Electrogenerated chemiluminescence from metal complexes-based nanoparticles for highly sensitive sensors applications

Coordination Chemistry Reviews 367 (2018) 65–81

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Coordination Chemistry Reviews journal homepage: www.elsevier.com/locate/ccr

Review

Electrogenerated chemiluminescence from metal complexes-based nanoparticles for highly sensitive sensors applications Giovanni Valenti, Enrico Rampazzo, Sagar Kesarkar, Damiano Genovese, Andrea Fiorani 1, Alessandra Zanut, Francesco Palomba, Massimo Marcaccio, Francesco Paolucci, Luca Prodi ⇑ Dipartimento di Chimica ‘‘Giacomo Ciamician”, Università degli Studi di Bologna, Via Selmi 2, 40126 Bologna, Italy

a r t i c l e

i n f o

Article history: Received 9 February 2018 Received in revised form 10 April 2018 Accepted 11 April 2018

Keywords: Electrochemiluminescence Luminescence Nanoparticles Electron transfer Nanotechnology

a b s t r a c t The coupling of nanomaterials, and nanoparticles in particular, with one of the most powerful transduction techniques, electrochemiluminescence (ECL), i.e., chemiluminescence triggered by electrochemical reactions at electrodes, has recently provided sensing tools with unprecedented sensitivity limits. This review aims to give an overview of the state of the art in the field over the last 5 years, i.e., a time span covering over 80% of the scientific production in this context. The results herein discussed would demonstrate that the use of nanoparticles in the ECL technique represents one of the most interesting research lines for the development of ultrasensitive analytical tools, offering an insight to recognize and select the best nanomaterials for ECL signal amplification, with particular emphasis in biosensing. Ó 2018 Elsevier B.V. All rights reserved.

Contents 1.

2.

3.

4. 5. 6. 7.

8.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Principles of electrogenerated chemiluminescence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Fundamentals of electrogenerated chemiluminescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. Coreactants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4. ECL luminophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Silica nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. ECL propriety of silica nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Silica nanoparticles applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Semiconducting nanocrystals (NCs) and quantum dots (QDs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. ECL propriety of quantum dots (QDs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. ECL application of quantum dots (QDs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Carbon based material and carbon nanodots . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. ECL propriety of carbon based material and carbon nanodots . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gold nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. ECL application of gold nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Polymer dots (PD) and gels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Functional electrode surface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. Nanocrystals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

⇑ Corresponding author. 1

E-mail address: [email protected] (L. Prodi). Current address: Department of Chemistry, Keio University, 3
14
1 Hiyoshi, Yokohama 223
8522, Japan.

https://doi.org/10.1016/j.ccr.2018.04.011 0010-8545/Ó 2018 Elsevier B.V. All rights reserved.

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Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Declarations of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix A. Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The importance of nanotechnology and nanosystems on chemical and materials science has steadily been increasing over the last decade, with an ever-larger impact at any level in the development of new technologies [1]. In the field of analytical sciences, in particular, nanoparticles have been playing a unique role among other nanosystems, in bringing the sensitivity of sensing devices to their ultimate levels, providing, e.g., ultrabright labels in clinical analysis (markers, tumor cells, and pharmaceuticals) and in the detection of pathogenic microorganisms, toxic agents, and pesticides in the environmental field and food products [2,3]. Coupling such nanosystems with electrochemiluminescence (ECL), which naturally brings improved signal-to-noise ratio compared to photoluminescence, with minimized effects due to light scattering and luminescence background, has brought about new systems and strategies for analytes determination, even in very complex matrices, such as urine, blood or lysate, thus finally shifting the detection levels from the ppm range to the ppb or pg mL
1, so far achievable only by other, technologically more demanding techniques. By coupling nanomaterials with ECL, for example, has provided a rapid, costeffective and ultrasensitive assay for the detection of Zika virus (ZIKV, emerging mosquito-transmitted flavivirus) that could be detected at levels as low as 1 virus particle in 100 lL of saline, human plasma, or human urine, a level which cannot be achieved by any other techniques [4]. In such a context, the results of a literature search carried out over the last decades, by combining the terms ‘‘nanoparticle” and ‘‘electrochemiluminescence”, have shown an exponential increase of scientific production in the field especially in the last years, with over 80% of documents concentrated in the last 5 years. This would suggest therefore the necessity of an update of our previous review, published in this Journal in 2013 [5]. Herein, the most original and influential contributions within a huge variety of recent scientific production have been carefully selected to provide a timely and, hopefully, useful tool to all those who are either already active or just approaching such a fascinating research field.

1.1. Principles of electrogenerated chemiluminescence Electrogenerated chemiluminescence, also electrochemiluminescence (ECL), is emission of photons from a molecular species (luminophore) following an electron transfer (ET) process in solution, triggered by an electrochemical reaction [6]. As a combination

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between electrochemical and photophysical methods, ECL shows several advantages over chemiluminescence (CL) and photoluminescence (PL), such as near zero background noise due to the absence of excitation light sources and superior temporal and spatial control on light emission. As a matter of fact, ECL has become a powerful analytical technique and has widely been applied in many fields including environmental investigations, bioanalysis and immunoassays [7–9]. The first appearance of this phenomenon can be traced back to 1920s, [10] but the beginning of this electrochemical technique, as it is known today, started in the 1960s from the pioneering works of Hercules, [11] Pragst, [12] Chandross [13] and Bard [14]. The story of ECL went rapidly from an academic curiosity to a powerful electroanalytical technique [7–8,15–16] and nowadays, the research on ECL is mainly focused on its analytical applications, mostly having important biological targets [9,17–21]. Although tris(2,20 -bipyridyl)ruthenium(II) [Ru(bpy)2+ 3 ] still remains the benchmark, there is extensive research activity in developing new inorganic complexes, organometallic species or organic molecules for ECL, either freely diffusing in solution or embedded within nanosystems [5,22–24]. In this context, nanomaterials play a crucial role that ranges from the investigation of the complex mechanisms for ECL generation to the study of the electrochemical behavior of new high efficient dyes. 1.2. Fundamentals of electrogenerated chemiluminescence In order to generate ECL, two species, an electron donor D and an electron acceptor A both produced at the electrode surface, may undergo an ET process with one another (in the diffusion layer) to obtain the excited state of one of them (the luminophore). The energy requirement is the first parameter to predict if the ECL emission will take place as the ET should provide enough energy for ‘‘energy sufficient” ECL. The energy involved in the ET can be expressed in term of formal potentials of the species: 




DH0 ¼ E ðDþ ; DÞ
E ðA;A
 Þ
T DS0 >

1239:81 kes ðnmÞ

ð1Þ

where, E°(D+, D) and E°(A, A
) are the standard potentials of the reacting species, and kes is the excited state emission wavelength of the luminophore. The term DS° arises from the Coulomb repulsion associated to bringing the reactants from infinite into the encounter complex, a term that is typically small (0.1 eV) at 298 K [6]. A good approximation is therefore:

Fig. 1. Relation of ECL pathways to energy requirements (adapted from Ref. [6]).

G. Valenti et al. / Coordination Chemistry Reviews 367 (2018) 65–81 



DGes ðeVÞ  E ðA;A
 Þ
E ðDþ ; DÞ þ Ees ðeVÞ

ð2Þ

where, DGes is the Gibbs free energy of excited state formation and Ees is the energy emitted from the excited state at the emission wavelength kes. The formation of the excited stated (DGes < 0) is thus allowed for Ees lower than the energy available in the electron transfer for E°(A, A
) and E°(D+, D). The T-route and S-route depicted in Fig. 1 are energy sufficient and the emission comes from triplet or singlet excited stated, respectively. If the energy is lower (E-route) radiation less decay takes place [25]. Beside the S-route, triplet-triplet annihilation (TTA) produces emission from the singlet excited state (Scheme 1) when the light emitted has energy greater than the enthalpy of the redox reaction of reacting species to reach the singlet excited stated [25–27]. This process denotes ‘‘energy-deficient” ECL. It is important to notice that the triplet excited state typically has the character of fluorescence. Quantitative analysis of ECL emission permits to identify the direct formation of the singlet excited state from TTA mechanism [26,28]. The ECL is possible because the formation rate of the groundstate products is slower than the formation of the excited state, even if the related driving force is higher. In fact, in the Marcus inverted region, the kinetic constant of ET decreases with the driving force, [28,29] and ECL was among the first experimental evidences of Marcus theory of ET [30,31]. Light generation by ECL occurs via two main general protocols: annihilation and coreactant. Annihilation requires that a homogeneous ET in solution takes place between two radicals, usually, deriving from the same starting species. The two radicals can be formed at two separate electrodes in close proximity to one another or by using alternating potential at the same electrode (Fig. 2). In the second case, a sacrificial coreactant species is present in large excess compared to the luminophore. Subsequent to its oxidation or reduction, the coreactant undergoes chemical decomposition to form a highly reducing or oxidizing intermediate. The ET between this radical intermediate and the luminophore, also in its oxidized or reduced form, lead to the excited state of

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the luminophore. Fig. 3a depicts the coreactant mechanism by using tri-n-propylamine (TPrA) as coreactant and Ru(bpy)2+ 3 as luminophore. While annihilation ECL is difficult to reach within the limited potential window of water (due to the ET energy requirements in the range of 2–3 eV) and it is performed almost exclusively in organic media or at most in water-containing mixed solvents, [32] coreactant ECL can easily be carried out in water, [33] whence the great success of ECL in bioanalytical applications. In this context a crucial point in the ECL generation is the chemical and physical state and the behavior of the electrode surface where the ECL process is initiated [34]. On the other hand, annihilation ECL, conversely to coreactant, permits to measure the ECL efficiency (UECL), described as the amount of photons for charge transfer events:

R1

0 UECL ¼ R 1 0

Idt Ndt

ð3Þ

Scheme 1. Emission mechanism from singlet excited stated by triplet-triplet annihilation.

Fig. 2. ECL annihilation mechanism, D and A may be the same species. If they are different, the ECL mechanism is called mixed annihilation.

Fig. 3. ECL coreactant mechanisms: example with TPrA and Ru(bpy)2+ 3 . (A) Both TPrA and Ru(bpy)2+ 3 are oxidized at electrode. (B) Only TPrA is oxidized to achieve + ECL emission. [Ru] = Ru(bpy)3. Products are Pr2N = CHCH2CH3 and its hydrolysis products Pr2NH + CH3CH2CHO.

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where I is the photonic emission rate (einsteins per second) and N is the total charge transfer rate (moles per second). Since the absolute photon emission is not easily accessible, common experimental methods require a comparison with a standard under the same experimental conditions [35–37]. 



UECL ¼ UECL

IQ  IQ

ð4Þ

where U°ECL is the ECL efficiency of the standard, I and I° are the integrated ECL intensity of the species and the standard, and Q and Q° the faradic charges (in coulombs) for the investigated and the standard species, respectively. 1.3. Coreactants Coreactants are molecules which, after oxidation or reduction, are able to provide a high energetic homogeneous ET reaction with the luminophore [38]. In this case, ECL needs only a single potential step, both for the coreactant and luminophore. Oxidation (or reduction) of the coreactant produces a primary unstable product (at the potential E1) which undergoes a homogeneous follow-up reaction (classic EC mechanism e.g. deprotonation, splitting) yielding a strongly reducing (or oxidizing) intermediate. This is either further oxidized (or reduced) heterogeneously at the electrode according to the classic ECE mechanism (in absence of a luminophore) or, alternatively, which homogeneously reduces (or oxidizes) the oxidized luminophore. Here is necessary to stress that the second redox potential E2 (which is hardly experimentally accessible) is much less positive (or negative) than E1. Therefore the difference between E2 and EOx (or ERed) of the luminophore could be sufficient driving force for the exoenergetic electron transfer generating the triplet and/or singlet excited state [12]. These two pathways are the ‘‘oxidative-reduction” and ‘‘reductive-oxidation” mechanisms, respectively. In the first category are amines [39–41] (Fig. 3a-b) and oxalate [42] while benzyl peroxide [43–45] and persulfate [46,47] are the most common example of the second category. Recently, a new method for coreactant ECL was proposed where sulfate is used instead of persulfate. In this case, the unique properties of boron-doped diamond

electrodes were exploited, and in particular, its great overpotential for the oxygen evolution reaction that allows the persulfate to be generated in situ from sulfate, thus marking the first example of ‘‘co-reactant on-demand ECL” [46]. A particular case of ECL was observed with amines, specifically with tri-n-propylamine (TPrA), that does not imply the direct luminophore oxidation (Fig. 3b). Bard’s research group was the first to report and unravel this particular pathway in 2002, [48] which is the fundamental theory behind the actual ECL immunoassay, where the luminophore, i.e., Ru(bpy)2+ 3 , is physically impeded to reach the electrode surface (because, for example, it is immobilized at the surface of a microbead) and therefore cannot be oxidized (heterogeneous ECL) [49,50]. Xu et al. [40] reported that 2(dibutylamino)ethanol (DBAE) is more efficient than TPrA in homogeneous solution, while emission is nearly suppressed in heterogeneous ECL [51] (Fig. 3b), due to the extremely fast deprotonation of its radical cation.

1.4. ECL luminophores The ECL luminophores can be grouped in two main categories: inorganic complexes and organic molecules [6–8,52]. Coordination complexes based on transition metals, such as ruthenium [37,53– 55] iridium, [55–64,150,151] osmium [65–67] and platinum [68– 69] are the main dyes used in real ECL application. Among all the investigated metals, ruthenium is the forefather and the most widely used, while iridium is gaining more attention for its promising higher efficiency. Among organic molecules, 4,4-difluoro-4-bora-3a,4a-diaza-s-i ndacene (BODIPY) dyes (Fig. 4) emerged as highly efficient ECL emitters [70]. The electrochemistry and ECL are strictly dependent on molecular substitution, [71,72] i.e. the electron density distribution in the BODIPY core [73,74]. In the quest for ever-increasing sensitivity of the analytical signal, ECL has been coupled to nanotechnology in order to (i) optimize kinetics of the electron transfer and the stability of the electrode surface, (ii) increase the efficiency of the ECL emission and (iii) increase the number of labels that can be loaded within a single nanomaterial. Among the most promising signal amplifica-

Fig. 4. Examples of ECL luminophores from left to right: first row are Ru(bpy)2+ 3 , (pq)2Ir(acac) and (piq)2Ir(pyqui); second row are BODIPY, fluorene and spirobifluorene.

G. Valenti et al. / Coordination Chemistry Reviews 367 (2018) 65–81

tion strategies is the use of nanomaterials such as dye-doped nanoparticles, quantum dots, polymer dots and carbon-based nanomaterials, that will be presented in the following sections. 2. Silica nanoparticles In the framework of all the possibilities available to develop ECL nanosystems, dye doped silica nanoparticles (DDSNs) exhibit many advantages since they can be obtained by quite simple and versatile synthetic schemes. Even more, silica is a material intrinsically hydrophilic with a well-established chemistry that makes it prone to bioconjugation, making silica nanoparticles suitable to work in water solution using the coreactant approach. A description of the synthetic schemes available to form silica nanoparticles is outside of the scope of this review, and have been described in several review papers [5,75,76]. The main advantage that silica nanoparticles offer is related to signal intensity, since a silica nanoparticle can concentrate a huge number of ECL active dyes at a single site and very bright nanosystems can be obtained. Silica is also inert from the photophysical point of view, and the protection offered by this matrix to the dyes toward oxygen and other quenching molecules often increases both quantum yield and photostability of the dyes. This is extremely evident in the ECL field where long lived triplet excited state 2+ dyes are used – such as in the case of Ru(bpy)2+ 3 . Ru(bpy)3 fits extremely well in terms of polarity and solubility most of the synthetic environment leading to the formation of silica nanoparticles. For this reason and for its intrinsic ECL efficiency this luminophore is the dye of choice to dope silica nanoparticles when Stöber, reverse microemulsion or direct micelles assisted methods are used. 2.1. ECL propriety of silica nanoparticles The emission properties of DDSNs depend on the doping dye, and in most cases these are Ru(II) or Ir(III) metal complexes. While the advantages of using Ru(II) complexes – high intense signals and synthetic versatility – have been already mentioned, Ir(III) complexes are particularly interesting since their emission can span from the near-IR to deep blue, a feature which is useful in the development of multichannel analytical techniques [77]. Another possibility to tune the emission colour of ECL active DDSNs is to exploit a Forster resonance energy transfer (FRET) with other fluorescent dyes, an approach that can be efficiently obtained thanks to the multicompartmental nature of the silica nanoparticles [78]. Besides synthetic accessibility and versatility, DDSN are also intriguing systems as complex multichromophoric structures, showing the coexistence of dye populations experimenting different local concentration and environment. This can lead to energy transfer processes such as resonance energy transfer or quenching. In the case of ECL active DDSNs this scenario is complicated by the interaction with coreactant molecules, that need to approach the dyes embedded in the silica matrix and the DDSNs surface. The complexity of these systems makes the fundamental studies of their ECL behaviour extremely important to understand its mechanisms. In this framework there are few examples both of experimental and theoretical nature. Very recently Kenta et al. [79] performed simulations of the ECL emission from a Ru(bpy)2+ 3 doped silica nanoparticle working in buffered conditions with TPrA as coreactant. This work considered experimental evidence obtained in a previous work in which Zanarini et al. measured the ECL emission of a self-organized layer of 30 nm Ru(bpy)2+ 3 doped silica nanoparticles on gold electrode [80]. The ECL intensity for this system in the presence of TPrA

69

showed two emission waves when moving the potential of the working electrode in the positive direction. The first ECL wave (peak at ca. 0.9 V vs Ag | AgCl) was governed by TPrA oxidation and by the deprotonation equilibrium of TPrA+ radical cation, while the second ECL wave (peak at ca. 1.2 V) was triggered by the direct Ru(bpy)2+ 3 oxidation. Kenta et al. modelled the second ECL wave as related to the electron hopping mechanism between Ru(bpy)2+ 3 labels inside the Ru-DSNP. This work highlighted that the deprotonation of TPrA+ is crucial in determining the ECL intensity since the reaction of TPrA with Ru(bpy)3+ 3 generates the dye excited state. This mechanism is expected to be dominant with ECL assays employing magnetic microbeads technology to trap active species to the electrode, since the labels are too distant to be directly oxidized at the electrode surface [50,51]. Amatore et al. [81] analysed recently from the theoretical and mechanistic point of view the Ru(bpy)2+ 3 /TPrA coreactant ECL pathways of Ru(bpy)2+ 3 in solution and within DDSNs. This work evidenced with 1D simulations that an efficient ECL response needs that the DDSN is located within the diffusion layer of the oxidized organic co-reactant. The most critical roles are played by the relative concentrations of amine radicals around the DDSN in turn affected by the buffer pH and concentration, efficient ECL requiring that pH be not too basic in comparison with the pKa of the amine radical cation. The predictions contained in that work are relevant to most ECL coreactant systems since they usually share the same mechanistic features. The mechanisms involved in ECL emission of DDSNs are also affected in a complex way by other parameters such as diffusion and surface properties of the nanoparticles. To sort out the influence of such parameters thus helping the design of new ultrasensitive devices, the ECL mechanisms in DDSNs need to be thoroughly investigated. Valenti et al. [82] gave a contribution in the field exploring the ECL behaviour in a family of core-shell silica-polyethylene glycol (PEG) nanoparticles doped with a Ru (bpy)2+ 3 triethoxysilane derivative (Fig. 5). These authors exploited a direct micelle-assisted synthetic method to obtain a set of Ru (bpy)2+ 3 DDSNs containing a variable number of doping dyes and displaying similar hydrodynamic and photophysical properties. This synthetic approach, making use of Pluronic F127 surfactant aggregates as templates to build up the nanoparticle structure, had the capability to form DDSNs with uniform size and a very large doping range (silica diameter 10 nm, hydrodynamic diameter 25 nm, due the presence of a PEG shell, from 2 to 24 ruthenium complexes per nanoparticle). The Ru(bpy)2+ 3 triethoxysilane derivative was used for covalently linking the dyes to the silica matrix and to prevent dye leaching from the DDSNs, thus making the nanoparticles the only possible emitting system in solution. In this work the ECL experiments were performed in solution using 2-(dibutylamino)ethanol (DBAE) as coreactant, and showed a first ECL mechanism that involves exclusively the radicals deriving from coreactant oxidation. A second mechanism was also evidenced involving the direct anodic oxidation of the Ru(II) centres. It was found that the first mechanism prevailed at low Ru(II) doping levels, producing an ECL emission intensity growing linearly with doping. The second mechanism, having lower efficiency than the first one, includes electron (hole) hopping between redox centres within the DDSN and was relevant only at high doping levels. Within the set of DDSNs the authors found that ECL intensity varied linearly just at relatively low doping levels while it deviates negatively at higher ones. The efficiency of the ECL emission was also affected by the surface charge properties of the DDSNs, that within the DDSNs set showed a f-potential increases with the doping level, from negative to slightly positive values. The accumulation of cationic charge within the silica core of the DDSNs, probably affected the ECL generation mechanism along the DDSN

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Fig. 5. (A) reagents used for the synthesis of core-shell silica-PEG nanoparticles. (B) synthetic process. Reprinted with permission from Ref. [82].

series hampering the interactions between the DDSNs and the radical cationic species involved in the ECL. This paper is of general interest since it shows that the ECL intensity of a dye doped nanosized system cannot be incremented just acting on dye doping, because surface charge properties can affect the interaction of the nanosystem with the coreactant. Very recently Kesarkar et al. [77] employed a similar synthetic approach to produce DDSNs doped with two neutral cyclometalated Ir(III) complexes, Ir(iqbt)2dpm and fac-Ir(iqbt)3 [iqbt = 1-(benzo[b]thiophen-2-yl)-isoquinolinate]. These complexes displayed near-infrared (near-IR) ECL emission with maxima at 712 and 706 nm in acetonitrile, respectively, and used as doping agents within silica-PEG nanoparticles provided water soluble nanomaterials with remarkable ECL emission in aerated conditions. 2.2. Silica nanoparticles applications From the analytical point of view ECL is a powerful technique with very high sensitivity, large linear response and very low limit of detection. The accumulation at a single site of many ECL active dyes by means of nanostructures such as DDSNs, is a promising strategy to boost even more the performances of this technique.

Within the examples present in the literature, is worth to mention the work of Dang et al. [83] that developed a label-free and sensitive ECL aptasensor for K+, based on a glass carbon electrode modified with G-rich DNA aptamer and chitosan/Ru(bpy)2+ 3 /silica nanoparticles. Aptamers are single-stranded DNA or RNA molecules, able to bind with high affinity and specificity a wide range of chemical or biological analytes. This ECL aptasensing platform, was composed by silica nanoparticles (diameter 50 nm) doped with Ru(bpy)2+ 3 and chitosan, that were synthesized by a reverse microemulsion approach. These nanoparticles were then selfassembled on CNT/Nafion coating film electrode obtaining a selforganized structure based on strong electrostatic interactions between the positive charged chitosan adsorbed to the NPs surface and the negative charged Nafion on the electrode. This electrode was incubated with guanine rich (G-rich) DNA aptamers able to bind K+. The guanine bases were able to enhance the ECL signal of Ru(bpy)2+ 3 embedded in the chitosan-silica nanoparticles thanks to the strong interaction of the positively charged chitosan with the guanine bases of the DNA aptamer. Such a label free sensing scheme, that eliminates separation, and immobilization steps, was based on the formation of a rigid folded structure in the aptamer-K+ complex, called Gquadruplex, that prevents for some

Fig. 6. Immunosensor fabrication process. Reprinted with permission from Ref. [84].

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extent the interaction of the G-bases in the aptamer with the DDSNs surface, resulting in a linear decrease of the ECL signal in the presence of potassium ion (detection limit for K+: 0.3 nM, S/ N = 3). The selectivity of the sensing scheme was good toward Na+, but quite poor in the presence of many other metal ions such as Hg2+, Zn2+, Cu2+, Ca2+, Fe3+, Al3+, Na+, and Mg2+. However, high selectivity for K+ was maintained when a chelating agent like EDTA was added in the samples. This aptasensor was also used in determining the K+ concentration in two biological samples containing SW480 colorectal cancer cells. In another example Zhou et al. [84] synthesized DDSNs containing Ru(bpy)2+ and passivated with PEI (Poly(ethylenimine)) to 3 develop an ECL immunosensor for the analysis of neuron specific enolase (NSE). NSE is a sensitive and reliable tumour marker for small lung cancer cell, useful to the early diagnosis and for the assessment of the patient’s recovery progress. In a quite simple preparation scheme (Fig. 6), PEI and Ru(bpy)2+ 3 – DDSNs produced by a standard microemulsion technique, were simply mixed together: PEI assembled on the surface of DDSNs by electrostatic interaction acting as internal co-reactant involved in the ECL emission, and also etched the DDSNs increasing their surface through the formation of porous shell. These DDSNs were then drop cast on the surface of a GCE electrode, covered by a Nafion film where a gold nanoparticles layer was produced. This surface was then treated with the Anti-NSE antibody. The presence of PEI coreactant on the Ru(bpy)2+ 3 doped silica nanoparticle enhanced the ECL signal. With the functioning scheme depicted in Fig. 6, the immunosensor showed a decrease in the ECL signal binding NSE, with a linear range from 1.0  10
11 to 1.0  10
5 mg mL
1 with a detection limit for NSE of 1.0  10
11 mg mL
1. The decrease of the ECL signal during the recognition of NSE was attributed to hindering effects on the electron transfer to the electrode. This immunosensor, thanks to the presence of PEI acting as ‘‘internal” coreactant, was successfully used to analyse clinical human serum samples, with results comparable to the commercial ELISA kits.

3. Semiconducting nanocrystals (NCs) and quantum dots (QDs) Since the ECL of silicon QDs was first reported by Bard and coworkers in 2002, [85] lots of QDs with different sizes and shapes have been investigated as ECL emitters mostly in the imaging and biosensing applications. As finding new luminophores with

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high ECL efficiency/sensitivity is highly demanding in this field, recently QDs has been dominating other species such as polymer dots (PDs) or traditional organic dyes. Their good photo- and electrochemical stability, functional flexibility, excellent optical properties such as size-dependent narrow and symmetric tunable emission, high absorptivity and long fluorescence lifetime make them promising candidates. 3.1. ECL propriety of quantum dots (QDs) Firstly, reported by Bard et al., highly crystalline, robust, organic-monolayer passivated Si QDs (2–4 nm in diameter) capped by agents consisting of a combination of hydrogen and alkoxide, showed significant red-shift in ECL emission peak in non-aqueous medium with a maximum centered at 640 nm compared to photoluminescence (PL) emission centered at 420 nm. The observed ECL emission was attributed to hole-electron recombination processes assumed to occur on QDs surface through annihilation and coreactant mechanisms which are confined to the surface states, whereas PL emission has been ascribed to excitation and emission within QDs core (Fig. 7). Thus, fully passivated QDs can show a much larger ECL peak around or at the wavelength of PL and ill-defined red-shifted ECL peak arising from a very few incomplete passivated QDs. The later peak can be more prominent with an increase in a number of incompletely passivated QDs. Moreover, unlike QDs size-dependent PL, non-sensitivity of ECL emission to QDs size allows ECL as an effective tool to investigate surface states of QDs. The passivation strategy of QDs can also be achieved by formation of inorganic core/shell system. For example, CdS/ZnSe QDs (CdS as core and ZnSe as shell) were studied in non-aqueous medium by Bard et al. displayed a red-shifted emission peak at 740 nm (200 nm red-shift compared to PL which is attributed to emission from surface states of non-passivated QDs) along with sharp peaks almost identical to PL spectrum (attributed to fully passivated QDs) [86]. Moreover, the PL peak intensity at 580 nm increased more than 10 times after passivation with a shell of ZnSe, compared to that of CdSe QDs. Despite of interesting properties displayed by QDs, insolubility in aqueous medium limited their practical applications in bioanalysis. The breakthrough of ECL of QDs in bioanalysis was represented by Lue et al. reporting for the first time the synthesis of water soluble CdTe QDs modified with 3-mercaptopropionic acid (MPA) for the detection of catechol derivatives [87]. The sensing strategy of catechol involved quenching of ECL emission by energy transfer from the exited CdTe QDs to

“Oxidative-reductive” pathway using oxalate as a coreactant C2O42- – e [C2O4− •] CO2− • + CO2 (oxidized) QD* + CO2 (anodic ECL) QD+ • + CO2− • QD* QD + hv (ECL emission)

or

Energy

•

•

tradionalPL organic dyes

ECL

Annihilation

•

QD – e QD + e QD+ •+ QD− • QD*

QD+ • (oxidized) QD− • (reduced) QD* + QD (annihilation) QD + hv (ECL emission)

or Si core Surface

2-+

S2O8 e QD− • + SO4− • QD*

SO42- + SO4− • (reduced) QD* + SO42- (cathodic ECL) QD + hv (ECL emission)

“Reductive-oxidative” pathway using peroxydisulfate as a coreactant Fig. 7. Schematics for PL and ECL emission of Si QDs (left), and ECL mechanism including annihilation and coreactant (oxidative-reductive and reductive-oxidative) pathways of ECL emission.

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catechol and proposed as a new methodology for analytical applications of QDs. Further, by combining the ECL emission quenching methodology, core/shell QDs synthetic strategy and imparting solubility to QDs by capping them with MPA, CdTe/CdS coresmall/ shellthick QDs capped with MPA were designed recently by Jiang et al. [88] The designed sensor showed anodic near-infrared electrochemiluminescence (NECL) without any co-reactants which quenched selectively upon addition Cu2+ ions, hence a simple and sensitive method for the determination of Cu2+ was demonstrated in real environmental and food samples with the detection limit as low as 20 nM. However, in biological applications, cytotoxicity could be observed due to leaking of Cd2+ ions from the QDs Cd-core/shell. Wang et al. reported that by adding an extra shell of ZnS, such a leaking could be prevented; moreover, increased structural stability and surface properties protection of QDs resulted into strong and stable enhanced ECL signal. Thus, the reported core/shell/shell QDs structure, CdTe/CdS/ZnS QDs, showed 9-fold higher ECL emission intensity in the near-infrared (NIR) region (702 nm) compared to CdTe/CdS QDs in aqueous medium, in the presence of potassium persulfate (K2S2O8) as coreactant [89]. Understanding the importance of NIR ECL emission in bioanalysis, as biological autofluorescence and tissue absorption are minimized in the wavelength range 650–900 nm, recently Wang et al. briefly reviewed synthetic strategy of binary component QDs (PbS, CdTe, Ag2Se) and core/shell QDs, and their applications in biosensing methodologies [90]. Addressing the toxicity of Cd, Te, Se and Pb based QDs, doping QDs with metal ions for example Mn2+, Co2+ or Eu3+, found to be a very interesting strategy to reduce toxicity as well as to increase ECL emission intensity coupled with suppression of defect-related emissions generally arises from QDs shell [91]. For example Mn2+ doped inside ZnS and CdS shell QDs showed well-distinguished Mn2+ related dominant ECL peaks at 590 nm and 585 nm attributed to the 4T1 ? 6A1 transition of Mn2+ ions [92] whereas CdS QDs doped with Eu3+ showed an ECL emission at 620 nm belonging to the 5D0 ? 7F2 transition of Eu3+ ions exhibiting 4-fold enhancement of ECL signal [93]. Upon doping CdSe with Co2+ ions, the system exhibited 3-fold enhancement of ECL signal [94].

3.2. ECL application of quantum dots (QDs) Given above an overview of synthetic development of different QDs, especially aiming to reduce their toxic effects and to enhance ECL intensity, many interesting reviews focused on detailed construction strategies and various role of QDs in ECL biosensing applications were recently reported [75,90,95–98]. Therefore, we’ll mainly discuss recent advances of QDs over the last five years to give some prospective for future development of QD-based ECL sensors. Focused on NIR ECL based sensors, Cui et al. reported ECL property of NIR fluorescent and low toxicity if ultra-small (1.5 nm) Ag2Se QDs for the first time [99]. The design strategy involved immobilization of negatively charged QDs onto the glassy carbon electrode (GCE) through the multiwalled carbon nanotubes (MWCNTs-for the fast electron transfer) and polyethyleneimine (PEI-positively charged film to trap QDs), and dopamine (DA) used as the model analyte. The detection strategy involved quenching of cathodic ECL emission of Ag2Se QDs/PEI/MWCNTs modified GCE upon addition of DA into the 0.1 M PBS (pH 7.5) containing 0.1 M K2S2O8 (as the reductive-oxidative co-reactant, Fig. 7) and 0.1 M KCl. This quenching phenomenon was attributed to the energytransfer process from QDs to DA, showed linear detection range from 0.5 to 19 lM with a detection limit of 0.1 lm. Furthermore; a perfect overlap of the ECL and the PL spectra indicated that the surface states of QDs are well passivated.

Based on the use of eco-friendly Ag2+ in QDs, water dispersible Ag2Te QDs were synthesized from CdTe QDs through ion exchange method by Peng et al. [100] The designed sensor showed quenching of ECL emission intensity upon addition of catechol due to the resonance energy transfer (RET) occurred between Ag2Te coated GCE and catechol, showed liner detection range of 1 nM to 10 lM with the detection limit of 0.31 nM in neutral aqueous solution with K2S2O8 as coreactant. Apart from the application of QDs as luminophores, recently they are also studied as coreactant, replacing amine based coreactants. For example, the system based on tris(2,20 -bipyridyl)ruthe nium(II), [Ru(bpy)3]2+, as emitter and TPrA as coreactant is very popular, being used in commercially available protocols. However, TPrA has low solubility and is highly volatile and poisonous. The use of QDs as coreactant could be an effective alternative. Dong et al. reported a sensor for quantitative detection of DNA by using CdSe QDs as coreactant of [Ru(bpy)3]2+ [101]. Through the electrostatic interaction, [Ru(bpy)3]2+ was intercalated into the loop of hairpin DNA (the amount of interaction depends on the loop size) and the resulted probe was bound to the CdSe QDs modified GCE. The system showed strong anodic ECL emission at 1.10 V in the absence of target DNA. Upon introduction of target DNA, the loop of hairpin DNA can be opened releasing the immobilized [Ru (bpy)3]2+, which resulted in the decrease in ECL intensity (Fig. 8) showing linear detection range of target DNA over the range of 5.0  10
16 to 5.0  10
12 M with a detection limit of 1.9  10
16 M. Recently L-cysteine-capped CdTe-QDs were also utilized to enhance the ECL intensity of a [Ru(bpy)3]2+ system by RET with CdTe-QDs. The capping ligand, L-cysteine, is used to maintain colloidal stability via electrostatic repulsion, and moreover found to have a strong effect on the fluorescent properties. The designed sensor showed quenching of ECL intensity in the presence of nitrofuran antibiotics linearly over the concentration range of 10–100 mM [102]. Another approach is recently presented by Dong et al. in which eco-friendly SiQDs were employed to design DNA biosensor. SiQDs modified GCE was further modified with gold NPs connected to hairpin DNA (as a signal probe). In this system QDs layer acted as energy donor and gold NPs as energy acceptor. Upon interaction with target DNA with signal probe, hairpin DNA releases gold NPs thus resulting in linear enhancement of ECL signal with increase in amount of target DNA. This ECL biosensor can be used to detect DNA in the range of 0.1 fM to 1 pM in aqueous medium using K2S2O8 as coreactant [103]. In another report, an aptasensor for the detection of lysozyme was reported using SiQDs as energy acceptor and enhancer of luminol ECL emission at gold electrode. The RET was inhibited upon addition of lysozymes, quenching strong anodic ECL signal, allowed sensitive detection of lysozyme [104]. Based on the RET concept, biosensors for the detection of Cytochrome C were also reported by the same group. The concept involved quenching of anodic ECL signal (resulted from RET between luminol and CdS-graphene nanocomposites modified gold electrode [105] or CdSe Qds modified GC electrode) [106] upon addition of Cytochrome C. As mentioned above, surface states generally show narrower band gaps compared with the core, resulting the ECL emission at longer wavelength and lower potential. This is highly desirable to maintain bioactivity of detection targets, suppressing the interference arising from the coexisting electroactive species and defectrelated emission from QDs shell. To produce these surface states, multiple approaches of QDs passivation were used for example 1) use of either single ligand or duel ligands coating such as mercaptopropionic acid (MPA) and sodium hexametaphosphate, and trioctylphosphine oxide (TOPO) and dodecylamine; 2) creating core/shell, core/shell/shell systems (CdTe/CdS, CdTe/CdS/ZnS) or

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Fig. 8. Schematic representation of the modification of the GCE and the detection of target DNA. Reprinted with permission from Ref. [101].

3) use of amphiphilic polymers with hydrophobic and hydrophilic groups interacting with organic capping agents and imparting solubility, respectively. However these approaches effectively failed to provide QDs with uniform surface-state controlled ECL emission. So, a novel method for the synthesis of polymer-stabilized CdS QDs through an one-pot hydrothermal reaction was reported by Deng et al. Using this approach, a phenol formaldehyde resin (PFR) polymer was formed in situ to passivate the surface of the CdS QDs with hexamethylenetetramine as the source of both the monomer and the crosslinking agent producing a uniform size distribution with controllable surface states and showed a unique ECL spectrum with two peaks at 537 and 573 nm, which corresponded to the core and surface states of the QDs, respectively. A lowpotential ECL emission with a relatively long lifetime at – 0.78 V was attributed to the partially non-passivated surface states. Taking advantage of the low potential ECL emission, sandwich-type immunoassay showed a linear range response to polyclonal anticarcinoembryonic antigen (CEA) (over 5 orders of magnitude) with high sensitivity [107].

4. Carbon based material and carbon nanodots Carbon dots (CDs) and graphene quantum dots (GQDs), recently, have attracted intense research because of their water solubility, low toxicity, and facile functionalization. In general, the synthesis of GQDs and CDs can be achieved by either bottom up or top down approaches [108,109]. The bottom up strategies which have been developed recently, are focused mostly on using green precursors such as amino acids, small amine molecules or saccharides and so on. The top down approach, instead, has been focused on the use, as carbon source, of bulky materials like graphite or fullerene, which are physically and/or chemically treated in order to obtain the desired material. These nanoparticles are characterized by their discrete and quasi spherical 10 nm size, and quite often are defined as 0D materials. CDs and GQDs are composed by one or few layers of graphene or small graphenelike structures, yielding fascinating electro-optical properties due to the quantum confinement effects related to the core of the structure, and to edge effects close to the surfaces [108]. For these

reasons CDs and GQDs have revealed interesting features as materials for photoinduced electron transfer, photoluminescence (PL) and electrochemiluminescence (ECL) [101–111]. 4.1. ECL propriety of carbon based material and carbon nanodots In ECL context, the stability and water solubility of this class of carbonaceous nanomaterials allow the use of CDs and GQDs as emitters not only to substitute the traditional molecular dyes, dye doped nanoparticles or quantum dots (QD), but they can also be managed together to gain synergetic system at the electrode where the CDs or GQDs can work as electrochemical enhancer. In fact, this 0D material have shown functional ECL properties where, by their combination with Ru(bpy)2+ 3 complexes or CdTe/CdS QDs, a remarkable increase can be achieved with respect to the isolate components [112]. The electronic properties of the CDs and GQDs characterized the peculiar PL as well the ECL response, which depends on the size of nanomaterials and on the oxidation level. In general, PL and ECL emissions can be quite different for materials with similar composition and size [113]. To describe the nature of the ECL processes, in these systems the electrochemical reactions can involve the valence band (VB) or the conduction band (CB) and/or the surface states, similarly to other quantum dots. Usually, CDs and GDs are characterized by emission bands which change in function on the excitation wavelength. This depends essentially, by the different bright states which can be populated, associated to either the inner portion of the nanostructure or the surface [114]. However, the nature and the localization of the different excited states is today under debate. As the PL, ECL emission can be obtained in some cases for different states but usually is promoted by reactions involving surface state transitions. For this reason, the coreactant plays an important role in the production of the CDs ECL signal since it may determine the prevailing ECL process. Oxygen, hydrogen peroxide or cysteine are generally used as coreactants [115]. When more than one ECL emission is achievable, at different potential and selecting the opportune coreactant, the CDs can be proposed as sensor with an internal standard since one of the two ECL emission peak can be influenced by the analyte while the second remains constant. In a two-peak system, the ECL pro-

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2+ Fig. 9. A) Tris(2,20 -bipyridine)ruthenium(II) (Ru(bpy)2+ 3 ), nitrogen-doped carbon nanodots (NCNDs) and methylated-NCNDs (mNCNDs) B) ECL emission of Ru(bpy)3 enhanced by 0.1 mg mL
1 NCNDs (red trace), 0.1 mg mL
1 (0.13 mM amine) mNCNDs (green trace) and 20 mM TPrA (black trace) in PBS solution (pH 7.4). GC electrode (d = 3 mm), potential referred to Ag/AgCl (KCl sat.) at room temperature. Platinum wire as counter electrode. C) ECL proposed mechanism for Ru(bpy)2+ 3 /NCND system. Reprinted with permission from Ref. [120].

cess, at
3.0 V in organic solvent, can be activated by an electron injection to the CB and subsequently, the electron in the CB annihilates with the hole in the VB (formed by reaction with coreactant radical) to produce a bright luminescence. At lower potentials (
1.5 V), another ECL emission can be obtained by the formation of an exciplex between the reduced CDs and the coreactant leading to an ion-ion annihilation type emission [116]. In water medium, the ECL process can be enhanced by the presence of the ferrocyanide-ferricyanide redox couple [117]. In this case the electron/hole recombination occurs in the immobilized CDs (with S2O2
8 as coreactant) leading to a 10-time enhancement of the solid state ECL exploited to develop a solid state sensor for GSH. Recently D. Pang et al. [118] have proposed the working mechanism of CDs as coreactant in the anodic ECL emission of Ru(bpy)2+ 3 . The benzyl units on the CDs are oxidized ‘‘homogenously” at about 1.0 V vs. Ag/AgCl by the electrogenerated Ru(bpy)3+ 3 to form a 2+⁄ reductive intermediate able to reduce Ru(bpy)3+ 3 into Ru(bpy)3 , finally yielding a strong ECL emission. They proposed a model where benzyl alcohol groups present on CDs would act as coreactants and such a mechanism was useful to highlight the chemical characteristics of CDs as nanomaterials to substitute molecular coreactants in the anodic Ru(bpy)2+ 3 ECL processes. Bottom up synthesis would permit the doping of such 0D materials directly (during the formation of the 0D material) or after the isolation of the nanostructure. Nitrogen doping of GQDs and CDs has been reported to give excellent optical properties and usually blue-shifted fluorescence. In most cases, the doping strategy is carried out under harsh conditions, especially for GQDs; nitrogen doped CDs can be synthesized from amino acids which are a carbon and nitrogen natural sources. Moreover, molecules containing primary amines allow simultaneous nitrogen doping and surface

passivation during the synthetic process (NCDs). The NCDs as ECL luminophores have been used for the development of an immunosensor based on the quenching effect of aminated graphene on the emission of NCDs [119]. The ECL self-enhancement promoted by CDs as coreactants has been proposed in 2017 by L. De Cola, M. Prato and co-workers [120] where amine-rich nitrogen-doped carbon nanodots (NCNDs) were used to enhance the Ru(bpy)2+ 3 complex ECL emission, Fig. 9. The comparison of the ECL intensity of primary amine-rich NCNDs, with tertiary ones (mNCNDs) and with TPrA revealed that a small amount of mNCNDs gave the same ECL intensity as when using TPrA, which corresponds to an improvement by ca. 150 times considering the slower diffusion coefficient of the mNCNDs vs. TPrA. When the Ru(bpy)2+ 3 is covalently linked to NCNDs, the ECL emission is twice as higher with respect to uncoupled systems, thus demonstrating the self enhancement ECL effect of the nitrogendoped carbon-based material as similarly reported for other systems.

5. Gold nanoparticles Despite the fact that they are typically not luminescent, gold nanoparticles (AuNPs) are, among the different kind of nanostructures, very actively used and studied in the framework of the ECL systems [5]. The reason for such an interest is manifold, since many factors, often synergic, come into play when AuNPs are used for generating an ECL signal, and is typically very difficult to discriminate which contribution is prevalent in the different systems. In particular, AuNPs have allowed a large increase of sensor performances because of their excellent conducting and electrocatalytic

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properties [121]. Previous studies showed that the use of AuNPs can enhance the ECL emission of luminol up to 3 orders of magnitude, with an important role of the catalytic effect of metal NPs on luminol oxidation, [122–124] a result that could explain why AuNPs are often used in combination with this dye. AuNPs are particularly valuable also because of their high surface area/volume ratio that allows a great increase of the electrode surface, and their loading to form multiple ECL labels, an aspect that has been widely used, as described below, to increase the ECL signal. The derivatization of AuNPs with many ECL dyes can, furthermore, be easily obtained thanks to the strong interaction of AuNPs with sulphur containing moieties and, although to a minor extent, to amines. This feature has also proven be very advantageous in the preparation of ECL biosensors since it allows an easy immobilization of biomolecules such as enzymes, that are rich of amines, and often contain cysteine residue [5]. 5.1. ECL application of gold nanoparticles Zhai et al. reported a label-free sensor for the I27L gene, whose variation is related to an increasing risk of type 2 diabetes, based on an ITO electrode [125]. This electrode has been functionalized though the adhesion of hydrolysed polymer of (3-aminopropyl) trimethoxysilane with 5 nm AuNPs, derivatized with a suitable single-stranded oligonucleotide as capture probe. The hybridization of the target DNA led to an increase of the negative charge on the electrode, and thus to a higher electrostatic repulsion towards the luminol anion, generating a quenching of the ECL intensity. A detection limit of 8.1  10
12 M has been reported, together with a good stability and reproducibility. An interesting approach is to combine the catalytic properties of AuNPs with those of other nanoarchitectures. With this aim in mind, Dong et al. have exploited the possible synergic effects of graphene, carbon nanotube, and gold nanoparticles on luminolbased ECL [126]. The authors concluded their work, after the investigation of the mechanism for the ECL generation, suggesting a very positive effect of the intercalation of carbon nanotube into the graphene film and of the electrocatalysis of AuNPs deposited at the graphene film. A synergic effect of the use of AuNPs was also found when combined with molybdenum disulfide (MoS2), [121] a semiconductor showing a highly electrocatalytic activity toward decomposition of H2O2 into reactive oxygen species which could accelerate the

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oxidation of luminol and amplify ECL response. A drawback of MoS2 is represented by its absence of conductivity, that in this report has been overcome by the combination with AuNPs. In particular, in this case, they have been synthesized using BSA as template, a strategy that allowed, on one hand, to maintain the good conductivity of the metal nanoparticles and, on the other hand, to take profit of the abundant active functional groups (such as – NH2 and –COOH) present on BSA. These functional groups have been used to immobilize, according to the Fig. 10, a large number of luminol moieties and a labelled antibody (Ab2) as recognition probe for the alpha fetal protein (AFP), which has been indicated as potential marker for primary liver cancer (PHC). With this approach, the authors reported a wide linear range from 0.1 pg mL
1 to 200 ng mL
1 with a detection limit of 1.0  10
5 ng mL
1. The strategy to use AuNPs as carriers for luminol molecules has been pursued also by other authors; in this context, for example, Li et al. developed a label-free ECL aptasensor [127] for the detection of thrombin with a low detection limit of 1.7  10
12 mol/L. Sharing the same idea of loading AuNPs with many luminol units, Zhang et al. [122] develop an even more complex methodology for the detection of telomerase, a possible biomarker for the diagnosis and prognosis of cancer. They in fact developed a device able to give ECL signals at two different potentials, functionalizing a glassy carbon electrode with CdS nanoparticles derivatized with a telomerase primer. The CdS NPs generate a weak signal at negative potential in the presence of H2O2 as coreactant; after the extension of primer with telomerase and dNTPs, telomerase primer was hybridized with its complementary DNA and the extended part was hybridized with Luminol–Au NPs derivatized with the capture DNA. The Luminol–AuNPs were prepared by adding a luminol and a NaBH4 solution to an aqueous solution of HAuCl4 resulting in a purple dispersion of L–Au NPs having a diameter of about 5 ± 1 nm. The assembly of these NPs onto the electrode produced, because of the luminol moieties, a signal at positive potential; enhancing, at the same time the one generated by the CdS. Both these signals, maintaining an almost constant ratio for a quite wide range of telomerase concentration, increased with an increase of the analyte concentration (Fig. 11). To underline even more the huge potential given by the possibility of derivatize the AuNPs with a large number of active species, such as ECL dyes or recognition units, we would like to conclude

Fig. 10. Schematic diagram illustrating (A) the formation of MoS2-PEI-Au nanocomposites, and (B) the preparation procedure of luminol-Au@BSA-Ab2 bioconjugation. Reprinted with permission from Ref. [121].

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Fig. 11. (A) ECL signal-time curves at the dual-potential ECL sensing interface with telomerase extracted from different numbers of HL-60 cells: 0, 100, 1000, 3000, 5000, 7000, and 9000 from a to g, respectively. The first signal was induced by luminol, and the second was induced by CdS NCs. (B) Dependence of DECL intensity of CdS NCs (a) and luminol (b) on the number of HL-60 cells. Inset: linear relationship between DECL intensity of CdS NCs (a) or luminol (b) and the number of HL-60 cells. All the detection was performed in 0.1 M Tris-HCl buffer (pH 7.4) containing 16 mM H2O2. Scan rate: 100 mV/s. Scan range:
1.3 to 0.6 V. Reprinted with permission from Ref. [122].

this section illustrating the indirect methodology for the detection of alkaline phosphatase (ALP) developed by Nie at al. [128] In this case, in fact, the high ECL signal produced by luminol-AuNCs having an average diameter of 3–5 nm, was efficiently quenched by effectively by phenol, which was the catalysed product of phenyl phosphate disodium (PPNa) by ALP, giving a remarkable detection limit of 0.1 nmol L
1 and a very good correlation with GSCC method in real human serum samples.

6. Polymer dots (PD) and gels In recent years, conjugated polymer nanoparticles and polymer dots (PD) have been largely studied as new fluorescent nanomaterials and have attracted considerable interest thanks to their excellent combination between fluorescence brightness, fast emission rate and photostability. PD have been applied in biosensing [129], in vivo imaging, controllable drug and gene delivery [130], and single particle tracking [131]. In this context, ECL from PDs was firstly reported by Chang et al. [132] and after this example, they gained more and more interest as ECL emitters. In fact, as it was mentioned above for DDSNPs,

Fig. 12. Schematic diagrams of preparation of Ru(bpy)2+ 3 doped nanoprobe using PFO, hydrophobic Ru(bpy)3 2+ derivative, and PSMA; SNP detection with ligase detection reaction and nanoprobe. reprinted with permission from Ref. [133].

encapsulating a large amount of ECL active molecules into one nanomaterial for single target recognition can greatly improve the sensitivity of ECL assay. This concept was applied by Ju H. and co-workers [133] for the detection of Single-Nucleotide Polymorphism. In this case the luminescent conjugated polymer was synthesized by one-step nanoprecipitation using poly(9,9-dioctyl fluorenyl-2,7-diyl) (PFO) as carrier, hydrophobic Ru(bpy)3[B (C6F5)4]2 as ECL active molecule and poly(styrene-co-maleic anhydride) (PSMA) as functional reagent (see scheme Fig. 12). The resulting material show high dye doping level, such as 537, 1354 and 1897 Ru(bpy)2+ 3 for individual PD, and good solubility in water. The same authors presented the ECL performance of nontoxic PD based on poly[2-methoxy-5-(2-ethylhexyloxy)-1,4-(1-cyanovi nylene-1,4-phenylene)]. These PDs were used with ECL imaging method for the detection of metal ions archiving excellent analytical performance with high sensitivity and a wide detectable concentration range [134]. Another approach for the generation of stable colloidal nanoparticles is based on the nanoprecipitation in water of a spirofluorene derivative, which leads to fluorescent organic nanoparticles (FONs) showing strong ECL emissions [135]. Dai et al. synthesized stable and uniform PDs from poly[2-meth oxy-5-(2-ethylhexyloxy)-1,4-phenylenevinylene] (MEH-PPV) and capped them with the non-ionic surfactant Triton X-100 [136]. For the first time, ECL of these PDs was investigated showing excellent activity and high colloidal stability in aqueous medium. Recently, Sojic and co-workers presented a novel approach where PD combines the high ECL emission and stimuliresponsive proprieties. In this case a polymer based on poly(Nisopropylacrylamide) (pNI-PAM) hydrogels was used for the covalent incorporation of Ru(bpy)2+ 3 units. At the swell-to-collapse transition temperature, the film showed up to 58-fold amplification of ECL intensity, when either cationic or anionic coreactants were used [137]. Such a phenomenon was attributed to the decrease of the average distance between adjacent ruthenium centres that would favor electron hopping among them and, as a consequence, the annihilation mechanism, thus effectively contributing to the ECL enhancement. Extending this approach to nanoparticles [138], they also reported for the first time a thermoresponsive 100 nm gel PDs based on pNIPAM grafted with Ru-complexes showing an ECL enhancement by up to 2 orders of magnitude at the swell-to-collapse transition temperature [138]. Multicolor systems were also exploited by designing different thermoresponsive

G. Valenti et al. / Coordination Chemistry Reviews 367 (2018) 65–81

gels based on the luminescent resonance energy transfer characteristics [139]. Thus, the reported strategy provides ways to design thermosensitive ECL labels based on PDs. Another important application based on stimuli-responsive PD was recently reported by Marken and co-workers. They presented a novel organic polymer nanoparticles where the ECL emission is pH dependent and, even more interesting, the ECL is generated in coreactant free solution [140]. 7. Miscellaneous In addition to various kinds of nanoparticles described in previous paragraphs, other nanostructured materials have recently been developed and tested to enhance the capabilities of electrochemiluminescence based techniques. In particular, the recent results obtained with nanostructured materials discussed in this paragraph can be organized in two main classes: on one hand, nanostructured electrodes, films, membrane layers have been tested for their ability to increase the efficiency of molecular ECL probes; on the other hand, unconventional nanoobjects such as nanoclusters, nanoprisms and nanocrystals have been subject to thorough investigation concerning their ability to form luminescent excited states upon electrochemical stimulation. The examples available in the recent literature will be briefly described and discussed as follows. 7.1. Functional electrode surface An interesting approach to functional electrode surfaces was developed by the group of Qi, who grew a mesoporous film with vertically aligned silica nanochannels (SNC) on a ITO electrode. They report that vertically aligned SNCs with uniform pore size of 2–3 nm in diameter and negatively charged surface can significantly accelerate the mass transport of the positively charged Ru(bpy)2+ 3 , resulting in a remarkably enhanced ECL signal. The SNC-assisted electrode array was coupled to a low cost paper cover to achieve simultaneous detection of six samples in 1 min. Finally, they tested the resulting device by detecting a series of alkaloidal drugs both in buffers and in human serum, finding very good performances in terms of linearity and sensitivity, with limits of detection in the nanomolar range [141]. A different functionalization of the electrode surface was developed by Chen et al., by growing a negatively charged polymeric film on the surface of a glassy carbon electrode via electrochemical polymerization 3-amino-4hydroxybenzenesulfonic acid (AHBS) [142]. The functionalized surface has a layered structure -rich in anionic sites- useful for adsorption of positively charged ECL probes and/or analytes. The sofunctionalized electrode was soaked in Ru(bpy)2+ 3 solution, yielding an ECL active surface, with an ECL signal that is strongly dependent on several factors, such as the thickness and uniformity of PAHBS layer which depends on polymerization conditions (i.e. the concentration of AHBS), the amount of Ru(bpy)2+ 3 adsorbed on the electrode which is a function of absorbing time, and the testing conditions (the pH of PBS and scan rate). The authors applied this ECL-active surface for detection of cationic dye Malachite Green via quenching of Ru(bpy)2+ 3 . The use of nanostructured functional electrode surface can also provide other advantages, such as the ability to produce coreactant for the ECL process in situ, at the electrode surface. ECL is indeed strongly dependent on the presence of co-reactant, since the annihilation mechanism has nowadays become of marginal application. Specifically modified ECL probes may also play the game and limit the need for co-reactant, due to intramolecular electron transfer from Schiff base ligands to the Ru(III) center, leading to the efficient generation of the Ru(II)-based excited state

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without the need for external co-reactants. Nonetheless, preparation of such peculiar ECL probes is still difficult and expensive. Paolucci et al. developed a nanostructured electrode based on borondoped diamond (BDD) to perform oxidation of sulfate to persulfate, which in turn is reduced to the sulfate radical anion (SO
4 ), a strongly oxidizing intermediate able to trigger the formation of the excited state of Ru(bpy)2+ 3 . It has been shown that the ECL effi2
ciency for the Ru(bpy)2+ 3 /S2O8 is about half that of the annihilation system. Therefore, the in situ electrogeneration of peroxydisulfate was proven to represent a viable strategy to obtain a co-reactant-free ECL system. In fact, the co-reactant was generated, at will, and in situ, by applying a suitably positive potential in a solution containing the sulfate precursor followed by the step to negative potential that ignited the ECL emission [46].

7.2. Nanocrystals Beside using nanostructured materials to functionalize electrode surfaces, many groups have tried to investigate their own capabilities in enhancing ECL of other probes, or directly in yielding electrogenerated luminescent excited states. In particular, perovskite nanocrystals (NCs) have been subject to intense interest of researchers in the optoelectronic fields due to their exceptional long lifetime and diffusion length of injected charges and generated excited states. Only very recently they have been tested as ECL emitters by the group of Zou. They demonstrated first an annihilation mechanism, where perovskite NCs could be electrochemically reduced to negative charge states by injecting electrons into the lowest unoccupied molecular orbitals and oxidized to positive charge states by removing electrons from the highest occupied molecular orbitals; charge transfer between NCs with positive and negative charge states could produce ECL [143]. Then, also in collaboration with prof. Wang, they showed a ‘‘co-reactant” mechanism in which reactive oxygen species (ROS) involved anodic charge transfer to all-inorganic halide perovskite CsPbBr3 nanocrystals (NCs) [144]. CsPbBr3 NCs could be electrochemically oxidized to positively charged states by injecting holes onto the highest occupied molecular orbitals and could be chemically reduced to negatively charged states by injecting electrons onto the lowest unoccupied molecular orbitals by ROS. Other traditional co-reactant were also tested and proved to generate ECL emission from perovskite nanocrsytals. In the first case, in particular, the redox sequence applied on perovskite NCs played an important role, and transient ECL could be achieved only by electrochemically reducing positive-charged NCs in an annihilation route. In all mechanisms investigated, large redox currents were observed to be unfavourable for ECL. Importantly, the ECL spectra of perovskite NCs were almost identical to their photoluminescence spectra, with a maximum emission around 530–535 nm and full width at half-maximum around 20– 25 nm; this might open a way to obtaining monochromatic ECL. Nanocrystals of self-assembled zinc 5,10,15,20-tetra(4-pyri dyl)-21H,23Hporphine (ZnTPyP), using sodium dodecyl sulfate (SDS) as ‘‘soft template”, were obtained by Shan et al. They featured the morphology of hexagonal nanoprisms with a uniform size (diameter of 100 nm), markedly different spectral properties compared to those of the original ZnTPyP, and a notable ECL emission on glassy carbon electrode by using H2O2 as co-reactant [145]. Other unconventional nanostructures recently investigated as ECL emitters are metal-hydroxyquinoline-halogen (MqX, M = Cd, Cu; q = 8-hydroxyquinoline; X = Cl, Br, I) nanowires. Typical CdqX and CuqX nanowires feature diameter of 30–50 nm and length of 400–600 nm. Such nanowires exhibited excellent properties for photoluminescence, ECL, and photoelectrochemistry. In particular,

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G. Valenti et al. / Coordination Chemistry Reviews 367 (2018) 65–81

Table 1 Decision table for nanomaterials in ECL. Nanomaterial

Advantages

Disadvantages

Silica nanoparticles

    

Semiconducting nanocrystals (NCs) and quantum dots (QDs)

   

Simple and versatile synthetic schemes Enhanced signal intensity Water soluble Easy bioconjugation The matrix protect the dyes toward oxygen and other quenchings, increasing both quantum yield and photostability of the dyes Good photo- and electrochemical stability Functional flexibility Excellent optical properties such as size-dependent narrow and symmetric tunable emission High absorptivity and long fluorescence lifetime

Carbon based material and carbon nanodots

   

Water soluble Low toxicity Easy functionalization Self-internal standard

Gold nanoparticles

 Excellent conducting and electrocatalytic properties  The high surface area/volume ratio allows a great increase of the electrode surface, and their loading to form either multiple ECL labels or immobilize biomolecules

Polymer dots (PD) and gels

 Doped particles for enhanced emission  Good solubility in water  Multicolor systems

ECL was shown to be sensitive to the presence of H2O2 in the range of 2–14 lM, with a detection limit of 0.26 lM [146]. In addition, complex hybrid structures such as the one developed by Wei et al. combine palladium nanoparticles, grapheneaerogels, supported Fe3O4 and electrostatically adsorbed Ru (bpy)2+ 3 for enhancement in ECL efficiency. They also show application in a novel immunosensor test for the real-sample detection of prostate specific antigen and other biomarkers [147]. Among the smallest nanostructures recently investigated for ECL properties, bimetallic nanoclusters have shown interesting features, performing better than reference monometallic nanoclusters. Wang et al., inspired by the phenomenon of metal enhanced fluorescence, prepared and studied a series of bovine serum albumin-protected Au–Ag bimetallic nanoclusters, tuning the molar ratios of HAuCl4/AgNO3. Interestingly, manifold higher efficiency was achieved with bimetallic clusters in reference to the monometallic ones. Moreover, the ECL was quenched by Hg2+ due to the formation of metallophilic bond, allowing for demonstration of ECL sensing for Hg2+ [148]. Finally, molybdenum carbides nanostructures were recently involved in ECL investigations as nanocarriers for ECL probes, owing to their the two-dimensional ultrathin nanosheet structure on the surface and excellent conductivity. The resulting hybrid structures exhibited enhanced ECL performance (6-fold) as compared to individual probes because of the facilitated electron transfer process [149].

Applications

 Doping (organic or inorganic) dye is necessary  ECL efficiency depends from many factor (z potential, doping level, dye efficiency, coreactant used)

 Water solution by using the coreactant approach  Developed a label-free and sensitive ECL aptasensors  ECL immunosensors

 Need for passivation with a shell to enhance the ECL signal  Insolubility in aqueous medium limited their practical applications in bioanalysis  Imparting solubility to QDs by capping agents  Cytotoxicity  ECL depend on the size of nanomaterials and on the oxidation level  Most of the times the doping strategy is carried out by harsh conditions, especially for GQDs  Typically is very difficult to discriminate which contribution is prevalent in the generation of the ECL signal

 Imaging and biosensing applications  ECL emission by energy transfer of soluble CdTe QDs  DNA biosensors sandwich-type immunoassay for polyclonal antigens  Oxygen, hydrogen peroxide, cysteine, and are generally used as coreactants  Immunosensors based on the quenching effect  Often used in combination with luminol  Label-free DNA sensors and aptasensors  Detection of alkaline phosphatase  Detection of SingleNucleotide Polymorphism  Detection of metal ions  pH dependent emission

 Limited analytical applications

ultrasensitive detection method widely used in biological assays, due to the required small sample volumes and its wide dynamic range. Dye-doped nanoparticles, quantum dots, polymer dots and carbon-based nanomaterials are at the basis of innovative experimental protocols showing among the highest ECL signal amplifications. In this wide context, as this contribution aims to show, nanotechnology can allow to mark some key steps in the generation of a new level of sensitivity and accuracy of analyte detection to enable improved performance of applications in the fields of medical diagnostics and prognostics. In order to increase the readability of the very large state of the art we summarize, in a practical decisional table, all the nanomaterial reported herein (Table 1). In this critical table we summarize the general advantages and limitations of all individually mentioned nanomaterials in order to give a practical guide, for non ECL experts, for recognize and select the best nanomaterials for ECL signal amplification. We believe that there is still a huge room for improvement and that, for this reason, the research in this field will continue to grow at a very fast pace; the understanding of the mechanisms leading to the ECL generation involving complex systems such as nanoparticles will be fundamental to reach this important, and ambitious, goal.

Acknowledgments 8. Conclusions and perspectives In the quest for ultimate sensitivity in bioanalytical determinations, the integration of nanoparticles with ultrasensitive innovative electrochemical transduction methods is bringing the detection levels beyond the limit of ppb or pg mL
1, that has so far been restricted to other, technologically more demanding, techniques. ECL, and above all coreactant-Ru(bpy)2+ 3 based ECL, is an

We thank the University of Bologna, Italian Ministero dell’Istruzione, Università della Ricerca (FIRB RBAP11C58Y, PRIN2010N3T9M4), FARB, Fondazione Cassa di Risparmio in Bologna.

Declarations of interest None.

G. Valenti et al. / Coordination Chemistry Reviews 367 (2018) 65–81

Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.ccr.2018.04.011.

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