Quantum dots: electrochemiluminescent and photoelectrochemical bioanalysis.

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Quantum Dots: Electrochemiluminescent and Photoelectrochemical Bioanalysis Wei-Wei Zhao, Jing Wang, Yuan-Cheng Zhu, Jing-Juan Xu, and Hong-Yuan Chen Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.5b00497 • Publication Date (Web): 29 May 2015 Downloaded from http://pubs.acs.org on June 1, 2015

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Analytical Chemistry

Quantum Dots: Electrochemiluminescent and Photoelectrochemical Bioanalysis In this feature, electrochemiluminescent (ECL) and photoelectrochemical (PEC) properties and mechanisms of semiconductor quantum dots (QDs) are reviewed, with emphasis on their specific fundamentals and concise comparison on their similarities and differences. With recent illustrative examples of bioanalytical applications, the main signaling strategies for QDs-based ECL and PEC bioanalysis are then highlighted. The future prospects in this field are also discussed. † † † † † Wei-Wei Zhao, Jing Wang, Yuan-Cheng Zhu, Jing-Juan Xu,*, and Hong-Yuan Chen*, ,‡

† State Key Laboratory of Analytical Chemistry for Life Science and Collaborative Innovation Center of Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, Jiangsu, P.R. China. ‡ Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Shandong Normal University, Jinan 250014, Shandong, P.R. China E-mail: [email protected], [email protected]

ACS Paragon Plus Environment

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HISTORICAL PERSPECTIVE In 1983, the discovery of colloidal semiconductor nanocrystals or quantum dots (QDs) by Brus et al. at Bell Labs has inaugurated a new era in nanoscience and nanotechnology.1,2 These QDs are monodisperse crystalline clusters with physical dimensions (typically within several nanometers) smaller than the bulk-exciton Bohr radius, i.e., the distance in an electron-hole (e−h) pair.3,4 For three decades, the unique chemistry and physics of QDs have been stimulating explosive experimental and theoretical research in a broad range of fields including: (a) the development of synthetic techniques for the fabrication of various QDs with size, shape and/or composition control;5-10 (b) the modification of QDs surface with specific (bio)molecular components or functional moieties;11-15 (c) the exploitation and understanding of their electronic, mechanical, catalytic, electrochemical and photophysical properties;16-20 (d) their manifold implications in electronics, energy conversion and storage, optoelectronic devices, photocatalysis, photovoltaics, nanobiotechnology, and particularly, bioanalysis and biosensor development.21-25 From the seminal studies of Alivisatos26 and Nie27 in 1998, QDs, coupled with specific biomolecules, have opened almost unlimited possibilities for novel bioanalytical applications. Several review articles have well documented the rapid advances in this subject.28-35 Electrochemiluminescence (ECL), also called electrogenerated chemiluminescence, is the process whereby species generated at electrodes undergo high-energy electron-transfer reactions to form excited states that emit light.36-45 Though the phenomenon of light emission during electrolysis was observed in the late 1920s,46,47 the first detailed ECL studies were reported by Hercules and Bard et al. in the mid-1960s.48-50 This technique represents the marriage of electrochemistry with spectroscopy,51 which was applied for bioassay purposes in 1989.52,53 After many years development, ECL has evolved as a powerful analytical technique featured


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with rapidity, high sensitivity and selectivity.37 In the early 2000s, Bard’s group further found the ECL phenomena from a series of QDs.54-59 Soon after, Ju’s group proposed the first QDs-based ECL biosensor.60 These works catalyzed broad interest among the analytical community for both fundamental research on ECL properties of QDs and practical application of various QDs (e.g., II-VI, III-V and IV-VI) for ECL bioanalysis.37,39 Photoelectrochemistry (PEC), resulted from light-electrochemistry interaction, studies the oxidation-reduction chemistry of the ground or excited states of molecules or ions by photochemical and electrochemical methods.36,61-65 In 1839, the discovery of photoelectric effect by Edmond Becquerel66 has attracted substantial attentions, and in 1954, Brattain and Garrett launched the modern PEC science,67 which has been actively developing in different disciplines.68 For example, PEC splitting of water was historically discovered by Fujishima and Honda in 1972, which then inspired extensive studies aiming at solar energy conversion.69 Semiconductor particles were of interest initially with PEC processes such as driving redox reactions at their surfaces upon irradiation.70 Integration of PEC process with electrochemical bioanalysis has led to advanced methodology of PEC bioanalysis, which affords great opportunities to probe various biological events.28, 30, 71-73 In 1988, Hafeman et al. first proposed a light addressable potentiometric sensor (LAPS) for biochemical system,74 and Weber et al. reported an early PEC sensor for catalase activity in 1992.75 In the early 2000s, Willner’s group exploited the construction of QDs–biomolecule hybrid nanoarchitectures for PEC bioanalysis.76 Since then, analysts have been infatuated with the idea of using QDs as light harvesting components and/or signal reporters for PEC transduction of various biorecognition events or biocatalytic transformations.71-73 Figure 1 illustrates the time line of some important events related to QDs for ECL and PEC bioanalysis.


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Figure 1. Time line of some important events related to QDs in connection with ECL and PEC bioanalysis: 1839, discovery of the photoelectric effect;66 1954, modern PEC;67 1964, first ECL experiment;48-50 1965, ECL theory;51 1972, PEC splitting of water;69 1977, semiconductor particles for PEC application;70 1983, discovery of QDs;1,2 1988, invent of LAPS;74 1989, ECL for bioassay;52,53 1998, QDs for bioassay;26,27 2001, QDs for PEC bioassay;76 2002, ECL of QDs;54 2004, QDs for ECL bioassay.60

Essentially, both ECL and PEC detection rely on the photoelectric interconversion processes, and the ECL process reverses that of PEC.37,62 Figure 2 shows the general instrumentations of ECL and PEC bioanalysis. Due to such total separation and the different energy forms of the input and output signals (electricity/light vs. light/electricity), both ECL and PEC techniques have reduced background signals and thus potentially higher sensitivity compared to traditional electrochemical methods. Matched with such energy conversion process, QDs provide excellent ECL/PEC signal-transduction platforms for bioanalysis. Sharing an opposite process, there is obviously intimate link between QDs-based ECL and PEC bioanalysis. Clear discern of the


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charge transferring routes and the final destinies of these charges in QDs-based systems could offer much better understanding of this intrinsic relationship. After the above introduction with historical background, this feature will start by describing the ECL and PEC properties of semiconductor QDs and their critical mechanisms to bioanalysis development. Special emphasis will be focused on the fundamentals and concise comparison on their similarities and differences between ECL and PEC. With selected illustrative examples, the third section will summarize the present status of signaling strategies for QDs-based ECL and PEC bioanalysis. The conclusion remarks and development prospects in this developing field are then included in the fourth section.

Figure 2. Schematic representation of the general instrumentations of ECL (blue box) and PEC (red box) bioanalysis. In ECL process, species generated at electrodes undergo high-energy electron-transfer reactions to form excited states that emit light, which is then acquired by a photomultiplier. In PEC process, the photo-to-electric conversion will occur due to the charge excitation and transfer of a material upon light illumination.

ECL & PEC PROPERTIES AND MECHANISMS OF QDs


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ECL and PEC features of QDs are principally based on their electrochemical and photophysical properties. It is QDs’ ability to undergo energetic electron transfer that forms the basis for their luminescent (e.g. ECL, chemiluminescence (CL) and photoluminescence (PL)) and PEC properties. This section focusing on “property” and “mechanism” will address the questions of “what” and “how”. For a better understanding of these, it is necessary to first discuss some surface and electro chemistry of QDs. Surface & Electro Chemistry of QDs. From the view of crystallography, a single QD could be divided into two crystalline regions, one is the bulk phase (core part) where ions align periodically in long-range order and the other is the surface part with an asymmetric environment (resulting from the unpaired electrons, dangling bonds, and crystalline defects etc.).44 For 5 nm sized nanoparticles (NPs), one third of atoms locate at the surface, while for a 1 nm sized NPs this number is 99%.77 According to Bloch theorem, different structures have disparate electronic states and level distribution. Given their large surface-to-volume ratio, the surface atoms of QDs results in their surface state energy levels,39 and the cores of QDs have band gaps greater than the energy separation of these surface states. Thus, the photophysical properties of QDs, theoretically, should relate to both the band-gap component and the surface-state component.37,39 These surface states could exert good or bad influence when aiming for different purposes. Taking an example of PL of QDs could provide a better understanding of this. Due to the quantum size effect, PL is mainly originated from photoexcitation (Figure 3A) and the subsequent e−h recombination from the core part (electronic or band-gap transition).39 For ideal QDs without surface defects, it will produce a narrow and sharp PL spectra and the band-gap width of the QDs can be deduced from the central PL wavelength position.78 For realistic QDs with surface defects, these surface energetic states could trap the excited electrons/holes that


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migrated from the conduction band (CB)/valence band (VB), resulting in the surface-staterelated e−h recombination and emission (surface-state transition). It will produce a broad, asymmetric and red shifted PL peak with a non-zero background tail.55 This role of surface states as quenching centers will cause a drastic reduction of PL quantum yields of QDs. Given the importance of preserving PL properties for bioanalysis applications, many works have been done for the surface passivation of QDs with protective layers in order to minimize the surface traps. Commercial QDs for PL purposes are commonly fabricated in a core-shell structure like ZnS@CdSe QDs to passivate the surface states for efficient PL intensity.79,80 Incidentally, inefficient surface passivation may generate multiple surface energy levels.

Figure 3. (A) Photoexcitation (PE, left part) and electrochemical electron processes (EC, right part) at a single QD with its core and surface parts and corresponding energy bands of CB and VB in connection with an electrode. In PE, electrons are excited from the occupied VB to the empty CB and thus forming electron−hole pairs. If in a PL process, the excitons recombination mainly occurs via the band-gap transition rather than the surface-state one. If in a PEC process, as discussed later, the excitons are commonly steered to react with solution species. In EC, surface states with lower energy levels would be more easily occupied by charge carriers than the band gap of core part. (B) Schematic representation of electrochemical reduction and oxidation of a single QD. ● and ○ refer to the electron and hole, respectively.

While absorption and PL spectroscopies mainly probe the interior of QDs and offer information about the electronic transitions (band gap) of the material, electrochemistry mainly


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probes the surface of QDs. Figure 3B displays the electrochemical reduction and oxidation of a QD. Under specific electrochemical conditions, the addition of an electron into the QD would cause its reduction and the generation of QD•-, whereas the removal of an electron from the QD •

would cause its oxidation and the generation of QD +. In other words, the CB and VB of an •

•

individual QD can accept (electron-injected, QD -) or donate (hole-injected, QD +) electrons, respectively, to produce a single QD anion or cation radical. In general, three different paths are followed when electrons are injected or removed from QDs: (a) Charging. Addition or removal of charges from elemental QDs (e.g. Si and Ge) would simply lead to the charging of these QDs, and multi-electron charging can last until the field at the surface of QDs becomes high enough to drive an electrochemical reaction; (b) Decomposition. Charge addition or removal can also lead to reduction or oxidation reactions of the compositions of compound QDs. For example, for CdS QDs, electron addition or removal can result in the generation of elemental Cd and S, respectively; (c) Doping. Charge added to the QDs can be compensated by moving an ion into the QDs lattice. Electron injection or hole injection could be compensated by a cation or an anion, leading to “n-doping” or “p-doping”, respectively. For a deep discussion of the electrochemistry of various QDs, readers are referred to a comprehensive review of this topic.39 ECL & PEC Property of QDs. ECL property of QDs also correlates to both the surface-state and band-gap transition, and thus it is rational to classify ECL of QDs into two basic types: the surface-state type and the band-gap type.40 Figure 4A illustrates a cathodic ECL of QDs with the two types. Essentially, ECL of QD is an electro-driven potential-dependent process and the charge carriers communicate between the QDs and electrode/coreactant via their surface states. Upon an increased potential scan, since the surface states in general have lower energies as compared to that of the core part, they would be first occupied by charge carriers from the


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electrode/coreactant, generating the surface-state ECL that obviously red-shifted as compared to their PL. Further increase of the applied voltage would lead to the injection of charge carriers into the higher energy levels of the QDs cores, generating the band-gap ECL emission that sometimes matched perfectly with PL. It not only explained why the surface states would peak earlier than the band gap in electrochemical studies,81-83 but also reflected the relationship between ECL and PL: despite with different excitation source, they are both the light emission resulted from the radiative e−h recombination. Obviously, compared with PL, ECL depends more sensitively on surface chemistry and the presence of surface states. In other words, PL specializes in exploiting the interior information of the band-gap transition, whereas ECL generally more experts in probing the surface chemistry of surface-state transition. In fact, besides the applied voltage, whether ECL is originated from surface states or band gap also relies on the used QDs themselves (e.g. composition, volume or morphology). And, according to the structure rheology, it is possible to adjust the QDs to manipulate their ECL varying between surface-state type and band-gap transition type. On one hand, for harvesting the surface-state ECL, one could intentionally change the stoichiometric ratio or arrange specific moieties on the surface of QDs. For instance, dual ligands of mercaptopropionic acid and sodium hexametaphosphate can hinder the formation of a well-coated shell and thus create a large number of surface states.44 A more recent example is that the activation of CdS QDs by H2O2 and citric acid could result in about 58-fold enhancement of ECL intensity.84 On the other hand, to eliminate the surface-state ECL, one could passivate the surface of QDs intentionally. For example, the synthesis of core-shell structure could inhibit the surface states of QDs. Besides, the shell components85-87 and numbers88 could further regulate the wavelength and intensity of the ECL emission. Note that doped QDs (e.g. Se, Mn, Co and Eu doped QDs ) could possess


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unexpected ECL behaviors as compared to the intact QDs.44,45 Moreover, similar to that of PL, band-gap ECL is also size-dependent and tunable due to the quantum confinement effect of QDs, though the reports on this topic are rather few.89,90 Among the two basic ECL types, because the carrier communication is generally assumed to occur via the surface states, the surface-state type has been recognized as the main type of ECL of QDs and possesses several superiorities over the band-gap type. Specifically, it is more susceptible to the surface states and can be employed to study the surface chemistry and charge transfer dynamics. What’s more, signals of the surface-state ECL always arise at a longer wavelength with a lower over potential, which undoubtedly is good for keeping the bioactivities of bioassay systems as well as inhibiting the interference from the coexisting electroactive species, thus permitting the sensitive and low-potential ECL bioassay applications. In contrast, the band-gap ECL also has its distinctive applications, e.g., for multiplexed bioassays and others.

Figure 4. Comparison of (A) ECL and (B) PEC property of QDs, both with cathodic ones as examples. The red arrows display the main routes in the corresponding ECL and PEC processes. In figure A of ECL, the electrons and holes are injected by electrode and coreactant, respectively. Surface states with lower energy levels will accept them before the band gap. In figure B of PEC, upon illumination, electrons can be excited from the VB of QDs to the CB and then to react with the solution-solubilized electron acceptor A, with the concomitant transfer of electrons from the electrode to the VB of QDs.

PEC property of QDs is the overall result of several factors (e.g. light intensity, the bias potential applied, the absence/presence of electron donor/electron acceptor as well as the


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photophysical properties of QDs themselves.) in a complex situation.71,72 Figure 4B depicts the typical cathodic photocurrent generation of QDs. Basically, the electrons can be excited from the VB of QDs to the CB upon the absorption of a photon with the energy exceeds the band-gap energy (hv > Ebg). This is the primary event in the conversion of light to electricity. The Ebg therefore sets the threshold response (λbg) for photon absorption, and different QDs possess disparate values of Ebg and λbg. For specific QDs, photons at wavelength greater than λbg are not absorbed by the QDs, whereas photons at wavelengths shorter than λbg are absorbed within a short distance of the QDs surface. For QDs associated electrodes, Fermi levels (Fermi energy) are also crucial for the PEC property of QDs. Fermi level is the energy (Ef) at which the probability of an energy level being occupied by an electron is exactly 1/2. In intrinsic (undoped) QDs, the Ef occurs approximately midway between the CB and VB edges, and the Ef of QDs can be manipulated by the applied potential. The energy difference between the two Fermi levels in the QDs and the electrodes would decide the direction of electron transfer between them.63 All theoretical and experimental studies describe the same above concepts, which have been presented in numerous current books and articles. PEC property of QDs also relates to the surface states. Significantly, their roles, in whether or not the photocurrent direction follows the applied bias voltages, have been a subject of controversial scientific debates.30 Several studies claimed that these surface traps played a crucial role for the resulting photocurrent, and the photocurrent direction doesn’t follow the bias voltages. For example, different directions in the photocurrent of PbS QDs have been observed for the same bias voltage range. In another work, both positive and negative bias voltages have resulted in the same positive photocurrents of multilayers of QDs on gold electrodes.91,92 However, most results suggested that the photocurrent couldn’t be disturbed by the surface states,


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and the photocurrent direction was clearly reversible and controlled by the applied bias voltages. Specifically, the bias voltages that are more negative than the Fermi level would result in negative photocurrents and, conversely, bias voltages that are more positive than the Fermi level would result in positive photocurrents. For example, it has been observed that the photocurrent direction followed the switching of bias voltages, and the photocurrent responding followed the absorption spectra of QDs.76,93 Similar to their ECL property, the observational discrepancies in the PEC property of QDs could be attributed to the used QDs themselves. The presence of excessive surface states (with varied energetic levels) and high probability of the trapping occurrence would depopulate the charge carries and reduce the charge transfer rate between QDs and electrodes/solution redox species, and thus rendering the unidirectional photocurrent. For QDs with fewer surface states, trapping of the charge carriers in these surface states may yield sufficiently long-lived e−h pairs that are advantageous to photocurrent generation. Identically, the undesired role of the surface states could be diminished by advanced synthesis of QDs. ECL & PEC Mechanism of QDs. The ECL mechanism of QDs involves the general annihilation and coreactant pathways.42 In the first QDs-based ECL study in 2002,54 the ECL of Si NPs was generated from both annihilation and coreactant systems. In the annihilation pathway, as discussed in electrochemistry of QDs, the electrochemical potential sweeping or differential pulsing of QDs at the electrode surface could generate both oxidized (QD•+) and reduced QD (QD•-) species. The subsequent radical collision and annihilation of QD•+ and QD•- would form a ground state QD and an excited state QD* that emits light.43 Though annihilation ECL does not necessitate additional coreactants, radical QDs must be chemically stable and survive long enough until colliding with oppositely charged QDs. Moreover, this type ECL requires high over potentials to overcome the surface energy of the QDs, which further restricts its practical


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applications. Thus, modern ECL applications of QDs are almost exclusively based on the coreactant ECL because of the higher ECL intensity. In the coreactant pathway, ECL is usually generated by one-directional potential scanning on the electrode in the presence of both luminophore QDs and a heterogeneously introduced coreactant, which should possess good solubility, stability, rapid kinetics, electrochemical properties and low ECL background. Unlike the annihilation pathway which needs both QD

•+

•

and QD -, the coreactant pathway, upon •

oxidation or reduction, would produce QD* via electron transfer between either electrolytic QD + or QD

•-

and the strong reducing or oxidizing intermediate of the coreactant. Although the

involvement of coreactant complicates the general ECL process, the coreactant pathway indeed could achieve more efficient and sensitive ECL and of wider practical applications.40 Based on the role of coreactant as a reductant or an oxidant, the coreactant ECL could further be divided into the “oxidative-reduction” (O-R, anodic) ECL and the “reductive-oxidation” (R-O, cathodic) ECL (Figure 5A). Typical coreactants include: tri-n-propylamine, dibutylaminoethanol, O2, H2O2, S2O82-, C2O42-, SO32- and CH2Cl2 et. al.41,43 The specific ECL reactions using these coreactants will not be discussed here, and interested readers are referred to well-documented literatures of this topic.40-45

Figure 5. (A) anodic and cathodic ECL mechanisms of QDs. In anodic ECL, the electrode first injects a hole to the VB of QDs, with the concomitant injection of an electron from the coreactant (after oxidation by electrode). Then the recombination of


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electron and hole would lead to an anodic ECL emission. In cathodic ECL, the roles of electrode and coreactant, i.e., the origins of the electron and hole, are exchanged. Noted that the use of CB and VB here may be not fully precise, because the locations of the electron and hole may also be surface energy states. (B) anodic and cathodic PEC mechanisms of QDs. In anodic PEC, photoexcitation of the QDs results in the transfer of electrons from VB to CB, thus yielding electron–hole pairs. Then the ejection of the CB electrons to the electrode, with the concomitant transfer of electrons from a solution-solubilized electron donor D, generates an anodic photocurrent. In cathodic PEC, the transfer of the CB electrons to a solution-solubilized electron acceptor A, with the concomitant ejection of electrons from the electrode to the hole in VB, produces a cathodic photocurrent.

The PEC mechanism of QDs mainly involves the donor-acceptor pathway, which could also be organized into two submodes: anodic and cathodic ones. As known, at proper bias voltages, when QDs absorb photons with energies > Ebg, electrons are excited from the occupied VB to the empty CB, thus forming e−h pairs. Once the charge separation occurs, the e−h would be destined for charge transfer or recombination. There would be two choices for the transfer of CB electrons. As shown in Figure 5B, the tunneling of CB electrons to the electrode, with the simultaneous transfer of electrons from reducing molecules (electron donors, D) in the surrounding solution to neutralize the VB holes, yields an anodic photocurrent. In contrast, transfer of CB electrons from QDs to oxidant molecules (electron acceptors, A) in solution phase, with the concomitant electron transfer from the electrodes to sacrifice the VB holes of QDs, generates a cathodic photocurrent.71-73 Obviously, the presence of the efficient D/A is of great significance; it would inhibit the exciton recombination and benefit the production of a stable and high photocurrent. On the contrary, the absence of these D/A could cause unfavorable results; take CdS QDs for instance, the absence of D could lead to the corrosion process (lattice dissolution) of CdS QDs under illumination: 2h+ + CdS → Cd2+ + S.74 The irradiation light intensity, the property of linker layer for QDs immobilization, the applied bias voltage and D/A concentrations will all affect the output characteristics of photocurrent. It can also be seen that, under appropriate conditions, photocurrent strength is in proportion to D/A concentration and also the applied bias


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voltage in specific ranges. Note that some work manipulated the formation and the annihilation of the exciton to influence photocurrent generation of QDs. For example, new surface states were created to form the surface traps for enhanced exciton recombination.95 Clearly, ECL is more prone to express the surface states of QDs while PEC is more inclined to reflect the photophysical property of the bulk phase of QDs. For bioanalytical applications, since both the QDs based ECL and PEC bioassays benefit from the separation and the different energy forms of the excitation and detection signals, the two techniques possess higher sensitivities as compared to the conventional electrochemical technique. In principle, because ECL and PEC bioassays employ emitted light and electricity as respective outputs, ECL could provide more information and PEC possesses potentially higher sensitivity. Comparatively, the uses of various coreactants would cause very complicated ECL processes than the PEC ones. And another advantage of PEC bioassay is that it permits zero-potential detection which is obviously desirable for retaining the bioactivities of the attached biosystems. In contrast, the ECL necessitates a certain, perhaps low, potential for the redox process of QDs, which will inevitably impair the bioassay by various coexisting electroactive interferents. SIGNALING STRATEGIES FOR QDs-BASED ECL & PEC BIOANALYSIS As stated before, with the capacity of control that can be engineered over the sizes, shapes and compositions of nanoscale precision, QDs have offered unprecedented opportunities for a plethora of bioassay techniques. To achieve QDs-based ECL and PEC bioanalysis, there are in general four aspects worthy of attention, i.e., synthesis and modification of proper QDs, assembly of QDs onto the electrodes, functionalization of QDs with biomolecules and integration of QDs bioconjugate into specific ECL/PEC bioanalysis systems. With recent illustrative examples, this section will highlight the main signaling strategies for QDs-based ECL


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and PEC bioanalyses from the view of using recognition events to impact on (1) the solution species, (2) the interfacial electron/mass transfer, and (3) the QDs (the QDs associated electrode or QDs reporters). On Solution-solubilized Coreactants or Electron Donor/Acceptor. Among these three strategies, on solution species seems to be the simplest way for the QDs based ECL and PEC bioanalyses. From the discussion about ECL mechanism, we have known that modern ECL applications of QDs are almost exclusively based on the coreactant ECL, and the corresponding ECL strength is highly dependent on the coreactant concentration, i.e., it will result in the ECL enhancement or quenching of QDs. Typically, dissolved oxygen (O2) and hydrogen peroxide (H2O2) are not only the basic ECL coreactants of QDs, but also the reactant or reaction product of enzyme-catalyzed reaction. One of the primary ECL methods was designed on the basis of the production or consumption of ECL coreactant in an enzymatic reaction in order to affect the ECL intensity. For example, based on the enzymatic generation of H2O2, an ECL “signal-on” enzyme biosensor was fabricated for detection of choline and acetylcholine based on the use of multi-walled carbon nanotubes (MWCNT)/CdS QDs composite.96 The MWCNT/CdS can react with the generated H2O2 to produce strong and stable ECL emission in neutral solution, and the MWCNT/CdS can greatly enhance the ECL intensity and move the onset ECL potential more positively for about 400 mV as compared with pure CdS QDs. In contrast, to consume coreactant is a more general ECL method for the “signal-off” ECL bioanalysis. For instance, Ju’s group used the enzymatic reactions of acetylcholinesterase and choline oxidase to consume dissolved O2 so as to decrease the ECL signals of QDs upon addition of the substrates, and thus realized the fast ECL responses to acetylcholine and choline with acceptable sensitivity.97 Using hemin/nitrogen-doped graphene (NG) as a novel tracing tag, a sensitive CdTe QDs based


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sandwich immunoassay was achieved because the tag could effectively quench the cathodic ECL emission of QDs via the consumption of dissolved O2.98 Interestingly, G-quadruplex-based DNAzyme can catalyze the reduction of dissolved O2 or H2O2 by some redox-active reagents. In a sandwich immunoassay, Lin et al. proposed the use of G-quadruplex-based DNAzyme to catalyze the reduction of dissolved O2 to quench the cathodic ECL emission of CdS QDs.99 As shown in Figure 6, based on K-doped graphene/CdS:Eu QDs and nicking endonuclease assisted strand-scission cycle, Zhou et al. reported the use of G-quadruplex-based DNAzyme as the electrocatalyst for the reduction of H2O2, which resulted in an obvious decrease in ECL intensity and thus achieved sensitive DNA detection.100

Figure 6. (A) Fabrication process of K-doped graphene–NC (K-GR–NC) composites modified glassy carbon electrode (GCE). The composites were prepared via electrostatic interactions between negatively charged 3-mercaptopropionic acid (MPA) modified

CdS:Eu

NCs

and

positively

charged

graphene,

which

was

noncovalently

functionalized

with

poly(diallyldimethylammonium chloride) (PDDA) via electrostatic interactions. (B) Detection principle of the ECL DNA biosensor. First, when target DNA hybridizes to the hairpin DNA, the stem of the hairpin DNA is opened. Then Nicking endonuclease (NEase) nicks the cleavage site and only the G-rich sequence remains on the electrode surface. The released target DNA can hybridize with a new un-nicked hairpin DNA and initiate the second cycle of cleavage. Finally, a G-quadruplex–hemin DNAzyme could form with the help of the hemin and K+, which electrocatalyze the reduction of H2O2, the coreactant for


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cathodic ECL emission, leading to an obvious decrease in ECL intensity. Reprinted from ref 100. Copyright 2013 Royal Society of Chemistry.

In PEC bioanalysis, the direct redox reactions of the QDs towards biochemical species in solution enables the simplest method for biomolecular detection.101-103 Upon such simple mechanism, the CdS QDs/Indium Tin Oxide (ITO) electrode fabricated by Long et al. permitted specific and sensitive detection of cysteine.101 Obviously, in PEC systems, enzymes could also be recruited as catalysts to produce soluble products acting as electron-acceptor or electron-donor to trigger photocurrent generation. Photocurrent can be enhanced by redox reactions between the photogenerated electron or hole and these active species in solution.104 Similarly, the QDs in the PEC system are also sensitive to the dissolved O2 and H2O2, which as stated above are the reactant or reaction product of enzymatic reaction. For example, the biocatalyst of glucose oxidase (GOx) can oxidize its substrate glucose by the reduction of dissolved O2 to generate gluconic acid and H2O2. Based on this biocatalytic system, various works have been reported for immunoassay,105 glucose detection106 and enzymatic activity evaluation.107 A typical illustration described by Tanne et al. was that they integrated GOx with CdSe/ZnS QDs to investigate the influence of O2 content in solution, glucose concentration as well as GOx activity.107 Note that O2 has been found more efficient than H2O2 for both ECL108 and PEC106 properties of QDs. Instead of GOx, other enzymes such as acetylcholine esterase (AChE),109 alkaline phosphatase (ALP),110,111 β-galactosidase (β-Gal),112 glucose dehydrogenase (GDH)113 and DNAzyme114 should also be possible for similar PEC applications. For instance, as demonstrated in Figure 7, with a CdS QDs equipped TiO2 nanotubes (NTs) electrode, an exquisite PEC immunoassay was developed for the sensitive and specific detection of prostate-specific antigen (PSA) based on in situ production of electron donor ascorbic acid (AA) via efficient ALP catalytic chemistry.110 Recently, using a CdS QDs/TiO2 NPs electrode, an advanced PEC immunoprotocol with


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innovative signaling mechanism was developed through the β-Gal catalytic system and the cardiac marker troponin T (cTnT) could be detected at neutral conditions.112

Figure 7. CdS QDs equipped TiO2 NTs-based sandwich-type PEC PSA assay with immunogold labeled ALP catalyzed AA production for in situ electron donating. CdS QDs equipped TiO2 NTs were fabricated via a facile electrostatic adsorption method. The coupling of CdS QDs and TiO2 NTs results in an enhanced excitation and photo-to-electric conversion efficiency. ALP could catalyze the in situ generation of AA, based on which an exquisite immunosandwich protocol could be constructed for the PSA assay due to the dependence of the photocurrent signal on the concentration of AA. Reprinted from ref 110. Copyright 2012 American Chemical Society.

On Interfacial Dynamics on the Electrode. Similarly, another relatively simple strategy is to impact the interfacial electron/mass transfer. For ECL systems, the generation of steric hindrance by the biorecognition events on the electrode surface could not only impede the mass transfer of the coreactant but also decelerate the interfacial electron transfer. As a consequence, the ECL signal will be reduced corresponding to the specific binding reaction. This strategy is mainly used for “signal-off” protein assay and cytosensing. For example, magnetic Fe3O4/CdSe@CdS nanoparticle/polyelectrolyte nanostructures have been used to fabricate such an ECL immunosensor for the detection of protein tumor marker carcinoembryonic antigen (CEA).115 Using CdTe QDs modified ITO electrode, Wang et al. have designed an ECL cytosensor for


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label-free and sensitive detection of HeLa cell. Due to the volume and insulation of cell adhesion on the electrode, it shows greater spatial hindrance and hence more effective impedance of the mass transfer of the coreacted dissolved O2.116 Towards human leukemic K562 cells, another steric hindrance-based ECL cytosensor for sensitive dynamic monitoring of carbohydrate expression on living cells was designed by combining the specific recognition of lectin to carbohydrate groups with the functionalization of immobilized CdSe QDs.117 Xu’s group integrated biocatalytic precipitation (BCP) with ECL biosensor and found thin precipitate coverage could effectively inhibit the reaction between coreactant K2S2O8 and CdS QDs.118 Because various enzymes could also stimulate the formation of BCP, this simple model work affords a new possibility for the development of advanced sensitive ECL bioassay. As shown in Figure 8, the binding of transcriptional factor TATA-binding protein (TBP) to its sequencespecific DNA could kink the DNA duplex and perturb the base pair stack, resulting in prominent steric hindrance to hamper the diffusion of ECL reagents towards the electrode surface.119


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Figure 8. The analytical procedure of the amplified ECL assay of TBP. (A) The SiO2 nanoparticles were employed to load a large number of CdS NCs with the aim of amplifying the ECL signal and then the biobarcode (bbc)-DNA and DNA duplex that contains the TATA box. (B) K-doped graphene was modified with abundant streptavidin through the electrostatic adsorption of PDDA, and then coated onto the electrode. (C) The binding of transcriptional factor TBP to its sequence-specific DNA on Kdoped graphene modified glassy carbon electrode (GCE) surface could kink the DNA duplex and perturb the base pair stack and also generate obvious steric hindrance, the resulted ECL biosensor could thus achieve the sensitive detection of TBP. Reprinted from ref 119. Copyright 2012 Royal Society of Chemistry.

In PEC bioanalysis, numerous steric hindrance-based works have been reported on the basis of blocking the diffusion of sacrificial species to electrode surface.120 For example, using a CdS QDs modified electrode, Wang et al. developed the first label-free PEC immunosensor for the detection of mouse IgG.121 The target concentration could be measured through the attenuation in photocurrent intensity resulting from the increase in steric hindrances due to the formation of immunocomplex.122 Similar mechanism was chosen in a series of following works.123-125A label-


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free PEC immunosensor based on CdSe0.75Te0.25/TiO2 NT electrode was developed by Cai’s group for the detection of environmental pollutant pentachlorophenol.123 They later constructed CdTe@CdS QDs/TiO2 NTs and ZnS/CdTe/Mn–CdS/ZnS QDs/ZnO nanosheet electrodes for the detection of toxicant octachlorostyrene and pentabromodiphenylether, respectively.124,125 Using CdS:Mn/CdTe QDs cosensitized TiO2 NTs electrode, Zhu et al. then proposed an enhanced sandwich immunoassay for the detection of matrix metalloproteinase-2 via the signal amplification of SiO2@Ab2 conjugates.126 Upon various QDs-based composites, many other PEC protocols were reported for aptasensing127 and cytosensing.128,129 Via BCP-induced insulating effect that impair the interfacial electron-transfer capacity of electrode, as shown in Figure 9, horseradish peroxidase (HRP)-induced BCP was integrated into a CdS QDs-based sandwich PEC immunoassay system for the sensitive protein detection.130,131 Using CdSe QDs composites and HRP-induced BCP, another competitive PEC immunoassay was then developed for CEA detection.132 Using G-Quadruplex DNAzyme to induce BCP on a CdS QDs electrode, Han et al. proposed a sensitive method for Pb2+ detection.133

Figure 9. Development of the amplified QD-based sandwich PEC immunoassay with HRP-catalyzed BCP format. The hybrid film consisting of oppositely charged polyelectrolytes and CdS QDs is developed by the classic layer by layer method and then employed as the photoactive immobilization matrix for the subsequent sandwich-type Ab-Ag affinity interactions. Improved


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sensitivity is achieved through using the bioconjugates of HRP-detection antibodies. In addition to the much enhanced steric hindrance compared with the original one, the presence of HRP would further stimulate BCP onto the electrode surface for signal amplification, concomitant to a competitive nonproductive absorption that lowers the photocurrent intensity. Reprinted from ref 130. Copyright 2012 American Chemical Society.

On QDs-Associated Electrode or QDs Reporters. Utilizing recognition events to affect QDs is another convenient avenue for signaling. For example, it is found that the deposition of electropolymerized phenol products may compete with electrophoretic-driven adsorption of CdSe QDs on glassy carbon electrode and induce ECL inhibition.134 In an amplified ECL detection, cyclic amplification technique could lead to enhanced release of composite Fe3O4@CdSe QDs from electrode and thus the decrease of ECL signal.135 Recently, ECL resonance energy transfer (ECL-RET), as a rising powerful technique for probing the change in the distance between energy donors and acceptors, has been served as a new ECL sensing strategy. Since the first work on the ECL of Mn-doped CdS QDs quenched by proximal Au NPs in 2009,136 a series of ECL-RET biosensors have been reported. Thanks to the high extinction coefficient and the broad absorption spectra of metal NPs, it is facile to overlap with the emission spectra of usual energy donors with QDs in the energy transfer systems. Experimentally, it was found the surface plasmons of Au NPs can greatly affect the ECL intensities of QDs, in which the ECL intensity is either enhanced or diminished by the proximal Au NPs. Upon such mechanism, various ECL biosensors addressing ions detection,137 DNA assay,138 aptasensing,139 protein assay140 and cytosensing141 were reported. To better understand the interaction between ECL of QDs and ECL-induced surface plasmon resonance (SPR) of Au NPs, the influencing factors such as separation distance, spectral overlap, and magnetic field were further investigated.139 Other than the metal NPs, several works also suggested that the QDs partners can be the traditional luminophore e.g. luminol or Ru(bpy)32+. In Dong’s work, the anodic luminol


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ECL could be enhanced greatly on the CdSe@ZnS QDs electrode due to the catalytic effect of QDs on the oxidation of luminol.142 The capture of Ru(bpy)32+ labeled cells on CdS QDs modified electrode would bring Ru(bpy)32+ near the CdS QDs and thus making RET happened.143 As shown in Figure 10, integrated with an microfluidic device platform, similar mechanism permits the on-chip multiplex immunoassay of protein biomarkers on cancer cell surface.144 Coupling with ratiometric sensing, Zhang et al. then reported a novel dual-potential ECL ratiometric sensing approach. Specifically, ECL from CdS QDs on electrode could be quenched by closely contacted Pt NPs via a biological binding event, while ECL from luminol could be enhanced by the same Pt NPs.145 Shortly afterward, a type of signal-on dual-potential ECL approach for telomerase detection based on bifunctionalized luminol−gold (L−Au NPs) was reported. In the presence of telomerase, L−Au NPs could not only enhance the ECL intensity of CdS QDs induced by the SPR of Au NPs but also produce a new ECL signal that resulted from luminol in L−Au NPs.146 For energy transfer between QDs themselves, Zhu and co-workers explored the ECL-RET properties in CdSeTe@ZnS-SiO2 QDs bilayers and developed a novel ECL immunosensor for CEA detection. Benefiting from a short interlayer distance and perfect spectral overlap in the graded-gap QD bilayers, highly efficient ECL-RET based energy funneling was observed.147 Shan et al. found CdTe QDs after activation of surface carboxyl groups could perform like black bodies and can effectively scavenge ECL energy due to their natural large absorption cross-section.148 The blackbody effect of the activated CdTe QDs could be further improved by integrating with SiO2 NPs149 or MWCN.150


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Figure 10. Layout of a microchip for multiplexed immunoassay, and the principle of competitive ECL-RET process in determination of antigen specific cells and receptor specific cells. It employed a 64-site antigen/CdS nanorod spots array to realize spatial resolution between adjacent detection locations. Based on the competitive immune reaction between cell surface antigens and the immunocomplex on the CdS nanorod surface, this microchip device exhibited an excellent identification and quantitative detection of cells in a complex matrix. Reprinted from ref 144. Copyright 2012 American Chemical Society.

Using recognition events to affect QDs species directly is also an effective approach for PEC bioanalysis. For example, in situ generation of CdS QDs, by HRP catalyzed reduction of Na2S2O3 with H2O2 to generate H2S that reacted with Cd2+, on graphene oxide (GO) was applied for the PEC immunoassay of CEA.151 Willner’s group has confined QDs to the electrode surfaces to form QDs–biomolecule hybrids associated with electrodes that enabled the photocurrent generation.76 Two examples are that CdS QDs were confined onto the electrode surfaces through boronate affinity and self-assembly of aptamer subunits for the determination of tyrosinase activity and cocaine, respectively.152,153 Another interesting method is the use of chemiluminescence (CL) to replace the external light for PEC bioanalysis.154 Tu et al. then constructed a new PEC immunoassay on the dependence of increased photocurrent response on the enhanced CL irradiation upon CdS QDs.155 Upon such mechanism, some other applications were then reported.156 By contrast, reduced irradiation on QDs by competitive light absorption may also offer a route for PEC bioanalysis.130,132 Significantly, RET has also been found in PEC


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systems and explored for novel bioanalysis. Under illumination, the interparticle energy transfer between CdS QDs and Au NPs will occur and could damp the photoresponse of the QDs.157 Further investigation with Ag NPs, as shown in Figure 11, demonstrated that the photoresponse of the QDs could be manipulated via tuning interparticle distances and even be completely damped by the generated exciton-plasmon interactions (EPI).158 Since the degree of interparticle interaction was directly related to the concentration of noble metal NPs-labeled target, these reports provided a new mechanism for subsequent PEC biodetection. For example, with the RET between CdTe QDs and reduced graphene oxide-Au NPs nanocomposites, a PEC protocol was developed for signal-on aptasensing of CEA.159 Based on the RET between CdSe QDs and Au QDs, a recent work reported a PEC assay for DNA methyltransferase activity and inhibitor screening.160 Using hemin/G-quadruplex-stimulated chemiluminescence resonance energy transfer (CRET) generation of photocurrents, Golub et al. demonstrated an interesting PEC system for probing enzyme activities and DNA sensing without external illumination.161

Figure 11. The schematic mechanism of EPI between CdS QDs and Ag NPs in a PEC system. With DNA as a rigid spacer, Ag NPs were bridged to CdS QDs for the stimulation of EPI in a PEC system. Due to their natural absorption overlap, the exciton of the QDs and the plasmon of Ag NPs could be induced simultaneously. The EPI resonant nature enabled manipulating photoresponse of the QDs via tuning interparticle distances. Reprinted from ref 158. Copyright 2012 American Chemical Society.


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CONCLUSIONS AND PERSPECTIVES We have witnessed the exponential growth of research interests and activities in QDs during the past years. The unique electrochemical and photophysical properties of QDs have found growing applications in a spectrum of fields. Especially, in bioanalytical areas, QDs afford exciting opportunities for specific and sensitive detection of numerous biochemical species. Through steering the energetic electron transfer for photo-electric interconversion processes, QDs functionalized with various biomolecules could offer unique platforms for ECL or PEC signal-transduction of novel biomolecular detection. The resulted QDs-based ECL and PEC bioanalysis have long been of considerable interest because of their exquisite routes for probing numerous biorecognition and biocatalytic events. The long-term needs in clinical diagnosis and industrial analysis have and will continue to push forwards the developments of QDs-based ECL and PEC bioanalysis. Despite the great advances in this field, some important challenges still exist among which are: (1) Compared to some other species, QDs suffer from the relatively low ECL and PEC efficiency and frequently encounter the toxicity issues. So eco-friendly and highly efficient QDs (and their composites) with special properties, such as various carbon, silicon, InP, Zn-based and nearinfrared QDs, need to be sought in order to meet the particular criterion for specific ECL and PEC analytical purposes. (2) With the rapid progress in bioconjugation chemistry, novel QDs/biomolecule hybrid systems may be used as functional building blocks or nanoprobes for advanced ECL and PEC bioanalysis with innovative principles. For example, the uses of exciton–plasmon interactions between QDs and noble metal NPs, the luminescence generated from chemiluminescence reactions and chemiluminescence resonance energy transfer (CRET) process all represent new sensing concepts in QDs based ECL and PEC bioanalysis. (3) To


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integrate current QDs-based ECL and PEC bioanalysis into various flow-injection systems, screen-printed and/or (paper-based) microfluidic chips may realize new electronic and optoelectronic devices capable of simple, low-cost, fast, automatic, visible, simultaneous, and/or multichannel detection. (4) Future applications of QDs based ECL and PEC bioanalysis should include in vivo bioimaging and biodetection as well as in vitro probing of intracellular processes. Moreover, efforts should also be given to the ECL and PEC detection of single particle, cell and molecule in the biological systems. (5) The poor selectivity and reproducibility still make it hard for the current QDs based ECL and PEC bioanalysis to parallel with the gold standards of enzyme-linked immunosorbent assay (ELISA, for protein assay) and polymerase chain reaction (PCR, for nucleic acids assay), future studies should be performed towards improving them for practical applications. Given the rapid developing pace in this area, we envision that QDs-based ECL and PEC bioanalysis will play more important roles in analytical chemistry for life science.

AUTHOR INFORMATION Corresponding Author *Tel/Fax: +86-25-83597294. E-mail: [email protected]. *Tel/Fax: +86-25-83594862. E-mail: [email protected]. Notes The authors declare no competing financial interest. Biographies Wei-Wei Zhao obtained his Ph.D. from Nanjing University (NJU) in 2012 and is currently an associate professor at the department of chemistry of NJU. His research is focused on biomolecular detection via various advanced electrochemical techniques. He is the coauthor of


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more than 30 international papers, and most of them are related to DNA and protein assay. He can be contacted by e-mail at [email protected]. Jing Wang received her Ph.D. from NJU and currently is a postdoc with Prof. Hong-Yuan Chen. She also teaches as a lecturer at the China Pharmaceutical University. The main objects of her research are ECL bioanalysis and biosensor development. Yuan-Cheng Zhu is currently pursuing her MSc with Prof. Jing-Juan Xu and Prof. Wei-Wei Zhao at NJU. Construction of new nanomaterial/biomolecule architectures and their applications for new PEC bioanalysis are among her main research interests. Jing-Juan Xu is a full professor in the department of chemistry at NJU and has published more than 200 scientific papers. She gained funding from the National Outstanding Youth Foundation of China (2010) and won the “10th Chinese young women scientists award” (2013). She was selected as “RSC Fellow” (2014), and approved as Chang Jiang Professor (2014). Her research interest focuses on developing various electrochemistry-based biosensors. Hong-Yuan Chen is a professor of chemistry at NJU and also an academician of Chinese Academy of Science. He is a member of several scientific societies and the advisory boards of several scientific journals. He has authored and co-authored over 740 papers, and several chapters

and

books.

His

research

interests

include

electrochemical

biosensing,

bioelectrochemistry, ultramicroelectrodes, biomolecular-electronic devices and the Micro-Total Analysis System.

ACKNOWLEDGMENTS We thank the 973 Program (Grant 2012CB932600), the National Natural Science Foundation of China (Grant Nos. 21327902, 21135003, and 21305063), the Natural Science Funds of


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Jiangsu Province (Grant BK20130553), the Fundamental Research Funds for the Central Universities (Grant 20620140748), and the State Key Laboratory of Analytical Chemistry for Life Science (Grant 5431ZZXM1503) for support. This work was also supported by a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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For “opening art” use:

Ya-Chao Su


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Quantum-size-controlled photoelectrochemical fabrication of epitaxial InGaN quantum dots.

Toward understanding of transfer mechanism between electrochemiluminescent dyes and luminescent quantum dots.

Signal Amplification Strategy Based on TiO2-Nanotube Layers and Nanobeads Carrying Quantum Dots for Electrochemiluminescent Immunosensors.

Label-free Electrochemiluminescent Immunosensor for Detection of Prostate Specific Antigen based on Aminated Graphene Quantum Dots and Carboxyl Graphene Quantum Dots.

Photovoltammetric behavior and photoelectrochemical determination of p-phenylenediamine on CdS quantum dots and graphene hybrid film.

Low-toxic Ag2S quantum dots for photoelectrochemical detection glucose and cancer cells.

Near-Infrared Colloidal Quantum Dots for Efficient and Durable Photoelectrochemical Solar-Driven Hydrogen Production.

Graphene-CdS quantum dots-polyoxometalate composite films for efficient photoelectrochemical water splitting and pollutant degradation.

Graphitic Carbon Nitride Sensitized with CdS Quantum Dots for Visible-Light-Driven Photoelectrochemical Aptasensing of Tetracycline.

Enhanced photoelectrochemical properties of nanocrystalline TiO2 electrode by surface sensitization with CuxO quantum dots.

Nonplasmonic Hot-Electron Photocurrents from Mn-Doped Quantum Dots in Photoelectrochemical Cells.

Photoelectrochemical biosensor using enzyme-catalyzed in situ propagation of CdS quantum dots on graphene oxide.

Using graphene-based plasmonic nanocomposites to quench energy from quantum dots for signal-on photoelectrochemical aptasensing.

Multiple signal amplified electrochemiluminescent immunoassay for Hg2+ using graphene-coupled quantum dots and gold nanoparticles-labeled horseradish peroxidase.

Visible light photoelectrochemical sensor for ultrasensitive determination of dopamine based on synergistic effect of graphene quantum dots and TiO2 nanoparticles.

graphene nanosheets hybrid films for photoelectrochemical and photocatalytic applications.

Polymer-coated quantum dots.

Enhanced photoelectrochemical aptasensing platform based on exciton energy transfer between CdSeTe alloyed quantum dots and SiO2@Au nanocomposites.

Colloidal Double Quantum Dots.

Core Concept: Quantum dots.

Quantum dots: Electrifying cavities.

Sensitive Bioanalysis Based on in-Situ Droplet Anodic Stripping Voltammetric Detection of CdS Quantum Dots Label after Enhanced Cathodic Preconcentration.

Graphene quantum dots, graphene oxide, carbon quantum dots and graphite nanocrystals in coals.

3D periodic multiscale TiO₂ architecture: a platform decorated with graphene quantum dots for enhanced photoelectrochemical water splitting.