton for AIE activation. The chemical structure of TPE-CLA and the proposed FL/CL turn-on mechanism is illustrated in Fig. 8a. It is important to note that the nonluminescence of TPE-CLA is the key point in rational design, which can be realized by the reasonable utilization of AIE effect. Endowed with some hydrophilicity by the relatively strong polarity, TPECLA is supposed to well disperse in aqueous media, experiencing no RIM and nearly nonluminescent. Upon recognizing O2%−, the CLA unit is first TPE-CLA successfully applied in imaging native O2%− in stimulated O2%− in inflamed mice (Fig.8b). From Fig. 8c, we can see that LPS-stimulated mice displayed strong CL and the signal was largely inhibited by Tiron, which demonstrated that TPE-CLA was able to monitor the endogenous O2%−. Additionally, FL images of O2%− in HL7702 cells stimulated by overdosed APAP (20 mg/mL) for different time was investigated.

4.2. Superoxide anion As the primary ROS, superoxide anion is produced during normal cellular respiration and plays a key role in cellular physiology. Therefore, dynamic quantification of this short-lived molecule with fine temporal resolution is demanded in cellular physiology and organismal biology. In particular, noninvasive in vivo imaging becomes an attractive avenue for elucidating its biological function. Coelenterazine is regarded as an ideal CL reagent for the determination of superoxide anion, which is in the neutrophilic oxidative burst [128] or produced from purified mitochondria [129]. It has also been used ex vivo and in vivo imaging for superoxide anion [113]. In ex vivo imaging, after intravenous injection in mice, prominent CL comes from both the pancreas and lung. In vivo imaging, after injecting coelenterazine at different doses, the upper-abdominal CL signal increased with the increasing doses of coelenterazine. The abdominal CL signal is partially mediated by superoxide anion production and that its concentration is dependent upon environmental cues. Coelenterazine imaging of superoxide anion was used to predict susceptibility to diabetes mellitus by employing the non-obese diabetic (NOD) mouse model, which is the predominant mouse model for type I diabetes. Besides coelenterazine, CLA has been proved to be good candidates for recognizing O2%− and applied to biological analysis of O2%− [33,130]. As mentioned in the last section, CRET is usually used in imaging because it effectively prolongs luminescence time and cause wavelength redshift. In the nonradiative resonance energy-transfer process, a higher efficiency can be achieved through covalent link between the acceptor and the donor than physical integration. In the meantime, CPs with distinguished signal amplification along the backbone and adjustable optical performance are suitable candidates as

4.3. Multiplex imaging Compared with imaging of individual molecules, multiple imaging of indicative molecules or biomarkers is more crucial in the diagnosis and study of disease. Imaging of ATP and H2O2 in biological samples is believed to be a 92

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Fig. 7. SPN-based activatable probes for chemiluminescence imaging of superoxide anion (O2%−). a) Schematic illustration of NPs preparation by “Nanoprecipitation” and O2%− sensing of PCLAO2%− and the structure of PCLA-O2%−. b) The linear relationship between chemiluminescence signals of the SPN-P16 probe and the concentration of O2%−. Inset, IVIS images of PCLA-O2%− probe in response to the indicated concentrations of O2%− with open filter (570 ± 10 nm). Representative images of mice (c) and the quantification (d) of luminescence signals for tumor (I), tumor+Tiron (II) and normal (III) tissues followed by injection of PCLA-O2%− probe. Images (λem = 570 nm ± 10 nm) were acquired using an IVIS Lumina II at 30 s after local administration of PCLA-O2%− probe [33].

model for Parkinson's disease, cellular and tissular damage, or some malignant tumors [28,131]. For multiplex imaging ATP and H2O2 in vivo, dual-functional NPs of HRPSiO2@FFLuc NPs with core–shell structures have been achieved [29]. The core and shell of the NPs are made of HRP and FFLuc, respectively. As well known, SiO2 components will be broken in vivo (weak acid condition). Then, HRP (outside SiO2 core) reacts with ATP to give light emission while FFLuc (inside of SiO2 core) is sequentially exposed to react with H2O2 to give light emission. It avoids the interference with each other. More importantly, the present HRP-SiO2@FFLuc NPs was employed to the in situ in vivo sequential imaging of ATP and H2O2 in mice. For ONOO− and H2O2 in biological samples, multiplex imaging of them is of great help to study the mechanism of drug-induced hepatotoxicity in vivo. Based on SPNs, Rao and coworkers presented some outstanding work in this field [132]. One of their studies is based on the

combination of CRET and FRET [31]. In their study, a near-infrared (NIR) fluorescent semiconducting polymer (PFODBT) (Fig. 9a), a cyanine dye (IR775S) (Fig. 9b), and a chemiluminescent substrate CPPO (Fig. 9c) were selected to design CRET-FRET-SP (CF-SP). In the presence of ONOO−, IR775S was oxidized and then the emission of PFODBT at 680 nm increased and the emission of IR775S at 820 nm decreased by FRET. In the presence of H2O2, the chemiluminescent reaction of CPPO (Fig. 9c) was induced and the CF-SPN emits at both 680 nm and 820 nm by CRET. The mechanism was shown in Fig. 9d. Since hepatotoxicity can result in the overproduction of H2O2 and ONOO−, the capability of real-time imaging of ONOO− and H2O2 was further tested in living mice suffered from hepatotoxicity (Fig. 9e). After challenging with the analgesic and anti-pyretic acetaminophen (APAP) or the chemotherapy agent isoniazid (INH), both the ratiometric fluorescence and CL signals increased, while the signals were Fig. 8. (a) Chemical Structure and Proposed Turn-on Mechanism of TPE-CLA, (b) CL image of O2%− in LPS-treated mice; (I) Saline + TPE-CLA (200 μM, 200 μL), (II) LPS (1 mg/mL, 200 μL) + TPE-CLA (200 μM, 200 μL), (III) LPS (1 mg/mL, 200 μL) + Tiron (20 mM, 200 μL) + TPE-CLA (200 μM, 200 μL). (c) Quantitative of CL intensity from groups (I − III). Data are presented as the mean ± SEM; ***p < 0.001. Results are representative of three independent experiments [61].

93

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Fig. 9. Design of CF-SPN for detection of ROS and RNS. Molecular components of CF-SPN are the NIR fluorescent semiconducting polymer PFODBT (a), a PEGgrafted poly(styrene) copolymer conjugated to galactose for hepatocyte targeting (PS-g-PEG-Gal), the FRET acceptor IR775S (b) that degrades after oxidation by ONOO− or −OCl (dark green), and the H2O2-specific chemiluminescent substrate CPPO (c) that serves as CRET energy donor. (d) Illustration of the mechanism of simultaneous and differential detection of ONOO− or − OCl and H2O2 by CF-SPN. (e). Representative images of mice receiving, from left to right, saline (−), 300 mg kg−1 APAP intraperitoneally alone, and 300 mg kg−1 APAP with GSH (200 mg kg−1, intravenously), 1-ABT (two intraperitoneal administrations of 100 mg kg−1 each), or t-1,2-DCE (0.2 mg kg−1 intraperitoneally), followed by CF-SPN (0.8 mg, intravenously) (n = 3 mice per treatment group) [31].

reduced after RONS scavenger and the inhibition agents were added. CL systems for in vivo imaging are always based on an energy transfer process from a CL precursor to a nearby emissive fluorescent dye. In order to open new doors for further exploration of complex biomolecular systems using non-invasive intravital CL imaging techniques, CL dioxetane luminophores with direct mode of NIR light emission has been designed [75]. The NIR luminophores were obtained by introducing an acceptor substituent with extended π-electron system (DCMC) at the para position of the phenol-dioxetane donor. Masking of the luminophores with analyte-responsive groups has resulted with two different turn-ON probes for detection and imaging of β-galactosidase and hydrogen peroxide. The probes' ability to image their corresponded analytes was effectively demonstrated in vitro for β-galactosidase activity and in vivo for inflammation model in mice.

based on chemical reagents (iodophenol blue or CuII-ILs) have shown good sensitivity toward H2O2. Nevertheless, same as the traditional CL system, they are often effected by some metal ion such as Co2+ and Cu2+. As a result, the selectivity go far from being desired. Furthermore, as shown in Table 1, there are less CL probes specially designed for sensing ROS except H2O2 in recent several years. To deal with the problems, the emerged materials which are used as catalyst, luminophors and support in CL systems have been considered to provide promising CL sensing platforms not only for H2O2 but for the other ROS. Take CdT QD and SiC NPs as an example, among all ROS, only %OH can inject holes into them to form excited-state CdT QD and SiC NPs to emit light. Both the CL probes for %OH with LOD down to nanomole level was selective and validated by monitoring %OH in living cells and in PM2.5, respectively. Obviously, the synthetize of new materials or modification of existing materials, especially which can act as luminophors would be one of fundamental trends in CL probes for ROS. In addition, various strategies involving self-immolation, self-catalyzing, conjugation and substituent effect, AIE, FI and CFCL system have been cleverly employed to improve the selectivity and sensitivity of CL probes for ROS. Thus, it will be help to fabricate new CL probes for ROS by considering these strategies. What is worth mentioning is, in the process of designing CRET, a suitable selection of the dye, which can give near-infrared emission and can match with a specific ROS (e.g.,

5. Conclusions and outlooks From our literature survey and the above discussion, the CL probes for ROS have shown their capability of making simple, rapid, and realtime in vivo measurements with high temporal resolution. However, the great challenge of designing ideal CL probe for ROS is still the improvement of selectivity and sensitivity, especially when it is used in biological samples and living cells. For example, the new CL probes 94

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O2 and O2%−) is an ongoing process. Similarly, the limitations including low emission intensity, short CL time, and short emission wavelength make it difficult to routinely use CL as an optical imaging strategy for various ROS, especially in vivo. CRET, structural manipulation of the triggerable dioxetane scaffold and AIE have been employed to improve the intensity and persistence of CL under physiological condition. For penetrating most animal tissues and bodies, near-infrared emission produced both by indirect or direct mode are available. The recent design of CL luminophores with direct mode of NIR light emission sheds new light on helping us to study ROS in complex biological systems. With continuous improvement on the sensitivity and selectivity of in vivo various ROS biosensors, the ROS research will be greatly facilitated.

[22]

[23]

[24]

[25] [26]

Acknowledgements

[27]

This work was supported by the National Natural Science Foundation of China (Nos. 21675113 and 21375089) and Science & Technology Department of Sichuan Province of China (2015JY0272).

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Yingying Su received her B.Eng. in Applied Chemistry from Central South University in 2000. Then she obtained her M.S. degree in Analytical Chemistry from Fuzhou University in 2004. After three years of research experience with Professor Xiandeng Hou at Sichuan University for her Ph.D degree, she joined the faculty of Analytical & Testing Center, Sichuan University as a lecturer, then as an associate professor in 2013. Her current research interests mainly focus on the development of chemo/bio-sensors with novel nanomaterials. She is the author or co-author of about 50 publications in peer-reviewed scientific journals.

Hongjie Song obtained her M.S. and Ph.D. degrees in Analytical Chemistry from Shaanxi Normal University and Sichuan University in 2007 and 2012, respectively. Then she joined the faculty of College of Chemistry, Sichuan University in 2012. Her current research interests mainly focus on the development of chemo/bio-sensors with novel nanomaterials. She is the author or co-author of 30 publications in peer-reviewed scientific journals.

Yi Lv is a full professor in College of Chemistry and director of Analytical & Testing Center at Sichuan University, China. He obtained his PhD degree in 2005 from Southwest China Normal University (currently Southwest University), China. After a two-year stay at Tsinghua University as a postdoctoral researcher in Professor Xinrong Zhang's group, he joined the faculty of the College of Chemistry at Sichuan University in 2005. His research interests are mainly in the areas of analytical spectrometry and nano-materials for analytical chemistry. He is the author or co-author of ~ 120 journal papers and one book chapter. He is a member of the international advisory board of Journal of Analytical Atomic Spectrometry (JAAS).

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