Recent Development of Chemosensors Based on Cyanine Platforms

Review pubs.acs.org/CR

Recent Development of Chemosensors Based on Cyanine Platforms Wen Sun, Shigang Guo, Chong Hu, Jiangli Fan, and Xiaojun Peng* State Key Laboratory of Fine Chemicals, Dalian University of Technology, 2 Linggong Road, 116024 Dalian, China ABSTRACT: The cyanine platforms including cyanine, hemicyanine, and squaraine are good candidates for developing chemosensors because of their excellent photophysical properties, outstanding biocompatibility, and low toxicity to living systems. A huge amount of research work involving chemosensors based on the cyanine platforms has emerged in recent years. This review focuses on the development from 2000 to 2015, in which cyanine, hemicyanine, and squaraine sensors will be separately summarized. In each section, a systematization according to the type of detection mechanism is established. The basic principles about the design of the chemosensors and their applications as bioimaging agents are clearly discussed. In addition, we emphasize the advances that have been made in improving the detection performance through incorporation of the chemosensors into nanoparticles.

CONTENTS 1. Introduction 2. Chemosensors Based on Cyanines 2.1. Cyanine Sensors Based on PET 2.1.1. Cyanine Sensors for Metal Ions and pH 2.1.2. Cyanine Sensors for Reactive Small Molecules 2.1.3. Cyanine Sensors for Enzymes 2.2. Cyanine Sensors Based on ICT 2.3. Cyanine Sensors Based on FRET 2.4. Sensors Based on Modulating the π-Conjugated System of Cyanine Derivatives 2.4.1. Cyanine-Ketone Involved Sensors 2.4.2. Cyanine-Quinone Involved Sensors 2.4.3. Sensors Based on Formation/Destruction of Cyanine Structures 2.5. Cyanine Sensors Based on Other Mechanisms 2.5.1. pH-Sensitive Non-N-alkylated Cyanines 2.5.2. Self-Aggregation of Cyanines 2.5.3. Rotation-Induced Fluorescence Quenching of Cyanines 2.5.4. Cu2+-Induced Fluorescence Quenching of Cyanines 3. Chemosensors Based on Hemicyanines 3.1. Sensors Based on Modulating the ElectronDonating Ability of the Electron Donor of Hemicyanines 3.1.1. Metal Coordination Involved Hemicyanine Sensors 3.1.2. Chemical Reaction Involved Hemicyanine Sensors 3.1.3. Protonation of Phenolate within Hemicyanines for pH Sensing 3.2. Sensors Based on Disruption of the πConjugated Systems of Hemicyanines © 2016 American Chemical Society

3.2.1. Hemicyanine Sensors for Nucleophilic Reagents 3.2.2. Hemicyanine Sensors for ROS 3.3. Other Hemicyanine Sensors 4. Chemosensors Based on Squaraines 4.1. Sensors Based on Aggregation or Disaggregation of Squaraines 4.1.1. Squaraine Sensors for Metal Ions 4.1.2. Squaraine Sensors for Biomolecules 4.2. Sensors Based on Modulating the π-Conjugated System of Squaraines 4.3. Polarity−Sensitive Squaraines as Protein Sensors 4.4. Other Squaraine Sensors 5. Concluding Remarks Author Information Corresponding Author Notes Biographies Acknowledgments Abbreviations References

7768 7769 7770 7770 7772 7774 7775 7778 7781 7782 7782 7783 7785 7785 7786 7787 7788 7789

7793 7795 7795 7797 7798 7798 7800 7803 7806 7807 7808 7808 7808 7808 7808 7808 7808 7809

1. INTRODUCTION In recent years, the recognition and detection of environmentally and biologically important analytes has become an essential research topic in chemistry and biology. Among different analytical methods, optical measurements in conjunction with suitable chemosensors are preferable approaches for detection, because they are convenient, low cost, nondestructive, and highly sensitive and selective to analytes.1−5

7789 7789 7790 7792

Received: January 2, 2016 Published: June 17, 2016

7793 7768

DOI: 10.1021/acs.chemrev.6b00001 Chem. Rev. 2016, 116, 7768−7817

Chemical Reviews

Review

carried out from 2000 to 2015 in a systematic and inclusive manner. The review contains three main parts, in which cyanine (section 2), hemicyanine (section 3), and squaraine sensors (section 4) will be separately summarized. In each section, we review the performance of these chemosensors according to their detection mechanisms. Design strategies of the chemosensors and their successful applications as bioimaging agents are also discussed in detail. In addition, we also pay attention to the advances that have been made in improving the detection performance through incorporation of the chemosensors into nanoparticles. The purpose of this review is to provide a general overview of the design and development of chemosensors based on cyanine platforms, and to stimulate future research studies in this attractive field.

Chemosensors are defined as chemical systems that transform stimuli into some form of response, such as a fluorescence or color change.6 A typical chemosensor contains a recognition site (the receptor) which is connected to the signal reporter, such as a fluorophore or chromophore. As an efficient approach to convert the act of detection into a fluorescent signal already on the molecular level, fluorescent chemosensors provide accurate quantitative detection toward analytes.7 Once the analyte interacts with the receptor, the fluorescence signal changes can be observed in forms of enhancement, quenching, or shift in the fluorescence maxima. Combined with imaging techniques such as laser scanning confocal microscopy (LSCM) and in vivo imaging systems, the range of its applications extends to imaging analytes in living cells, tissues, and even whole animal bodies.3,8−10 Colorimetric chemosensors also attract much interest by which the detection of targets could be carried out by the “naked eye”.11,12 This provides reliable qualitative and quantitative information for a variety of analytes even when they are located in extreme and complicated environmental systems.13−16 To date, various classic dyes have been developed as signal reporters of chemosensors, such as coumarin,17−20 pyrene,21−23 1,8-naphthalimide,24,25 xanthenes,26 boron dipyrromethene difluoride (BODIPY),27,28 diketopyrrolopyrrole (DPP),29 dicyanomethylene-4H-pyran (DCM),30−32 etc. Among them, the sets based on cyanine platforms have attracted considerable interest from researchers because these dyes feature favorable optical properties such as high absorption coefficient, high fluorescence quantum yield, and relatively long absorption and emission wavelength.33 Moreover, the outstanding biocompatibility and low toxicity to biosamples further make cyanine platforms an attractive choice as chemosensors for medicinal and biological applications. The history of cyanine dyes goes back already to one-and-ahalf centuries ago with the first reported synthesis of a blue solid by Williams in 1856.34 With great efforts of researchers across several disciplines, a diverse array of cyanine dyes and their derivatives have been constructed. Generally, these dyes are classified as five categories: cyanine dyes, hemicyanine dyes, oxonol dyes, merocyanine dyes, and squaraine dyes.33 Among these dyes, cyanine, hemicyanine, and squaraine are the most commonly used scaffolds for developing chemosensors. A large number of papers involving these chemosensors have been published to date. These sensors have been demonstrated to detect various objects, such as metal ions, anions, reactive small molecules, and biomacromolecules, among others, as well as to assess environment-related parameters including temperature, polarity, viscosity, etc. Several excellent reviews related to this topic have been published. For example, in 2000, Behera compiled a nice review on the topic of “cyanines during the 1990s”, which covered the progress during the 1990s in the synthesis and evaluation of cyanine platforms.33 In this review, chemosensors for metal ions reported before 2000 were summarized. A review about “squaraine-derived materials” by Alayaghosh discussed squaraine-based ion probes with coverage before 2005.35 Recently, Yoon presented a review on “nearinfrared (NIR) fluorescent probes” which covered a few NIR cyanine chemosensors.36 However, because of the widespread coverage and fast development of this topic, until recently there has been no comprehensive review for a systematic and timely survey of the progress in this attractive field. In this review, we attempt to describe the recent development of chemosensors based on cyanine, hemicyanine, and squaraine

2. CHEMOSENSORS BASED ON CYANINES Classic cyanine dyes contain two nitrogen-containing heterocycles, one of which is positively charged and conjugated through a chain of an odd number of carbon atoms to the other nitrogen center (Figure 1).33 According to the number of carbon atoms of

Figure 1. Schematic illustration of classic cyanine structures.

the chain, cyanines are divided as monomethine (Cy1), trimethine (Cy3), pentamethine (Cy5), and heptamethine cyanines (Cy7). The absorption and emission spectra of cyanine dyes are tunable with the variation of the length of the conjugated polymethine chain: extension of the chromophore backbone by one vinylene moiety leads to a bathochromic shift by about 100 nm.37 For instance, classic Cy3 fluoresces greenish yellow (λex = 550 nm; λem = 570 nm), while Cy5 is fluorescent in the nearinfrared region (λex = 650 nm; λem = 670 nm). Since the absorption and emission maxima of Cy5 and Cy7 are well into the NIR region, these two dyes are more favorable for developing chemosensors because, compared with UV and visible light, NIR light is less photodamaging, has minimum fluorescence background, and is less light scattering.38−40 With tremendous efforts, effective methods have been carried out for the synthesis of cyanine dyes (Scheme 1). Generally, cyanine dyes are obtained by the condensation of aromatic quaternary ammonium salts with different condensing agents.33 Cy3 dyes can be synthesized from the reaction of quaternary ammonium salts with trimethyl orthoformate. Cy5 are generally prepared through the condensation between quaternary ammonium salts and chain cyanine agents, by taking advantage of which, Cy5 fluorophores with different meso-substituents could be conveniently synthesized. The commonly used method for the synthesis of Cy7 is displayed in Scheme 1, which provides a simple synthetic process with a good reaction yield.33 Traditional cyanine dyes, in essence, suffer from several limitations, including undesired aggregation in aqueous solution,33 poor photostability,41 and narrow Stokes shift.42 Since the 1990s, numerous attempts have been made to improve the physical and chemical properties of cyanine dyes. Introducing two sulfonate groups to the nitrogen-containing heterocycles of cyanines can provide a sphere of solvation in aqueous solvents, which will afford better water solubility.43 Consequently, the phenomenon of self-aggregation would be alleviated to a large 7769


Chemical Reviews

Review

Scheme 1. Classic methods for synthesis of cyanine dyes.

electron acceptor (Figure 2a). On the other hand, if the excited state of the fluorophore can donate electrons to the recognition

extent. Poor photostability is a major limitation for cyanine dyes. A cyanine dye, indocyanine green (ICG), for example, approved by the United States Food and Drug Administration (FDA) for bioimaging, suffers from severe photobleaching. The low stability of cyanine fluorophores is generally ascribed to the interaction between the fluorophore molecules and dissolved oxygen.44 Incorporation of cyanine dyes into silica nanoparticles has been proven to be a promising strategy for photostability enhancement due to the effective protection from the nanoparticle shell. The encapsulated fluorophores possess a 95-fold longer half-life period than the FDA-approved ICG under identical continuous illumination.45 Classic cyanine dyes also suffer from a narrow Stokes shift (Δλ < 25 nm). A small Stokes shift may result in selfquenching and measurement error, which can decrease the detection sensitivity to a great extent. Peng’s group unprecedentedly synthesized two heptamethine cyanines dyes by introducing alkyamino groups to the meso-position of Cy7.42 The resulting dyes exhibited large Stokes shifts (Δλ > 140 nm) due to excited-state intramolecular charge transfer (ICT). Since then, quite a number of fluorescent chemosensors have been reported based on this platform. Therefore, as important fluorophores, cyanine dyes have been broadly employed to develop chemosensors for various targets. The corresponding sensing mechanisms involved are mainly based on the classical sensing mechanisms such as photoinduced electron transfer (PET) (section 2.1), excited-state intramolecular charge transfer (ICT) (section 2.2), and fluorescence resonance energy transfer (FRET) (section 2.3). Also, modulation of the π-conjugated system of cyanine derivatives (section 2.4) is also one of the commonly used methods. In section 2.5, some other sensing mechanisms will also be discussed, including pH-induced transformation of non-Nalkylated cyanine structures, regulating the dye aggregation, rotation-induced fluorescence quenching of cyanines, and metalinduced fluorescence quenching of the chemosensors.

Figure 2. Schematic representation of the a-PET (a) and d-PET (b) processes.

site lowest unoccupied molecular orbital (LUMO) and cause fluorescence quenching, then the term “d-PET” is used instead (Figure 2b). Analytes can induce fluorescence recovery by blocking the PET process through the interaction with the recognition site, which is the PET “on−off” mode for detecting. The PET “off−on” mode, on the contrary, realizes the detection of targets through fluorescence quenching of the fluorophore. 2.1.1. Cyanine Sensors for Metal Ions and pH. Tang and co-workers reported a pioneering work for sensing Zn2+, by introducing DPA (2,2′-dipicolylamine), a commonly used Zn2+ receptor, to the scaffold of Cy7.49 The fluorescence of the sensor (1; Figure 3) was greatly quenched by the PET process from pyridine to the fluorophore. In the test solution (HEPES buffer, 100 mM, pH 7.4, 100 mM KCl), the DPA group of 1 recognized and coordinated with Zn2+ to form a 1:1 metal−ligand complex, and consequently the PET process was blocked to a large extent. Meanwhile, a 20-fold enhancement of fluorescence at 800 nm was observed. The authors demonstrated that this sensor displayed an excellent selectivity toward Zn2+ over other metal ions including Ni2+, Hg2+, Co2+, Cu2+, and Fe2+. Tang et al. designed a Hg2+-sensitive chemosensor, 2, in which 3,9-dithia-6-monoazaundecane ligand was employed as the binding moiety.50 The fluorescence quantum yield (ΦF) of 2 was measured to be 0.02 in aqueous solution, indicating that the PET process between the receptor moiety and the fluorophore was efficient. In the presence of Hg2+, strong fluorescence was obtained immediately and fluorescence quantum yield increased to 0.12. The application of 2 was further demonstrated by its use for real-time monitoring the cellular uptake of Hg2+. Two cyanine fluorescent indicators, 3 and 4, for sensing Cd2+ were designed by Qian et al.51 Sensor 3 contains two sulfonate

2.1. Cyanine Sensors Based on PET

Photoinduced electron transfer (PET) is one of the most commonly used mechanisms in constructing fluorescent cyanine sensors. These sensors, generally, consist of three parts: cyanine fluorophore, spacer, and recognition site. Recognition sites, with different oxidation potentials, can act as electron donors or acceptors.46,47 When the oxidation potential of the recognition site is smaller in magnitude than that of the cyanine fluorophore, electron transfer occurs from the recognition unit to the cyanine group, resulting in the quenching of the fluorescence.48 This process is called “a-PET”, as the cyanine fluorophore acts as the 7770


Chemical Reviews

Review

Figure 3. Molecular structures of 1−8 for metal ions.

groups which could increase its solubility and reduce the selfaggregation in water. The fluorescence quantum yield of 3 increased from 0.0065 to 0.0145 after interaction with Cd2+, because the long pairs of two aniline nitrogen atoms become involved in Cd2+ coordination and the PET process was suppressed. The stoichiometry of Cd2+:3 was further determined from the Job’s plot experiment, indicating a 2:1 species. 3 failed to realize fluorescence bioimaging, since it is not membrane permeable. In a similar approach, 4 without two sulfonate groups could penetrate into the cells and, therefore, imaged Cd2+ in living Hela cells. Sensor 5, for detection of Fe2+, was synthesized from the combination of BODIPY with Cy7.52 5 emitted strong fluorescence with two emission maxima at 507 and 635 nm in HEPES solution (pH 7.4), which can be assigned to BODIPY and Cy7 fragments, respectively. The typical fluorescence of Cy7 gradually decreased in response to Fe2+, due to an effective PET process from the Fe2+−Tpy complex to Cy7 moiety, whereas the fluorescence intensity of BODIPY fragment was basically unchanged. Based on the two different fluorescence behaviors, a ratiometric detection method for Fe2+ was achieved. The ratio of fluorescence intensity (F507 nm/F635 nm) showed a linear relationship toward the concentrations of Fe2+ from 1.0 × 10−7 to 7.0 × 10−6 M with a calculated detection limit of 12 nM. Copper is an essential trace element for living systems. The redox activities of Cu2+ and Cu+ influence the function of many enzymes including copper/zinc superoxide dismutase (CuZnSOD), respiratory enzyme cytochrome coxidase (COX), and metallothionein (MT).53 On the other hand, they are toxic to living organisms by oxidative damage to DNA, proteins, and other biomolecules. The first NIR Cu2+ sensor 6, presented by Li et al., depicted a “turn-on” mode toward this cation.54 The indicator showed a high selectivity and sensitivity to Cu2+ by forming a 1:1 complex in aqueous solution (10 mM HEPES, pH 6.85, 1% DMSO as cosolvent). The fluorescence intensity of 6 exhibited more than 10-fold enhancement upon addition of 5.0 mM Cu2+, and the fluorescence quantum yield of the Cu2+

complex was 6-fold higher than that of 6 alone (ΦF = 0.11 and 0.016 for Cu2+-6 and 6, respectively). The proposed chemosensor has been used for direct monitoring of Cu2+ in HepG2 and RAW264.7 macrophages using confocal microscopy. Additionally, the sensor imaged Cu2+ in rat hippocampal slices and living zebrafish. Sensor 7, reported by Lin et al., was sensitive to Cu+.55 A high affinity Cu+ receptor, bis(2-((2-(ethylthio)ethyl)thio)ethyl)amine (BETA), was conjugated to a cyanine fluorophore. The sulfur atoms in the BETA moiety, tended to bind with Cu+, acted as the electron donor for a PET system. 7 displayed 9.6-fold fluorescence enhancement when a 1:1 sensor−Cu+ complex formed under physiological conditions. The apparent dissociation constant, Kd, calculated by using thiourea as a competitive ligand is 6.1 × 10−12 M. Other transition metal ions, including Mn2+, Ni2+, Zn2+, Cd2+, Co2+, Pb2+, Fe2+, and Cu2+, only induced minimal effect on the fluorescence intensity of the sensor (6, but exhibited obvious fluorescence in acidic media. The pKa value of 104 was calculated to be 4.7. Owing to its sensitivity to the acidic condition, 104 was applied as an imaging indicator to visualize primary and metastatic breast tumors in both subcutaneous and orthotopic mouse models, demonstrating its practical applications for biomedical research. Very recently, a mitochondria-targeting pH sensor, 105, was devised by Yan and Chen et al., via the conjugation of a

Figure 42. Molecular structures of 106−109. 7786


Chemical Reviews

Review

exhibited high thermosensitivity within a broad range of temperature ranging from 1 to 80 °C. Nagano et al. developed a fluorescent sensor, 111 (Figure 44), for ROS detection.148 The system was comprised of two components: a less ROS-susceptible Cy5 as the fluorescence reporter and a highly ROS-susceptible Cy7 with thioether mesosubstitution as the ROS-sensitive detector. Since the two cyanine fluorophores were linked to each other with a short distance, the fluorescence of the sensor would be quenched because of stacking of the two dyes in aqueous solution. ROS including • OH, ONOO−, ClO−, and •O2−, with high reactivity, could oxidize Cy7 preferentially. As a consequence, the quenching effect was eliminated and the fluorescence emission of Cy5 at 668 nm (λex = 645 nm) was then observed simultaneously. By monitoring the fluorescence emission increase of the Cy5 part, the changes of the ROS level in living cells could be detected. The sensor was able to image oxidative stress (caused by ROS) in a mouse model of peritonitis. Recently, Tan et al. reported a general strategy to create fluorogenic sensors for selective detection of proteins by taking advantage of the aggregation properties of cyanines.149 112−114 (Figure 45) were constructed by conjugating small molecular ligands to a γ-phenyl-substituted Cy5 fluorophore. In the absence of target proteins, these sensors formed fluorescence-quenched J-type aggregates, whereas bright fluorescence was emitted as a response to the target protein through the recognition-induced disassembly of the aggregates. 112, 113, and 114 were utilized to detect human carbonic anhydrase (hCA), SNAP-tag protein, and fructose, respectively. In addition, 112 permitted no-wash imaging of tumor cells through specific visualization of cell surface proteins and transmembrane-type human carbonic anhydrase. 2.5.3. Rotation-Induced Fluorescence Quenching of Cyanines. The chemosensor 115 (Figure 46), capable of dual mode fluorescence imaging (fluorescence lifetime imaging and ratiometric imaging) of intracellular viscosity, was synthesized in Peng’s laboratory.150 Cy5 was employed as the fluorophore with an aldehyde group substituted at the central position. The free rotation of the aldehyde led to internal conversion via a nonradiative process in nonviscous media. By contrast, the restraining of rotation in viscous media resulted in 6-fold fluorescence enhancement and lengthened the lifetime (from 200 to 1450 ps). The chemosensor displayed two emission maxima at 456 and 650 nm, respectively. However, it was only the red emission (λem = 650 nm) that was viscosity sensitive, providing a ratiometric response to the viscosity changes. 115 was successfully used in observation of the viscosity changes inside cells. According to the same approach, the research group reported chemosensor 116, bearing two benzyl groups in Cy5, which realized monitoring of the mitochondrial viscosity in a single cell.151 Very recently, by taking advantage of 115, Li et al. reported sensor 117 for detection of ascorbic acid (AA).152 117, bearing a hydrazone moiety, was hydrolyzed by Cu2+ to generate 118 accompanied by an 8.2-fold fluorescence quenching (660 nm). However, the fluorescence quenching ability of Cu2+ could be weakened or even disabled in the presence of ascorbic acid; thereby the fluorescence of 117 was restored and AA was detected. The quantitative detection of AA was carried out in DMSO−PBS mixture (20 mM, pH 7.4, 9:1, v/v), and a detection limit was reported as 26 nM. The sensor has been used for direct measurement of AA in human urine samples.

absorption maximum at 648 nm. This absorption peak decreased after treatment with Ag+, accompanied by a new peak that emerged at 511 nm. A distinct hypsochromic shift of emission wavelength from 731 to 546 nm was also observed. The phenomena were ascribed to the aggregation state of the molecule resulting from the coordination of Ag+. There was a good linear correlation between the fluorescence ratio (F546 nm/ F731 nm) and Ag+ concentration over the range 0.6 × 10−7−50 × 10−7 M, with a detection limit of 34 nM. In another approach, by using thymine as the ligand, the research group synthesized 107 as a specific Hg2+ indicator, which exhibited high selectivity toward Hg2+ with little changes induced by other metal ions.145 Peng’s group reported an interesting phenomenon that nonconjugated organic selenium structure can induce the aggregation of cyanine dyes. Based on this finding, a HClO sensor 108 was developed. Selenomorpholine was incorporated into a Cy7 skeleton, which served as a facilitator for the aggregation of the chemosensor and also a redox-sensitive group.146 After being treated with HClO, the emission intensity at about 786 nm increased gradually and a 19.4-fold fluorescence enhancement was achieved. This phenomenon has been proved that after the reaction with HClO, 108 was converted into 109: the aggregated sensor was gradually released and the fluorescence intensity boosted. The enhancement in fluorescence intensity was proportional to the concentration of HClO ranging from 12 to 60 μM. A detection limit of 0.31 μM toward HClO was evaluated. Kim’s group devised a NIR thermosensor 110 (Figure 43), by applying a combination of a thermoresponsive polymer

Figure 43. Molecular structure of 110 and its sensing behavior toward temperature changes. Reproduced with permission from ref 147. Copyright 2009 Wiley-VCH Verlag GmbH & Co. KGaA.

(Pluronic F127) and a NIR cyanine dye (Cy5.5).147 At low temperature, block copolymers existed as a linear state in solution as dissolved monomers and emitted NIR fluorescence (695 nm). Above the critical micelle temperature (CMT), the polymer gradually self-assembled into micelles with increasing temperatures, resulting in the gradual quenching of the fluorophore. Further increase in temperature would lead to nonfluorescent aggregates by micelle packing. The sensor 7787


Chemical Reviews

Review

Figure 44. (a) Presentation of an approach proposed by Nagano et al. for detection of ROS. Reproduced from ref 148. Copyright 2010 American Chemical Society. (b) Molecular structure of 111.

demonstrated for the determination of Cu2+ in real water samples. Yoon and co-workers devised a CN− indicator based on the Cu2+ involved complex 121-Cu2+.156 Compound 121, comprised of a N5-donor coordination group bearing three pyridine moieties, exhibited strong affinity toward Cu2+ and obvious fluorescence quenching in the presence of this cation. However, when 100 equiv of CN− was added to the solution of 121-Cu2+ (ΦF = 0.005), an apparent fluorescence enhancement at 748 nm was observed (ΦF = 0.026). It can be attributed to the stronger coordination effect between CN− and Cu2+, by which the free fluorophore (121) was released. Confocal laser scanning microscopy experiments revealed that 121-Cu2+ could be applied to monitor CN− levels in Caenorhabditis elegans. In another approach, Lin’s group reported a fluorescence “turn-on” chemosensor for S2− by taking advantage of the 122-Cu2+ complex.157 122 was constructed by introducing 8-aminoquinoline ligand to a Cy7 scaffold through a piperazine linker. The free compound 122 was fluorescent with an emission peak at around 794 nm (ΦF = 0.11) in HEPES buffer/ethanol solution (25 mM, pH 7.0, 6:4, v/v,), while Cu2+ could quench the fluorescence almost completely through the generation of 122-Cu2+ complex. Upon addition of S2− to 122-Cu2+ solution, a large fluorescence enhancement could be elicited. 122-Cu2+ exhibited high selectivity for S2− over other test anions, which was ascribed to the low solubility product constant of CuS. Apart from Cu2+, other metal ions such as Co2+,154 Pd2+,158 and Cd2+159 have also been employed to develop metal-involved chemosensors for detection of analytes including O2, CO, and H2S. However, these complexes were only reported by using BODIPY or fluorescein as the fluorogenic ligands, which are not

Figure 45. Molecular structures of 112−114.

Molecular rotor 119 was reported to measure protein-specific local environmental viscosity.153 Due to the rotation of the backbone, Cy3 served as a viscosity-sensitive reporter. In its structure, trimethoprim was expected as a specific targeting moiety toward E. coli dihydrofolate reductase (eDHFR). Based on fluorescence lifetime imaging microscopy (FLIM), 119 reported eDHFR-specific microenvironments in living cells. This methodology provided a promising tool to obtain valuable information about specific protein functions in the complicated and constantly changing microenvironment with high spatial− temporal resolution. 2.5.4. Cu2+-Induced Fluorescence Quenching of Cyanines. It is known that Cu2+, a kind of heavy and transition metal ion, has a strong fluorescence quenching effect on fluorophores.154 Based on this idea, Han et al. reported a “switch-off” fluorescent sensor, 120 (Figure 47), for selective signaling of Cu2+.155 120 was composed by the conjugation of a Cy7 fluorophore with a 2-(2-aminoethyl)pyridine moiety. Upon titration of Cu2+ in CH3CN−H2O solution (1:1, v/v), the fluorescent emission peak at about 715 nm gradually decreased, due to the Cu2+ induced quenching of Cy7. 120 was

Figure 46. Chemosensors 115−117 and 119 based on rotation-induced quenching of cyanines. 7788


Chemical Reviews

Review

Figure 47. Molecular structures of 120, 121, and complex 122-Cu2+.

group reported rhodamine−hemicyanine hybrids, which features the same fluorescence switching mechanism as rhodamine dyes while having the advantage of NIR absorption and emission wavelengths.166 The combined photophysical properties made this hemicyanine hybrid compound to be an effective new platform for designing chemosensors. The detection of analytical targets based on hemicyanine chemosensors is usually achieved by adjusting the ICT process (ICT enhancement or ICT blocking). In these sensors, modulating the electron-donating ability of the donor, for example, results in obvious absorption/emission wavelength shifts, thereby providing a colorimetric/ratiometric mode for determination. Some analytes can also be detected by adjusting the ICT process through influencing the π-conjugated structure of hemicyanines. In this section, the detection mechanisms of heimicyanine sensors will be discussed in two main parts: (1) modulating the electron-donating ability of the electron donor (section 3.1) and (2) blocking the π-conjugated systems of hemicyanines (section 3.2). Hemicyanine sensors based on other detection mechanisms are also discussed in section 3.3.

suitable for biological applications because of their short excitation and emission wavelengths. Cyanine dyes bearing longer or even NIR excitation and emission wavelengths would be an alternative for further development of metal-involved chemosensors.

3. CHEMOSENSORS BASED ON HEMICYANINES Hemicyanines, another main member of the cyanine family, are known for their wide applications in many research fields, such as photosensitizers in dye-sensitized solar cells160,161 and molecular labels in the study of complex biological systems.162 They are also used as chemosensors owing to their unique structures and desirable properties including good biocompatibility and low toxicity to biosamples. As a particular class of organic dyes, hemicyanines feature the donor−π−acceptor (D−π−A) system in terms of their structures. Typically, a hemicyanine structure contains a positively charged nitrogen heterocyclic moiety as the electron acceptor and a terminal hydroxyl, alkoxy, or amino group as the electron donor, which are connected via a conjugated system. A general method for the synthesis of this kind of compound is to condense heterocyclic bases (Fischer’s base) containing activated methyl groups with unsaturated benzaldehydes (Figure 48).33 Because of the strong excited-state intramolecular charge transfer (ICT) process from electron donor to acceptor, traditional hemicyanines display large Stokes shifts.

3.1. Sensors Based on Modulating the Electron-Donating Ability of the Electron Donor of Hemicyanines

Modulation of the electron-donating ability of the donor provides one of the most commonly used strategies to influence the ICT process within hemicyanine molecules, based on which diverse chemosensors have been developed. Specifically, enhancing the electron-donating ability of the donor could result in red shift of the absorption/emission spectra. Reducing the electron-donating ability of the donor, on the opposite side, could cause blue shift of the absorption/emission spectra of the fluorophore. 3.1.1. Metal Coordination Involved Hemicyanine Sensors. A water-soluble Hg2+-selective sensor, 123, was reported by Zeng et al., where hemicyanine acted as the fluorescent reporting group and NO2Se2 chelating unit acted as the ion binding site.167 Upon the addition of Hg2+ to 123 (Figure 49) EtOH−H2O solution (1:1, v/v), the absorption band assumed a hypsochromic shift from 542 to 400 nm, due to the reduction of the electron-donating ability of the chelating unit. Meanwhile, the solution color changed from red to colorless. In the presence of other metal ions, 123 displayed nearly no change in absorption wavelength except that Ag+ could induce a slight decrease in the absorption intensity. However, Hg2+ could quench the fluorescence of the sensor (590 nm). The combination of a chelating group with hemicyanine is an ordinary approach for generating colorimetric sensors for metal ions. However, their fluorescence is usually quenched upon metal complexation. On the contrary, the stronger complexation of some anions may make the fluorophore release from the sensor complex, thereby recovering the fluorescence of hemicyanine fluorophore. According to this approach, Yang’s group reported sensor 124-Cu2+ for CN− detection with a DPA−

Figure 48. Schematic illustration of a general method for the synthesis of classic hemicyanines.

To enrich hemicyanine scaffolds with tunable emission wavelengths, numerous attempts have been tried. For instance, Chang et al. conducted the diversification of hemicyanine fluorophores through a condensation reaction of different pyridinium salts with aromatic aldehydes.163 The so-obtained library of fluorophores covered a broad range of emission wavelengths, from 420 to 730 nm. Lin’s group unexpectedly got a novel hemicyanine dye through treatment of chloro-mesosubstituted cyanine with resorcin. The obtained molecule features both absorption and emission maxima in the NIR region.164 Recently, much attention has also been focused on developing new functional hemicyanine scaffolds through the hybridization with other dyes, regarding that traditional hemicyanines offer limited positions for modifications. Renard and co-workers, to the best of our knowledge, first reported hybrid coumarin−hemicyanine compounds.165 This work resulted in a great deal of attention being given to the application of the hybrid compounds as fluorescent chemosensors. Lin’s 7789


Chemical Reviews

Review

Figure 50. Hemicyanine sensors 127 and 128 for Pd2+.

ether.174 Compared with 127, 128 displayed a fluorescence response to Pd2+ in the NIR region (F716 nm/F670 nm). The sensor was highly selective to Pd2+ over other metal species tested because the Pd2+-involved deprotection reaction is specific. The detection limit of 127 for Pd2+ was reported as 340 nM. In addition, the bioimaging of palladium species was demonstrated by using 128 in living cells. Hemicyanine derivative 129 for detection of Hg2+ was reported by Han and colleagues.175 A vinyl group that protected the hydroxyl group of the dye blocked the ICT process of the molecule. Hg2+ promoted hydrolysis of the ether group, reconstructed the ICT process, and as a result evoked the fluorescence of the hemicyanine fluorophore (Figure 51). The indicator realized monitoring Hg2+ concentrations in the range 0−25.0 μM by recording the fluorescence intensities at 551 nm.

Figure 49. Molecular structures of 123, 124-Cu2+, 125, and 126-Zr4+.

Cu(II) complex conjugated to a hemicyanine fluorophore.168 In HEPES buffer (20 mM, pH 7.2), precursor 124 exhibited a fluorescence quenching effect toward Cu2+. Afterward, the addition of cyanide induced apparent fluorescence enhancement at 580 nm and a visible colorimetric change from light yellow to orange. 124-Cu2+ displayed competitive sensitivity to CN− with a low detection limit of 1.3 μM. The conjugation of hemicyanine and DPA−Zn(II) was utilized as a pyrophosphate (PPi) fluorescent sensor (125-Zn4+).169 125-Zn4+ achieved fluorescence enhancement (558 nm) toward PPi in water without interference by any of the following species: PO43−, CN−, F−, HCO3−, OAc−, and N3−. Zheng and co-workers constructed 126-Zr4+ for the determination of F− by applying EDTA (ethylenediaminetetraacetic acid)−Zr(IV) complex as the sensing unit.170 The spectroscopic investigations were carried out in DMSO−water solution (3:7, v/v). 126-Zr4+ displayed obvious absorption changes (from 513 to 427 nm) and fluorescence enhancement (540 nm) in the presence of F− at acid conditions (pH 4.4). The detection limit was as low as 2.8 × 10−6 M. Analysis of quantitative determination of F− utilizing 126-Zr4+ indicated that the sensor was capable of detecting F− in commercial toothpaste. 3.1.2. Chemical Reaction Involved Hemicyanine Sensors. Compared with metal coordination involved sensors, chemical reaction involved detection pathways are more advantageous in terms of selectivity and sensitivity.171,172 Some profluorescent hemicyanine molecules whose fluorescence could be unmasked only through specific chemical reactions have been elaborated for detection of metal ions, anions, thiols, and enzymes. Based on palladium (Pd)-induced cleavage reaction of allyl carbonate, Pd2+-specific sensor 127 (Figure 50) was reported, in which benzothiazolium hemicyanine was chosen as the fluorescence reporter.173 Owing to the electron-withdrawing effect of the carbonate group, 127 displayed a relatively short emission wavelength with a maximum at 510 nm. With addition of Pd2+ to the sensor solution (10 mM, 80% DMSO), the maximum emission peak underwent red shift to 566 nm, leading to a ratiometric response. A feasible mechanism was that palladium triggered the cleavage of allyl carbonate, and then decarboxylation of the product enhanced the ICT process of the sensor. The indicator displayed high selectivity for Pd2+, and the sensing process hardly experienced interference from other metal ions and anions. Lin et al. reported Pd2+ fluorescent sensor 128 based on Pd2+-induced deprotection of the aryl propargyl

Figure 51. Hemicyanine sensor 129 for Hg2+.

Feng’s laboratory synthesized a colorimetric and fluorescence “turn-on” sensor (130; Figure 52) for F− based on the F−-

Figure 52. Molecular structure of 130 and its sensing scheme for F−.

mediated desilylation reaction.176 In PBS buffer (20 mM, pH 7.4, 30% ethanol), the nucleophilic attack of F− to 130 caused a gradual decrease in its absorption intensity at 420 nm, accompanied by the formation of a new absorption peak at 535 nm. Accordingly, the color of the sensor solution was changed from red to colorless. A 25-fold enhancement of the fluorescence intensity at 558 nm indicated that 130 also displayed a good fluorescence turn-on response to F−. The 7790


Chemical Reviews

Review

indicator was further applied to detect F− in real water samples using easy-to-prepare test papers as the testing media. Chemosensor 131 (Figure 53) was sensitive to hydrazine (N2H4).177 The molecule contained an acetyl moiety as the

limit of 8.5 nM. Moreover, 133 was successfully demonstrated for the fluorescent detection of Cys34 in BSA (bovine serum albumin) and bioimaging of Cys in living cells. Thiol-sensitive fluorescent indicator, 134, was designed via modification of the hydroxyl group of hemicyanine with a 2,4dinitrobenzenesulfonyl group.180 The electron-withdrawing group hid the ICT process, and thus 134 was fluorescence “off”. Removal of the protected group from the dye structure resulted in strong fluorescence emission (λem = 553 nm, λex = 490 nm). Different from 132 and 133, 134 could also detect other biothiols including Hcy and GSH. To red shift the absorption and fluorescence wavelengths of thiol sensors, hemicyanine derivative 135 was devised by Lin and co-workers.164 A large fluorescence “turn-on” response up to 50-fold enhancement at 716 nm (λex = 690 nm) was noted after adding Cys to the sensor solution (PBS buffer, pH 7.4, 30% CH3CN). Because of its suitable excitation and fluorescence wavelengths to biosamples, 135 imaged endogenous thiols not only in living cells, but also in living mice for the first time (Figure 55). Selenocysteine (Sec) is an important low molecular weight selenium-containing amino acid that plays an important role in cancer prevention.181,182 However, the anticancer mechanism for Sec is still not fully understood. Therefore, it is of scientific importance with regard to the real-time monitoring of Sec in living systems and discovering its biological functions. Hemicyanine derivative 136 for fluorescence imaging of Sec was designed based on Sec-induced cleavage reaction of the Se−N bond in benzoselenadiazole.183 In PBS buffer (10 mM, pH 7.4), Sec transformed the benzoselenadiazole moiety into a diamine group, and thus 136 emitted a bright fluorescent signal (580 nm). Because of the stronger nucleophilic ability of Sec, other biothiols such as Cys, Hcy, and H2S did not cause any interference. Confocal fluorescence microscopy experiments established the utility of 136 for monitoring cell apoptosis induced by Na2SeO3. Recently, by using a 2,4-dinitrobenzenesulfonyl moiety as the masking group, Lin et al. reported sensor 137 for detection of

Figure 53. Molecular structure of 131 and its sensing scheme for N2H4.

sensing unit. Due to the blocked ICT process in the molecule, 131 exhibited no fluorescence, while hydrazine could remove the acetyl group and light up the fluorescence. According to the fluorescence enhancement at 706 nm, a good linear relationship toward the concentration of hydrazine was achieved (0−50 μM). The detection limit was calculated as 5.4 ppb, indicating that the probe was highly sensitive. The authors further applied this probe to visualize hydrazine, for the first time, in tissue including liver, kidney, spleen, etc. By employing a Cys-involved intramolecular cyclization reaction, Liu et al. reported sensor 132 for detection of Cys (Figure 54).178 The sensor, treated with Cys for 10 min in PBS (30% CH3CN, pH 7.4), displayed a new fluorescence peak appearing at 716 nm, with a 50-fold enhancement. Spectroscopic results revealed high specificity of 132 toward Cys over other structurally and functionally similar amino acids and thiols. This property was ascribed to the specific cyclization reaction and the corresponding reaction rate. The detection limit of 132 to Cys was reported as 0.5 μM. In another approach, Kan and coworkers designed Cys sensor 133 by taking advantage of the benzothiazolium−quinoline hemicyanine dye.179 Compared with 132, 133 featured higher sensitivity to Cys with a detection

Figure 54. Hemicyanine sensors 132−135 for biological thiols. 7791


Chemical Reviews

Review

induced a strong fluorescence of the sensor (λem = 636 nm), indicating the catalytic cleavage of the carboxamide bond and the release of free fluorescent 141. Taking advantage of the mechanism about the enzymecatalyzed cleavage of the β-lactam ring, a NIR chemosensor, 145, was reported for detection of β-lactamase.186 After treatment with β-lactamase, a dramatic fluorescence increase appeared at 707 nm due to the recovery of the ICT process of the structure (146). The favorable features of 145 include rapid response (within 15 min), high selectivity, cell membrane permeability, and successful applications in visualizing the expression levels of β-lactamase in different Staphylococcus aureus strains. In another approach, sensor 147 was devised for in vivo imaging of nitroreductase (NTR).187 147 displayed off−on response to NTR owing to the enzyme-catalyzed reduction of the 4-nitrobenzene moiety (Figure 57). As 147 reacted with

Figure 55. Representative fluorescence images (pseudocolor) for mice intraperitoneally (ip) injected with different amounts [(a) 0, (b) 20, (c) 40, or (d) 160 nmol] of 135. (e) Quantification of the fluorescence intensities from mice (ip) injected with different amounts (0, 20, 40, or 160 nmol) of 135. The images were obtained 10 min after the injection of NIR-thiol into the ip cavity of the mice. The mice were imaged using an FMT 2500 LX quantitative tomography in vivo imaging system, with an excitation filter of 670 nm and an emission filter of 690−740 nm. Reproduced from ref 164. Copyright 2012 American Chemical Society.

Sec.184 The ICT process, prohibited because of the electronwithdrawing masking group, was activated through the reaction of Sec. Subsequently, an apparent NIR fluorescence peak appeared at 712 nm. The mice treated with Sec and 137 exhibited a 6.5-fold fluorescence increase. Hydrogen selenide (H2Se), another reactive Se species, is involved in many physiological and pathological processes and has been associated with a number of diseases. Compound 138 was a H2Se sensor, according to the fact that the Se−N in benzoselenadizole moiety could be specifically destroyed by H2Se through nucleophilic addition.185 Because of the heavy atom effect of Se, the fluorescence of 138 was effectively quenched. As expected, the reaction of the sensor with H2Se yielded a diamine product (Figure 56) and recovered the fluorescence of the fluorophore (735 nm, λex = 688 nm). Interestingly, Sec exhibited no interference to its detection.

Figure 57. Molecular structures of 139−144 and the sensing schemes of 145 and 147 for enzymes.

NTR, a gradual fluorescence increase at 705 nm was observed. The fluorescence enhancement and NTR concentration (0.05−3 μg/mL) showed a linear correlation, based on which the detection limit was determined to be 14 ng/mL. This detection limit toward NTR was claimed to be the lowest one compared with the existing NIR fluorescent chemosensors. Moreover, the sensor, for the first time, realized visualizing the distribution of nitroreductase in zebrafish during their early development (1−5 days). 3.1.3. Protonation of Phenolate within Hemicyanines for pH Sensing. In hemicyanine scaffold, pH sensors are devised by constructing the equilibrium between phenol and phenolate based on the protonation and deprotonation of the hydroxyl group (specified with red in Figure 58).188 The deprotonation form leads to red shift of the absorption and emission spectra, while the protonation process blue shifts the spectra of the fluorophore. This phenomenon was attributed to the stronger electron-donating ability of deprotonated phenolate, which, as a result, enhanced the ICT process of the hemicyanine structure. The reversible absorption and emission

Figure 56. Hemicyanine sensors 136−138 for Se species.

According to the profluorescent strategy, various enzymes could be visualized through enzyme-initiated specific unmasking reactions. Romieu and colleagues reported a series of far-red to NIR coumarin−hemicyanine conjugates, 139−143, with emission maxima ranging from 620 to 722 nm.165 These dyes were further exploited as a platform to construct a fluorescent chemosensor (144) for sensing penicillin G acylase (PGA). Sensor 144 consisted of a phenylacetyl moiety (PGA-sensitive substrate) and the phenol-based fluorophore (141). PGA 7792


Chemical Reviews

Review

Figure 58. Molecular structures of pH sensors 148−155.

changes toward proton concentration provide colorimetric and ratiometric modes for pH sensing. Recently, Sun and co-workers constructed two pH indicators, 148 and 149, based on tetramethylene hemicyanine, which adopted phenol and o-bromophenol as the pH-sensitive moieties.188 Both sensors displayed colorimetric and ratiometric responses to pH changes. 149 exhibited a lower pKa value (6.21) than that of 148 (6.80). Because of low cytotoxicity, 148 was applied for monitoring the near-neutral pH fluctuations in HeLa cells. Yang et al. reported a series of NIR emissive fluorophores 150−153 that displayed pH-dependent optical responses.189 These sensors demonstrated various emission shifts from 31 to 76 nm toward pH changes, and owned different pKa values ranging from 6.2 to 7.4. Sensor 153, with an ideal pKa value of 7.2, realized real-time monitoring of the near-neutral pH values. Very recently, Yu et al. introduced a sulfonic acid group to 153 to improve the solubility of the compound (154).190 The indicator featured a broad pH response range and the fluorescence intensity ratios (F764 nm/F713 nm) increased by 43-fold as the pH value changed from 4.11 to 8.64. The pKa of 154 was reported as 6.71. Additionally, it could be used as a candidate for detection of acidosis caused by inflammation in a living mouse model. Similarly to 150−154, pH determination using 155 was based on the red shift of the emission spectrum (from 670 to 708 nm) upon pH increase (from 4.0 to 7.4).191 With the help of a typical lysosome-targeting moiety, morpholine, Ma and co-workers measured lysosomal pH changes in living cells by using sensor 155. Moreover, the change of lysosomal pH with temperature was also investigated, revealing the increase of the lysosomal pH during heat shock and the irreversibility of this process.

Figure 59. Hemicyanine sensors 156−158 for H2S.

disruption of the π-system of hemicyanine structures. Imaging of H2S by using the two indicators was demonstrated in both HepG2 and MCF-7 cells, with 157 localizing to mitochondria. The effective use of this strategy must account for possible crossreactivity with other nucleophilic thiols such as Cys, Hcy, and GSH.193 However, HS− was expected to be a better nucleophile than these biological thiols in neutral medium owing to its lower pKa value (ca. 7.0) and smaller size. Thus, for these ratiometric sensors, 156 and 157 were demonstrated to be of high selectivity for H2S determination. Nanosensor UC-158 for detection of H2S was designed on the basis of H2S-sensitive hemicyanine modified NaYF:Yb,Er,Tm upconversion nanoparticles (UCNPs).196 The design strategy relied on the H2S-triggered absorbance changes in 158 which then modulated the emission intensity of UCNPs. The hybrid material showed ratiometric response (F514 nm/F800 nm) to different H2S concentrations under 980 nm excitation. 158 was demonstrated for ratiometric fluorescence monitoring of the generation of pseudoenzymatic H2S in HeLa cells. Moreover, with the help of NIR excitation and upconversion emission, evaluating the risk of endotoxic shock in a mouse model was achieved through the imaging of endogenous H2S levels in plasma. Guo et al. reported a ratiometric fluorescent chemosensor, 159, for sensing HSO3− and SO32−, another kind of nucleophilic agents.197 In PBS buffer (10 mM, pH 7.4, 30% DMF), the interaction between 159 and HSO3−/SO32− caused a gradual decrease in fluorescence intensity at 633 nm, accompanied by the formation of a new emission peak at 478 nm. The optical changes could be explained by the nucleophilic addition of HSO3−/SO32− to the CC bond specified in Figure 60, which interrupted the π-conjugation system and blocked the ICT process. The indicator did not respond to other reactive sulfide species including glutathione and H2S. Another similar ratiometric sensor, 160, was reported by Guo and colleagues.198 However, in this case, CN− caused some interference to HSO3−/SO32− detection. Recently, nanosensor 161 for HSO3−/SO32− detection was reported by taking advantage of hemicyanine functionalized carbon nanodots (CDs).199 Since the absorption spectrum of the hemicyanine overlapped well with the emission of CDs, the fluorescent intensity of CDs was very weak. HSO3−/SO32− could

3.2. Sensors Based on Disruption of the π-Conjugated Systems of Hemicyanines

Disruption of the π-conjugated system of hemicyanine is a promising methodology to construct ratiometric sensors. This strategy could remit the ICT effect of the whole molecule, leading to blue shift of the fluorophore absorption and emission spectra. Disruption of the π-conjugated system of hemicyanine is usually realized by nucleophilic addition or oxidative cleavage reactions. Therefore, common nucleophilic reagents, such as cyanide and sulfide as well as ROS species, are the major analytical targets. 3.2.1. Hemicyanine Sensors for Nucleophilic Reagents. As a nucleophilic agent, HS− can undergo addition to electrophilic centers in fluorescent molecules.192,193 This strategy has been harnessed for the development of ratiometric H2S sensors 156194 and 157195 (Figure 59), which relies on the 7793


Chemical Reviews

Review

A long-wavelength latent fluorimetric indicator, 164, could selectively detect Cys, Hcy, and GSH over other amino acids.203 The fluorogenic chemical transformation of 164 triggered by thiols was conducted through different reaction sites of the compound (Figure 62), which were utilized to discriminate Cys, Hcy, and GSH. The authors evaluated the capability of 164 to selectively image Cys and GSH in COS-7 cells.

Figure 60. Proposed reaction schemes of 159−161 with HSO3/SO3−.

disrupt the π-conjugated system of the dye and then enhance the CDs fluorescence. The nanosensor was demonstrated for detection of HSO3−/SO32− in aqueous solution (PBS buffer, pH 7.0) with a detection limit of 1.8 μM. The authors further prepared a test paper for visually monitoring of SO2 gas in air through simply assembling the sensor onto a strip. Biothiols including Cys, Hcy, and GSH could also be detected through nucleophilic addition to hemicyanine structures.16,200 Sun and co-workers devised compound 162 for detection of biothiols, which featured the Michael-type reaction of thiols with the double bond conjugated unit (Figure 61).201 The

Figure 62. Molecular structure of 164 and its sensing mechanism for Cys, HCy, and GSH. Reproduced from ref 203. Copyright 2014 American Chemical Society.

A ratiometric sensor, 165, was developed for CN− based on the nucleophilic attack of CN− into the indolium group of a hybrid coumarin−hemicyanine structure (Figure 63).204 Upon the addition of CN− to the sensor solution (MeOH−Tris·HCl, 10 mM, pH 9.3, 1:1, v/v), the original emission of 165 at 630 nm decreased, followed by the increase in the emission of the coumarin moiety at 514 nm. The phenomenon indicated that the reaction between CN− and 165 interrupted the π-conjugated system and recovered the optical performance of the coumarin part. According to the changes of the two emissions, ratiometric fluorescence response toward CN− was achieved. The ratio changes (F514 nm/F630 nm) produced an excellent linear function with the concentration of CN− from 0 to 4 mM, based on which a detection limit was calculated to be 0.6 mM. Another coumarin− hemicyanine hybrid compound (166) for detection of CN− was reported, which, compared with 165, displayed a much lower detection limit (0.64 μM) toward CN− in the CH3CN−H2O (9:1, v/v) test system.205 Guo and Yang et al. designed sensor 167 with high selectivity to CN−.206 The absorption of 167 at 510 nm exhibited a remarkable decrease upon injection of CN− in MeOH buffer (NaHCO3−Na2CO3, 10 mM, 1:1, v/v), which simultaneously resulted in a clear color change from red to yellow. Other nucleophilic reagents, on the contrary, did not cause any considerable influence to the adsorption shift. A hybrid carbazole−hemicyanine dye (168) was developed as a CN− chemosensor.207 In CH3CN−H2O solution (1:1, v/v), 168 displayed unique colorimetric (A493 nm/A285 nm) and ratiometric (F732 nm/F600 nm) responses only with CN− even in the presence of excess amounts of other anions. The detection limit of 168 toward CN− could reach 0.54 μM. Yang et al. devised CN− sensor 169, based on the conjugation of anthracence and hemicyanine.208 The conjugated compound displayed a short responding time (within 1 s) and excellent selectivity to CN−. Very recently, sensor 170 for detection of CN− was synthesized by Huo and co-workers.209 The emission intensity of the sensor at 477 nm showed a good linearity with CN− concentration in the range 0−1.8 μM, based on which a

Figure 61. Hemicyanine sensors 162 and 163 for biothiols.

nucleophilic attack of thiols toward CC interrupted the πsystem of the molecule, after which the fluorescence of benzoxazine part was recovered. 162 exhibited high sensitivity for Cys (as a thiol model) with a 10-fold enhancement of the emission ratio (F570 nm/F679 nm). Also, a wide detection range for Cys from 0 to 4.8 mM was realized by using the sensor. Fluorescence imaging of intracellular thiols with 162 was also examined in KB cells. In another approach, a thioester-functionalized coumarin− hemicyanine dye (163) was presented to selectively detect Cys over Hcy and GSH.202 Sensor 163 reacted with Cys via the native-chemical-ligation and cyclization cascade reactions to produce a coumarin derivative. This process resulted in a 145 nm blue shift of the fluorescence due to the interruption of the πconjugated system. However, the reaction of 163 with Hcy or GSH only stayed at the initial stage of transthioesterification reaction, and thus cannot induce any fluorescence response. 7794


Chemical Reviews

Review

Figure 63. Hemicyanine sensors 165−170 for CN−. Red arrows point to reaction sites.

quite lower detection limit was reported as 0.05 μM. Different from CN− sensors 165−168, the cell fluorescent imaging experiments demonstrated the value of 169 and 170 in tracing CN− in living cells. 3.2.2. Hemicyanine Sensors for ROS. Sensor 171, reported by Yoon’s group, exhibited peroxynitrite (ONOO−)sensitive absorption and emission responses.210 Due to an ONOO−-induced oxidation process that disrupted the πconjugated system of the molecule, 171 displayed 142 nm blue shift in the absorption (from 568 to 422 nm), and 120 nm blue shift in the emission spectra (from 635 to 515 nm). In PBS buffer (pH 7.4), 171 showed high selectivity toward ONOO− without interference from other ROS including ClO−, H2O2, t-BuOO−, • O2−, and •OH−. The detection of exogenous and endogenous peroxynitrite by using 171 was successfully realized in WI38VA13 cells and RAW264.7 cells, respectively. Another ROS sensor, 172, based on a phenothiazine− hemicyanine hybrid, was described by Peng’s group, which possessed two active reaction sites for ClO−.211 The fluorescent response of 172 to ClO− resulted in a blue-shifted emission with the wavelength changing from 595 to 470 nm. The change of the emission signal was ascribed to the oxidation of the sulfur atom by ClO− and the concomitant destruction of the π-conjugation of the compound (Figure 64). It was capable of visualizing endogenous ClO− within the mitochondria of HeLa cells. Very recently, Lo et al. reported a two-photon chemosensor, 173, for detection of three ROS species: •OH, O2−, and ClO−.212 173 displayed bright fluorescence (λem = 575 nm), while ROS could induce a strong fluorescence quenching due to the cleavage of the double bonds after the oxidation reaction (Figure 64). By taking advantage of the two-photon microscopy, the chemosensor was able to image ROS in living cells when excited at 810 nm.

Figure 64. Hemicyanine sensors 171−173 for ROS.

they constructed hydrazine derivative 175 as a NIR fluorescent sensor for detection of HClO.166 Free 175 was nonfluorescent because of the spirocyclic structure. HClO was found to induce the generation of 1,3,4-oxadiazole-based product (176), which, as expected, resulted in strong NIR fluorescence (746 nm). 175 was able to visualize endogenously produced HClO in the peritoneal cavity of mice during an LPS-induced inflammatory response. To further demonstrate the capability of this platform for developing NIR chemosensors, by encapsulating a rhodamine−hemicyanine dye to sialic acid capped polymeric nanovesicles, a tumor-targetable pH nanoprobe (177) was reported by Han and colleagues.213 Because of the acidic pH sensitivity in 4.0−6.5 and low cytotoxicity to biosamples, 177 was a good candidate for fluorescence imaging of tumor lesions in living animals. Very recently, the group devised 178 for imaging lysosomal pH through direct conjugation of a sialic acid with a rhodamine−hemicyanine profluorophore.214 Compared to 177, the advantageous biomedical properties of 178 exhibited the feasibility of lysosome as the target for in vivo inflammation imaging through the monitor of pH changes. A carbazole-equipped hemicyanine rotor, 179, for ratiometric imaging of subcellular viscosity was reported by Peng’s group.215

3.3. Other Hemicyanine Sensors

Lin’s group reported the rhodamine−hemicyanine hybrid (174), exhibiting the same fluorescence switching mechanism as rhodamine dyes and possessing NIR absorption and emission wavelength (Figure 65).166 Based on their proposed platform, 7795


Chemical Reviews

Review

Figure 65. Sensors 174, 175, 177, and 178 based on rhodamine−hemicyanine hybrids.

The fluorescence quantum yield of 179 was measured as 0.012− 0.04 in low-viscosity solvents, because of the rotation of the bond labeled with red in the molecule structure (Figure 66). With the

Figure 66. Molecular structures of 179 and 180.

reagent.217 The compound displayed two emissions with the maximum intensities at 467 and 642 nm, respectively. However, only the green emission was markedly sensitive to polarity changes, thus providing a ratiometric fluorescence response to solution polarity. Due to its specificity to mitochondria, 181 was reported as the first fluorescent indicator for imaging of mitochondrial polarity. The mitochondrial polarity in cancer cells was found to be lower than that of normal cells by ratiometric fluorescence imaging with 181, based on which the chemosensor distinguished cancer cells from normal cells (Figure 68).

increase of the solvent viscosity, the rotation of the band was gradually restricted, and thus 179 displayed dramatic fluorescence enhancement at 580 and 380 nm, respectively. Based on these two emission wavelengths (F580 nm/F380 nm), ratiometric viscosity imaging in HeLa cells can be achieved. Additionally, the authors demonstrated the excellent two-photon properties of 179, by which the rotor was able to report viscosity in living tissue at depths of 60−130 mm by using 720 nm as the two-photon excitation wavelength. In another approach, Kumar and colleagues reported sensor 180 for detection of human serum albumin (HSA).216 Due to the nonradiative pathway caused by intramolecular rotation, the sensor lost its fluorescence. However, upon interaction with HSA, the rotation was restricted and obvious fluorescence enhancement (680 nm, λex = 550 nm) was achieved. Interestingly, no significant change in fluorescence intensity was observed in the presence of other proteins including BSA, demonstrating its specific interaction with HSA. The sensor was highly sensitive to this protein with a detection limit of 11 nM. Fan et al. developed a polarity-sensitive chemosensor, 181 (Figure 67), by using coumarin−hemicyanine as a chromogenic

Figure 68. Ratiometric fluorescence images of normal and cancer cells with 181. (a−a3) cos-7 cells, (b−b3) RAW264.7 cells, (c−c3) HeLa cells, (d−d3) HepG2 cells, and (e−e3) MCF-7 cells. (a−e and a1−e1) Confocal fluorescence images with λem = 435−535 nm for (a−e) and λem = 575−675 nm for (a1−e1). (a2−e2) Bright-field images of the cells. (a3−e3) Fluorescence ratio images. Reproduced with permission from ref 217. Copyright 2015 Wiley-VCH Verlag GmbH & Co. KGaA.

Figure 67. Molecular structure of 181.

AIE (aggregation-induced emission)-active fluorogen 182 (Figure 69) for pH sensing was synthesized through the combination of a tetraphenylethene (TPE) moiety with a hemicyanine dye.218 182 inherited the AIE feature of TPE and displayed pH sensitivity. 182 was proposed to sense the broadest pH range on the basis of different emission wavelengths and intensities: strong to moderate red emission at pH 5−7, weak to no emission at pH 7−10, and no emission to strong blue 7796


Chemical Reviews

Review

Due to its good biocompatibility and photostability, 185 was able to image rRNA in the cell nucleolus under a two-photon excitation imaging system.

4. CHEMOSENSORS BASED ON SQUARAINES Squaraine, an important part of the cyanine family, features a central ring based core and a resonance-stabilized zwitterionic structure.35 The classical examples can be seen in Figure 71. The

Figure 71. Resonance structures of classic squaraines.

birth of squaraine dyes can be traced back to 1965 in the report of Treibs and Jacob, which pertained to the reaction of 3,4dihydroxycyclobut-3-ene-1,2-dione (squaric acid) with pyrrole.225 Later, an increasing number of squaraines started appearing in the literature. These squaraine dyes were generally prepared by condensation of electron-rich aromatic or heterocyclic compounds such as N,N-dialkylanilines, phenols, benzothiazoles, and pryrroles with electron-deficient squaric acid.226 Croconium dye is an attractive squaraine derivative (Figure 72). Due to the presence of a croconaine acid as a

Figure 69. Proposed mechanism for fluorometric switching of 182 and 183 based on AIE. Reproduced (182) with permission from ref 218. Copyright 2012 The Royal Society of Chemistry.

emission at pH 10−14. The AIE-active CN− indicator, 183, was also designed based on a TPE−hemicyanine hybrid.219 The indolium moiety rendered 183 water solubility and weak fluorescence in aqueous solution. After treatment with CN−, the product displayed low water solubility and, consequently, aggregation occurred and the fluorescence of the TPE part was observed. There has been great interest in the development of chemosensors for detecting nucleic acids owing to their potential roles in biomedical and clinical applications.220−222 Based on a hemicyanine fluorophore, a two-photon DNA-sensitive chemosenosr (184; Figure 70) was reported by Wong’s group.223 As a

Figure 72. Molecular structure of classic croconium dye.

stronger electron-acceptor core, these molecules display around 100 nm red shift in absorption compared to the classic corresponding squaraine dyes.227 Squaraine and its derivatives typically display sharp and intense absorption and emission bands, which are associated with the donor−acceptor−donor (D−A−D) electron-transfer structure.228 These dyes are suitable for applications related to the photosensitization phenomenon. Up to now, squaraines have been applied in the design of a variety of photonic materials that are used for nonlinear optics,229 photovoltaics,230 biological labeling,231 and photodynamic therapy.232,233 Because of their high extinction coefficients, high fluorescence yields, long excitation/emission wavelengths, and great photostabilities, squaraines are also very attractive in the development of chemosensors. As an ideal platform for the design of chemosensors, there are three main strategies based on squaraines. First, a squaraine dye tends to form π−π stacking or electrostatic interactions with other dye molecules or materials. This may result in the generation of aggregates whose optical properties are drastically changed.234 According to this approach, a target of interest can be detected through regulating squaraine-involved aggregation or disaggregation. Second, regulating the electron-donating (or


fluorescent light-up probe, 184 exhibited high sensitivity and efficiency for double-stranded DNA (dsDNA) because of the selective binding interaction with the AT-rich regions. The bishemicyanine skeleton showed a 25−100-fold two-photon excited fluorescence in the presence of dsDNA upon excitation at 800 nm. Sensor 185 was a two-photon RNA selective indicator, devised on the basis of an indole−hemicyanine structure.224 In the presence of RNA, a strong fluorescence peak at ∼540 nm was observed when the chemosensor was excited at 820 or 930 nm. 7797


Chemical Reviews

Review

fluorescence intensity at 663 nm of these molecules gradually decreased upon treatment with these cations.

electron-withdrawing) ability of the electron donor (or acceptor) in squaraine structure may influence the π-conjugated system of the dye. Also, the π-conjugation structure of squaraine could be destroyed in the presence of strong nucleophilic reagents due to the fact that the 2- and 4-positions of the central ring in the squaraine structure are liable to be attacked by nucleophilic agents (Figure 71).235,236 This can result in decoloration and fluorescence quenching of the squaraines. Accordingly, the second strategy involves regulating the π-conjugated system of squaraine through target-specific interaction with the donor (or acceptor), or target-elicited destruction of the squaraine structure. Third, some designed squaraines are reported to display high sensitivity toward the polarity of the surrounding environment, whose fluorescence quantum yields tend to increase dramatically in the presence of biomolecules, such as proteins and antibodies.237−241 Therefore, various proteins could be determined through the polarity-sensitive squaraine chemosensors.

Figure 74. Molecular structures of 186−188 and schematic representation of the complexation between metal ions and the sensors. Reproduced from ref 234. Copyright 2004 American Chemical Society.

Bridged bis-squaraines with NIR absorption wavelengths such as 189−191 (Figure 75) have been designed and synthesized.248

4.1. Sensors Based on Aggregation or Disaggregation of Squaraines

A striking property of squaraine dyes is their ability to form aggregates in appropriate conditions, which show distinctly different optical profiles between aggregates and monomers.242,243 H-aggregates are considered to be “face-to-face” aggregation, exhibiting blue shift of the major long wavelength transitions in the absorption spectrum relative to the corresponding monomers (Figure 73).244−246 J-aggregates,

Figure 75. Molecular structures of 189−192. Figure 73. Schematic illustration of the squaraine monomer, Haggregates, and J-aggregates.

These compounds displayed an intense absorption at 815−828 nm in chloroform. Compound 191 was demonstrated as a potential molecular sensor for transition metal cations. Complexation with Cr3+, Mn2+, Fe2+, Co2+, or Cu2+ resulted in large hypsochromic shifts of absorption maximum (59−196 nm) because of the formation of H-aggregates. The methine-bridged squaraine probe 192, absorbing between 600 and 850 nm, was capable of detecting trace amounts of toxic and environmentally hazardous metal cations: Hg2+ and Pb2+.249 In aqueous media, the detection of Hg2+ and Pb2+ could also be carried out by using 192 even in the presence of alkali and alkaline earth metal cations. Croconium dyes 193−196 displayed absorption maxima in the infrared region (840−870 nm) with high molar extinction coefficients.250 The authors demonstrated their colormetric responses to metal ions. Specifically, divalent metal ions such as Zn2+, Pb2+, or Cd2+) would coordinate with 196 to form 2:1 dyemetal complexes (Figure 76), and meanwhile, significant hypsochromic shifts of absorption were observed. On the contrary, the monovalent metal cations displayed weak interaction with 196. In another approach, croconium chemosensor 197 (Figure 77) was reported to sense Cu2+ and Fe3+, respectively, through the generation of a 1:1 stoichiometry of the host−guest complexation.251 After treatment with Cu2+ and Fe3+,

with a “head-to-tail” or “in-line” dipole arrangement, display a sharp, narrow, and red-shifted band compared to the absorption of the monomers (Figure 73).246,247 In the majority of the cases, squaraine dyes form H-aggregates. Also, squaraines can also form aggregates through electrostatic interactions or π−π stacking interactions with other organic or inorganic materials. According to this property, many chemosensors for metal ions have been designed by using the coordination-induced aggregation or disaggregation of squaraines. Besides, controlling the aggregation behavior of squaraines is also applied for developing chemosensors for detection of biomolecules including amino acids, proteins, and nucleic acids. 4.1.1. Squaraine Sensors for Metal Ions. Ajayaghosh and co-workers synthesized three squaraine tethered bichromophoric molecules 186−188 with a different numbers of oxygen atoms in the podand chain.234 186−188 showed colorimetric response to alkaline earth metal cations including Ba2+, Sr2+, Mg2+, and Ca2+. In response to these cations, the main absorption of bichromophores blue-shifted from 652 to 548 nm owing to cation-induced H-aggregation of the dyes through the formation of foldamers or sandwich dimers (Figure 74). However, the 7798


Chemical Reviews

Review

due to the coordination-induced disaggregation of the sensor aggregates. Later, Fu et al. took advantage of alkyl chains with appropriate lengths to enhance the solubility of such a Hg2+ sensor. They reported an unsymmetrical squaraine compound, 200, which was incorporated with an N,N-dibutylanilino group as a side arm.254 200 exhibited good solubility and, importantly, recognized Hg2+ selectively in aqueous medium (AcOH−H2O 1:9, v/v) by signaling the sensing event through visual color change and “turn-on” fluorescence intensity. To further improve the sensing properties for Hg2+ in aqueous solution, recently the research group constructed three thiopodand tethered squaraine−aniline dyads, 201−203, by introducing thioether chains into the fluorescent skeleton.255 Based on the strategy of Hg2+ coordination induced disaggregation of the aggregates, 201−203 realized detecting Hg2+ in water media containing a minute quantity of nonionic surfactant (0.005% TW-80). The presence of EDTA (ethylenediaminetetraacetic acid) within a range of environmental, biological, and industrial samples could seriously interfere with the detection of Hg2+, due to its strong dentate chelating ability to metal cations. However, being inspired by this chelating agent, Fu and colleagues developed an EDTA assisted chemosensor for detection of Hg2+ via a complexation process accompanied by disaggregation of aggregates between Hg2+ and 204.256 Interestingly, the disaggregation process could be improved by EDTA through the formation of 204−Hg2+−EDTA trinary complex, resulting in a greater fluorescence enhancement at 671 nm (Figure 79). In AcOH−H2O solution (35:65, v/v), 204 displayed an excellent sensitivity to Hg2+ with a detection limit of 7.6 × 10−9 M. In another approach, symmetrical squaraine chemosensor 205 with two dithiocarbamate (DTC) side arms also exhibited fluorescence “turn-on” response to Hg2+ in the prescene of EDTA.257 Besides, the designed chemosensor was able to sense Hg2+ in river water after removal of chloride ions with AgNO3. Cucurbit[8]uril (CB8), a synthetic pumpkin-shaped cation receptor, was also used by the squaraine family for detection of Hg2+. Pang et al. reported that the interaction between 206 and CB8 effectively removed the aggregation of 206 in aqueous solution by forming a 1:1 inclusion complex.258 However, upon addition of 3 equiv of Hg2+, the complex fluorescence at 673 nm could be completely quenched due to the synergetic binding between CB8, 206, and Hg2+. The fluorescence quenching behavior of 206*CB8 to Hg2+ enabled the possibility for such a method to detect Hg2+ in pure water solution.


Figure 77. Molecular structure of 197.

the absorption peak of 197 at 798 nm gradually decreased, also leading to a visible color change from brown to blue and to yellow, respectively. In the meantime, Cu2+ and Fe3+ could also induce pronounced fluorescence quenching of 197 (λem = 818 nm). Different from 186−197, most squaraine chemosensors ́ exhibited specific affinity to metal ions. Martinez-Má ñez and co-workers employed a squaraine reporter 198 (Figure 78) for selective signaling of Hg2+, by choosing dithia-dioxa-aza crown AT215C5 as the binding site.252 In the optimized detection medium MeCN−H2O (1:4, v/v), 198 displayed two absorption peaks at 647 and 540 nm, assigned to the monomers and Haggregate states, respectively. The selectivity of 198 to Hg2+ was remarkable: only Hg2+ binding led to a bleaching of both the monomer and the aggregate bands, while other cations and salts did not cause any noticeable bleaching changes in the absorption. A squaraine-based chemosensor (199) bearing two symmetrical metal-binding arms was sensitive to Hg2+.253 199 formed Haggregates in AcOH−H2O (4:6, v/v) solution. When Hg2+ was added to the test system, a dramatic color change from purple to blue was observed. In the corresponding UV−vis spectra, the original absorption at 548 nm disappeared while a strong absorption centered at 636 nm gradually increased. Simultaneously, the addition of Hg2+ led to a prominent fluorescence enhancement (700-fold) at 660 nm. These optical changes were

Figure 78. Squaraine sensors 198−203 for Hg2+. 7799


Chemical Reviews

Review

Figure 79. Squaraine sensors 204−206 for Hg2+. Reproduced (204) with permission from ref 256. Copyright 2015 Elsevier.

The design of chemosensors for detection of Ca2+ is also a research topic of considerable interest, especially in the presence of Na+, K+, and Mg2+. The bichromophore-featured 207 (Figure 80), containing five oxygen atoms in the flexible podand moiety,

maximum at 670 nm in the presence of Ca2+. Very recently, Fu et al. synthesized a series of bichromophore squaraine sensors, 209−212, with a varying number of sulfur atoms in the flexible chain.262 Among these, bichromophore 211, containing three sulfur atoms, was found to selectively bind with Ca2+ in acetonitrile and result in a folded conformation. Although 207, 208, and 211 are excellent colorimetric sensors for Ca2+, their fluorescence quenched upon the generation of aggregates. Further design of Ca2+-sensitive sensors may consider the Ca2+-induced disaggregation approach, which will in turn recover the sensor fluorescence. 4.1.2. Squaraine Sensors for Biomolecules. Serum albumin (SA), one of the most abundant proteins in blood plasma, plays a dominant role in the transportation and deposition of endogenous and exogenous ligands.239 Due to its important functions, reliable detection agents for SA are required. Pang and co-workers reported 213−215, which displayed sensitive fluorescence response to BSA (bovine serum albumin) over other proteins.246 213−215 had high tendency to form H- and J-aggregates in aqueous solutions. Through noncovalent interaction with BSA, these dyes exhibited a large fluorescence enhancement with the emission peaks located in the NIR region (λem = 690 nm). The sensing mechanism was attributed to the transformation of the dye compounds in aggregate states, which are nonfluorescent, to the disaggregated fluorescent state upon protein binding. Although both H- and J-aggregates contributed to the observed fluorescence “turn-on” response, the former appeared to be a more important factor. Later, the research group introduced 213−215 to the surface of chemically converted graphene (CCG), which was also found to greatly enhance the fluorescence response of these dyes to BSA.263 Since CCG sheets in aqueous dispersion are negatively charged, positively charged squaraines can be absorbed on CCG surface through electrostatic and π−π stacking interactions (Figure 81). Addition of BSA to these nanosensor solutions, 216−218, would raise the fluorescence intensity (λem = 672 nm) by as much as 80-fold. Xu et al. reported chemosensor 219 (Figure 82) for detection of avidin, a kind of protein that more frequently exists in tumor cells than in normal cells.264 219, containing a squaraine fluorophore and avidin-specific ligand (biotin), formed aggregates in aqueous solution. The nonfluorescent sensor aggregates could be converted to fluorescent monomer in the presence of

Figure 80. Squaraine sensors 207−212 for Ca2+.

was found to specifically bind to Ca2+ through metal-induced generation of foldamers to form H-aggregates.259,260 Addition of Ca2+ to the acetonitrile solution of 207 induced a color change, gradually from light blue (λmax = 630 nm) to an intense purpleblue (λmax = 552 nm). Apart from these changes, the fluorescence emission at 652 nm underwent considerable quenching when excited at 580 nm. Later, the research group constructed a tripodal squaraine dye, 208, which experienced a similar decrease in the original absorption (650 and 619 nm) with the formation of a new band at 547 nm with the addition of Ca2+.261 Meanwhile, the fluorescence spectrum displayed a gradual quenching of the 7800


Chemical Reviews

Review

Figure 81. Molecular structures of 213−215 and nanosensors 216−218 for BSA. Reproduced (213−215) from ref 246. Copyright 2010 American Chemical Society. Reproduced (216−218) with permission from ref 263. Copyright 2011 The Royal Society of Chemistry.

Figure 83. Molecular structures of 221 and 222. Reproduced from ref 266. Copyright 2015 American Chemical Society.

interacting with BSA and thus maintaining the form of nonfluorescent H-aggregates. However, it was able to image the oxytocin receptor of HEK293 cells due to the specificbinding induced polarity change. Moreover, the fluorescence intensity of the foldamer is proportional to the receptor expression level. Therefore, the concept of polarity-sensitive dimers will pave a new way to generate chemosensors for targetspecific detection of proteins in living cells. Molecular assembly offers an excellent tool to construct diverse supramolecular architectures in which the organization of individual molecules can be controlled by proper selection of different self-assembling components. Several squaraine-involved supramolecular systems have been reported as chemosensors. Pang et al. reported the formation of a nanostructured assembly, by using CTAB (cetyltrimethylammonium bromide) and a squaraine dye, which acted as an ATP (adenosine triphosphate) fluorescent indicator.267 In this system (223), the squaraine dye tended to form H-aggregates owing to its poor solubility in aqueous media. After interacting with ATP at the outer surface of CTAB-formed sphere, these dyes in Haggregates transformed to J-aggregates (Figure 84). As a result, the emission maximum red-shifted from 645 to 676 nm. 223 exhibited excellent sensitivity toward ATP (with a detection limit of 10−6 M), but moderate selectivity with interference from ADP (adenosine diphosphate). Another self-assembly platform 224 based on squaraine-embedded CTAB micelles was demonstrated to readily discriminate Cys and Hcy with the help of CBT (2cyano-6-methoxybenzothiazole).268 CBT can react with Cys and Hcy at room temperature with fast kinetics and a high conversion rate to form five- and six-membered ring-based luciferin derivatives (Figure 85a). These products then transformed CTAB micelles to rodlike and spherelike micelles, respectively. In the case of different transition processes, different fluorescent


avidin. As a consequence, a large fluorescence enhancement at 664 nm was observed. 219 displayed sensitivity to avidin without interference from other nontargeted enzymes and proteins. Additionally, the sensor was membrane permeable and imaged cancer cells through selective detection of avidin. Shangguan and colleagues reported dicyanomethylenefunctionalized squaraine 220 as a highly selective sensor for parallel G-quadruplexes (G4s), an important formation of DNA sequences.265 The sensor experienced strong interaction with the parallel G4s, but no interaction with other DNA. In Tris·HCl buffer (pH 7.4), this interaction caused the transformation of 220 from H-aggregates to monomers, leading to growth of the absorption spectrum of the monomer state (685 nm). Meanwhile, the fluorescence emission of 220 at ∼710 nm was gradually enhanced when 0−20 μM G4s were added to the sensor solution. Very recently, the polarity-sensitive foldamer of dimeric squaraines 221 was constructed by Bonnet and co-workers.266 In aqueous solution, the foldamer displayed nonfluorescence due to the formation of H-aggregates, whereas in organic media, its fluorescence drastically increased because of the unfolding state (Figure 83). To further explore its potential as bioimaging agent, they coupled 221 with an oxytocin receptor ligand (Lys8carbetocin) to obtain conjugate 222.266 The foldamer showed low nonspecific binding in the presence of lipids or proteins (BSA was selected as an example), because PEG groups from both ends of the squaraines prevent the molecule from 7801


Chemical Reviews

Review

Figure 84. Schematic illustration of the working system 223. Reproduced with permission from ref 267. Copyright 2011 The Royal Society of Chemistry.

Figure 86. Schematic illustration of working system 225. Reproduced with permission from ref 269. Copyright 2014 The Royal Society of Chemistry.

the reaction of OPA and GSH. This kind of GSH adducts owning a large aromatic plane and negative charge would interact with cationic squaraine dyes through self-assembly and create a FRET system (Figure 87). Through monitoring the FRET-induced emission at 820 nm (λex = 600 nm), the concentration of GSH can be calculated.

Figure 87. Schematic illustration of working system 226. Reproduced with permission from ref 270. Copyright 2013 The Royal Society of Chemistry. Figure 85. Schematic illustration of working system 224. Reproduced with permission from ref 268. Copyright 2013 The Royal Society of Chemistry.

Since most squaraine dyes display poor water solubility, and there are no squaraine-based chemosensors for detecting nucleoside phosphates. Lan and colleagues reported a imidazolium-functionalized squaraine (227; Figure 88) as a sensitive colorimetric and fluorescent indicator for a vital member of nucleotides, GTP (guanosine 5′-triphosphate).271

outputs of micelle-encapsulated squaraines could be detected (Figure 85b). On the basis of sodium hexametaphosphate (NaPO3)6, Xu and co-workers presented an inorganic−organic hybrid system (225; Figure 86) for detection of acid phosphatase (ACP).269 Commercially available (NaPO3)6, with negative charges, served as a building block to induce the formation of squaraine aggregates through intermolecular electrostatic interactions. As a consequence, an obvious fluorescence quenching was observed. Upon addition of ACP to the detection system, (NaPO3)6 can be hydrolyzed to the phosphate segment. The disruption of the supramolecular architecture resulted in the release of squaraine monomers. Meanwhile, the fluorescence intensity of squaraine at 644 nm could be recovered up to 94.5% of the original value. This system can selectively detect ACP at a quite low concentration of less than 4.9 nM. Pang et al. constructed a squaraine-involved fluorescent system (226) for GSH recognition based on the self-assembly of squaraines and GSH adducts.270 In the presence of ophthalaldehyde (OPA), isoindole−GSH can be formed through

Figure 88. Molecular structure of 227 and the proposed interaction mode between 227 and GTP. Reproduced with permission from ref 271. Copyright 2014 The Royal Society of Chemistry. 7802


Chemical Reviews

Review

Compared with traditional squaraines, electron-donor-substituted squaraine derivatives, 230−232 (Figure 90), displayed a

Two imidazolium rings in the structure not only provided effective binding sites for GTP, but also improved the water solubility of the squaraine derivative. 227 assembled on the GTP template to form aggregates via electrostatic interactions, resulting in the changes of the absorption and emission spectra. The sensor solution of 227 exhibited a high selectivity for nakedeye detection of GTP with the color change from blue to purple. The detection limit of GTP using the colorimetric approach was estimated to reach 5.4 ppb. The fluorescence quenching response (λem = 680 nm) to GTP enabled the sensor to monitor GTP concentration changes in Bel-7402 cells. 4.2. Sensors Based on Modulating the π-Conjugated System of Squaraines

Modulating the π-conjugated system of squaraine provides anoter attractive approach for the construction of chemosensors. This strategy usually modulates the π-electron system through metal coordination induced alteration of the ICT process, which may result in shift of the squaraine absorption or fluorescence spectrum. Son and co-workers employed a pyrylium−squaraine platform (228) as an indicator for detection of Hg2+.272 The sensor displayed two absorption peaks at 641 and 697 nm. Upon addition of Hg2+, the intensities of the absorption peaks were decreased along with bathochromic shifts of the absorption maxima to 682 and 708 nm, respectively. In addition, a new absorption peak appeared at 840 nm. Fluorescence spectroscopy demonstrated a 400-fold fluorescence increase at 683 nm when excited at 641 nm. These optical changes were explained by the regulation of the molecular electronic transition: two Hg2+ ions binding at the dilolate oxygen anion of the four-membered ring (C2O4) in 228 made the C2O4 ring more electron deficient and thus enhanced the ICT process. The proposed binding mechanism was well supported by 1H NMR titration experiments. After addition of Hg2+ to the solution of 228, the olefin protons near the C2O4 ring shifted downfield from 5.7 to 8.0 ppm in the NMR spectra. A ratiometric fluorescent Zn2+ sensor, 229, was designed and synthesized, in which two bipyridyl moieties were chosen as the ion binding arms.273 In acetone, 229 displayed a selective fluorogenic response to Zn2+, accompanied by a 22 nm red shift of the fluorescent emission (from 698 to 720 nm). The proposed binding mode is depicted in Figure 89 (229-Zn2+). Upon Zn2+

Figure 90. Squaraine sensors 230−234 for Cu2+.

relatively larger red shift in their absorption spectra (λmax = 704, 724, and 708 nm for 230, 331, and 232, respectively, in THF).274 These molecules were functionalized with tetrahydroquinoxaline as the terminal group. This phenomenon indicated that the donor group directly conjugated to the central four-membered ring strongly affected the excited state energies of these compounds. Among them, 232, due to its better solubility and stability, was selected as a chemosensor for Cu2+. In the presence of Cu2+, the absorption maximum of 232 decreased to a large extent, whereas two new bands at 652 and 784 nm appeared and gradually increased. The stoichiometry of the complex generated from 232 and Cu2+ was found to be in the ratio of 2:1, as evidenced from Job’s plot test. Chemosensors 233 and 234 functionalized with 2-picolyl units were also reported as Cu2+specific indicators.275 In HEPES/THF solution (6:4, v/v, pH 7.4), 233 displayed the maximum absorption at 514 nm and shifted significantly to the red region by 161 nm when combined with Cu2+. The dramatic red shift of the absorption spectrum led to the color change of the solution from pink to blue, which was clearly visible to the “naked eye”. Sensor 234 also experienced red shift in its absorption spectrum from 554 to 640 nm. Additionally, the fluorescence of 234 was effectively quenched by Cu2+; thus 233 was presented as a Cu2+-selective probe in the fluorescence imaging of living cells through a fluorescence switch-off manner. It was reported that coordination with specific metal ions delocalizes the π-conjugated system and leads to the quenching of squaraine fluorescence. Biological thiols are able to sequester metal ions, release the free squaraine, and thereby recover their fluorescence (Figure 91). So far, several squaraine−Hg2+ complexes have been developed for detection of thiols. Wang and colleagues constructed a squaraine derivative, 235, bearing sulfur-containing binding units at the two terminals of the πconjugating scaffold.276 Chelation of Hg2+ diminished the electron-donating ability of nitrogen atom and switched off the fluorescence (λem = 678 nm). In contrast, after addition of Cys to the 235-Hg2+ complex solution, the fluorescence was restored to

Figure 89. Molecular structures of complexes 228-Hg2+ and 229-Zn2+.

binding, the twist angle between the two bipyridyl groups is decreased, which results in a more planar conformation of the sensor complex. The conformational restriction increased the ICT effect and produced a red shift in the fluorescence spectrum. Sensitivity and selectivity studies revealed that the calculated detection limit of 229 for Zn2+ was 6.1 × 10−8 M and the identification toward Zn2+ was unaffected by other competing metal ions. 7803


Chemical Reviews

Review

Figure 91. Schematic illustration for sensing thiols based on squaraine−Hg2+ complex; chemosensors 235−237.

a large extent. Similarly, Fu et al. reported complex 236-Hg2+ which displayed weak fluorescence around 668 nm in EtOH− PBS solution (50:50, v/v) due to the quenching effect of Hg2+.277 Further addition of Cys, GSH, or histidine to the test solution evoked the fluorescence of 236. By introducing an 8hydroxyquinoline group to a squaraine scaffold, the research group constructed 237 which was applied as a Cys-sensitive fluorescent indicator after complexation with Hg2+.278 The complex expressed outstanding sensitivity toward Cys and the detection limit was calculated to be 36.7 nM in an EtOH−H2O test system (30:70, v/v). Modulation of the squaraine structure provides another way for changing the π-conjugated system of the dye, according to the fact that nucleophilic species can easily cause destruction to the electron-deficient cyclobutene ring of squaraines (Figure 92).

acridinium moiety to a squaraine scaffold, Fu et al. reported a colorimetric sensor, 241, for detecting thiols.281 The nucleophilic addition of thiols decreased the conjugation in 241 and induced a color change from green to yellow instead of a color bleaching. In the presence of surfactant (CTAB, cetyltrimethylammonium bromide), 241 was able to detect biothiols in near-physiological conditions (PB buffer, pH 7.5). Interestingly, due to the different response kinetics to Cys, Hcy, and GSH, the sensor could discriminate Cys from Hcy and GSH. Recently, Wu and coauthors developed a turn-on strategy for detection of acetylcholinesterase (AChE) inhibitor by using sensor 242.282 AChE catalyzed the hydrolysis of acetylthiocholine (ATCl) to form thiocholine products, which in turn reacted with 242, leading to both dye bleaching and fluorescence quenching. However, the catalytic hydrolysis of ATCl was blocked in the presence of AChE inhibitor. As a consequence, the squaraine dye remained intact and displayed signal-on fluorescence. 242 exhibited an obviously improved sensitivity toward the target with a detection limit of 0.018 nM for the AChE inhibitor. ́ Martinez-Má ñez and co-workers reported a squaraine−thiol conjugate, 243, for detection of Hg2+ in aqueous environments with great selectivity and sensitivity.283 The molecule was designed based on the strong thiophilic affinity of Hg2+ and the subsequent generation of a squaraine dye (Figure 94). 243 exhibited an apparent fluorescence enhancement at 670 nm in response to Hg2+. Meanwhile, its absorption spectra displayed a very large red shift from 305 to 642 nm. Since this process is reversible, further addition of thiols resulted in the reproduction of 243. In addition, the authors also reported sensor 244, which was incorporated of hydrophobic n-butyl chains. The induced alkyl chains made it possible to adsorb or anchor the sensor molecule in suitable supports, and thus allowed the preparation of reusable dipstick assays for rapid screening of Hg2+. Afterward, Anslyn et al. employed a single squaraine chemosensor, 245, for the differentiation of five metal ions and five thiols.284 The metal ions and thiols act as both analytes and modulators of the chemosensor, allowing pattern-based discrimination. Five metal ions including Hg2+, Pd2+, Cu2+, Fe2+, and Ni2+, were successfully differentiated when combining 245 with five different thiols: propanethiol (PT), 3-mercaptopropionic acid (MPA), naphthalene-2-thiol (NT), 2,3-dimercaptopropanol (DMP), and 2acetylamino-3-mercaptopropionic acid methyl ester (ACM). Similarly, the five thiols could also be distinguished using the same molecule 244 and the corresponding five metal ions. Notably, Hg2+ displayed the best discrimination ability for thiols, while 245-ACM adduct was most effective for distinguishing the metal ions.

Figure 92. Schematic illustration of destruction of the cyclobutene structure of squaraines by nucleophilic agents, and metal coordination induced squaraine regeneration.

This process usually results in squaraine bleaching and fluorescence quenching. By taking advantage of this feature, some nucleophilic species including thiols and CN− could be detected. On the contrary, squaraines in combination with nucleophiles afford good differentiation of metal ions through “metal coordination induced dye regeneration” (Figure 92). ́ Martinez-Má ñez et al. first employed this strategy to construct Cys sensors (238 and 239).279 Both 238 and 239 displayed high fluorescence at about 640 nm in acetonitrile−water solution (2/ 8, v/v) and owned a quantum yield of 0.1. Upon exposure to Cys, a complete fluorescence quenching was observed. In addition, the response of the sensors to Cys could also be monitored through a remarkable color bleaching. These were attributed to the destruction of their conjugation structure caused by the nuclephilic attack of Cys to the cyclobutene ring (Figure 93). Ajayaghosh’s group reported a NIR squaraine derivative, 240, as a latent ratiometric chemosensor for biological thiols.280 Cys (selected as an example of biological thiols) interacted with the sensor to form a 240-Cys adduct. This process induced the decrease of the original NIR emission band (λem = 800 nm), while led to the formation of a new emission peak with red fluorescence (λem = 592 nm, λex = 410 nm). 240 was able to monitor Cys content in blood plasma. By incorporating an 7804


Chemical Reviews

Review

Figure 93. Proposed reaction schemes of 238−242 with thiols.

Figure 95. Molecular structures of 246 and 247. Red arrows point to reaction sites.

more rapid response to CN− due to the stronger electronwithdrawing ability of the central croconic acid ring. 247 faded immediately from the original color (λab = 823 nm) and became dark green (λab ∼ 675 nm) in the presence of 2 equiv of CN−. A detection limit of 1.3 ppm CN− was reported when 247 was used as the colorimetric indicator. Two FRET cassette-type probes, 248 and 249 (Figure 96), which contain two naphthalimide donors and a squaraine acceptor, were reported by Xiao and co-workers.287 The sensing approach was on the concept of “switching-off” FRET through removing the spectral overlap by the nucleophile-induced destruction of the squaraine acceptor. Before recognition of targeted nucleophiles, intramolecular fluorescence resonance

Figure 94. Proposed reaction schemes of 243−245 with metal ions.

As another kind of nucleophile, cyanide (CN−) could also be detected through the destruction of fluorophore structures. Cyanide sensor 246 functionalized with ether chains displayed good solubility in aqueous solution.285 In the presence of CN−, the absorption of 246 at 641 nm gradually decreased, as the conjugated system of the dye was destroyed by nucleophilic attack of CN−. 246 allowed quantitative detection of low cyanide concentrations with the detection limit of 0.1 ppm. The sensing time was reported as 18 min. Croconium chemosensor 247 also underwent decoloration in response to CN− (Figure 95).286 Compared with 247, the sensor exhibited higher sensitivity and 7805


Chemical Reviews

Review

self-aggregation, Peng’s group reported sensor 253 for detection of BSA.291 Squaraines 254 and 255 containing sulfonate pendants exhibited enhanced water solubility and reduced aggregation.292,293 Both of them displayed bright fluorescence upon forming dye−protein conjugates. Squaraine divertive 256 with long N-hexyl pendent groups displayed higher fluorescence increase values in response to proteins compared with its analogues with short N-alkyl tails.294 Authors demonstrated the possibility of 256 as an indicator for HSA quantification. Volkova’s group tested a series of aza-substituted squaraines for detection of albumins. They found dyes with a N,N-diethylamino (257), aminoethylamino (258), or N,N-dimethylhydrazino (259) substituent on the central four-membered ring demonstrated good emission intensities, observed in the presence of BSA.295,296 Moreover, unlike 257−259 which gave week fluorescence to BSA with the existence of surfactant, 2sulfoethylamino substituent 260, on the contrary, showed bright emission in the BSA/SDS mixture.295 Sensors 251−260 are good representatives for sensing proteins with high sensitivity and fast response time. However, without specific responsive or binding moieties, their detection toward proteins is lack of satisfactory selectivity. In contrast, squaraines with the ability of modulating dye−protein binding affinity through specific reaction or binding interaction are able to display excellent selectivity. Nagano et al. reported two fluorescent indicators for enzymes using squaraine derivatives 261 and 262 (Figure 99).297 Based on modulation of the binding affinity of the squaraines to proteins, chemosensors 261 and 262 were reported to be sensitive to alkaline phosphatase (ALP) and β-galactosidase, respectively. In the presence of untargeted proteins, free 261 and 262 displayed nearly no fluorescence emission as a result of the weak proteinbinding affinity. Nevertheless, after separate treatment of 261 and 262 with ALP and β-galactosidase, the emission intensity of the two sensors was strongly enhanced (λem = 658 nm). This phenomenon can be attributed to the hydrolysis of 261 and 262, yielding 263, which showed strong affinity to the target proteins. 261 was employed to detect ALP-labeled secondary antibodies in Western blotting analysis, while 262 was able to determine βgalactosidase activity in vivo. A squaraine derivative, 264, that incorporated the structure of dansylamide (DNSA), was presented as a selective probe for BSA.298 With the aid of DNSA moiety, 264 displayed selective binding affinity toward site I (a specific substructure) of BSA. 264 showed weak fluorescence in aqueous solution, whereas the fluorescence intensity at 674 nm (λex = 600 nm) increased significantly with the addition of BSA (around 140-fold fluorescence enhancement). In response to different BSA concentrations, the fluorescence intensity of 264 displayed good linear correlation over a wide concentration range and the detection limit was calculated to be 1 mg/mL. There was no obvious fluorescence change of the probe in the presence of other proteins including lysozyme, trypsin, formaldehyde

Figure 96. Molecular structures of 248 and 249. Red arrow points to the reaction site.

energy transfer occurred within 248 and 249 (FRET on). For example, being excited at 402 nm corresponding to the absorption of naphthalene unit, an emission at 659 nm from the squaraine moiety of 249 could be observed. However, after treatment with nucleophiles, the fluorescence of squaraine was strongly quenched whereas that of the naphthalene group was revived (FRET off). The authors utilized 248 and 249 to detect F− and CN− in CH2Cl2 and acetonitrile−water solution (1:10, v/ v), respectively. You and colleagues constructed a type of water-soluble imidazolium-anchored squaraine derivative, 250, and explored it for detecting Fe2+ in the presence of H2O2.288 No color variation occurred upon individual addition of Fe2+ or H2O2 into the sensor HEPES buffer solution (10 mM, pH 7.2), whereas a remarkable bleaching of 250 was observed with concomitant fluorescence quenching in the presence of both Fe2+ and H2O2. It was attributed to a nucleophilic attack of the generated hydroxyl radical on the central ring of the squaraine (Figure 97). Sensor 250 was found to be internalized into living cells and successfully applied for Fe2+ sensing at the cellular level. 4.3. Polarity−Sensitive Squaraines as Protein Sensors

Squaraines are among the most popular dye scaffolds for designing protein chemosensors. A few protein sensors, for instance, were reported based on the aggregation behavior of squaraines, which has been discussed in section 4.1.2. Recently, it was also reported that polarity-sensitive squaraines may occupy a common hydrophobic binding site of proteins to form dye− protein conjugates, which could enhance the dye fluorescence. Therefore, these molecules are useful in detection of proteins. For instance, the first squaraine sensor 251 (Figure 98) for recognition of BSA through dual mode of color change and fluorescence enhancement was reported by Ramaiah et al.289 Addition of BSA induced visualization of color change from pinkishred to bluish and an 80-fold enhancement in fluorescence quantum yields. Yokoyama and colleagues have since reported a similar example 252, which exhibited applications in protein staining in the gel after SDS-PAGE.290 By incorporation of two N-carbamoylmethyl groups into a squarylium structure to reduce

Figure 97. Proposed sensing schemes of 250 with Fe2+. 7806


Chemical Reviews

Review


Figure 100. pH indicator 265 and its sensing mechanism for pH changes.

was gradually enhanced and the energy transfer from the nanocrystal to the squaraine became more efficient; then the main emission peak was from the dye at 650 nm. Therefore, when the nanocrystal was excited at 380 nm, the solution pH value could be read out precisely by monitoring the ratio of emission intensities of the CdSe/ZnS core and the squaraine dye. Recently, Belfield et al. reported two NIR molecular rotors, 266 and 267 (Figure 101), for measuring intracellular viscosity.301 The hydrophilic and biocompatible properties of deoxyribonucleosides were incorporated into the new molecules, which endowed them with good solubility in polar protic solvents. Both 266 and 267 displayed obvious viscosity-


dehydrogenase, lipase, chymotrypsin, and fibrinogen. The successful application of 264 to recognize BSA in living zebrafish embryos demonstrated its potential for in vivo specific noncovalent labeling of protein in biology. 4.4. Other Squaraine Sensors

Squaraine dyes are known to be sensitive to pH changes, and they have been reported as pH indicators. For instance, in 2009 Terpetschnig’s group reported a pH chemosensor by directly conjugating a commercial squaraine dye (Square-650-pH) to an antibody, which exhibited a pKa value of 6.28 in PBS buffer.299 Taking advantage of CdSe/ZnS semiconductor nanocrystals, Nocera and co-workers constructed a FRET pH nanosensor 265 (Figure 100).300 The core of CdSe/ZnS served as the FRET donor, while the squaraine dye conjugated to the surface of the core acted as the pH sensitive moiety and FRET acceptor. Under high pH conditions the squaraine absorption was suppressed, which made the FRET process inefficient. Consequently, the emission spectrum was dominated by the CdSe/ZnS nanocrystal at 613 nm. As the pH value decreased, the absorption of the dye

Figure 101. Molecular structures of 266 and 267. 7807


Chemical Reviews

Review

moiety, ratiometric sensing through the FRET approach can be built up. Thus, further investigation and development of cyaninebased nanosensors will generate significant interest. Therefore, given the desirable properties of cyanine platforms, the development of related chemosensors is of great importance for environment analysis and pollution evaluation as well as for better understanding the roles of various species in living systems and will continue to be attractive in the wide scientific community.

dependent properties in a glycerol/water mixture system. With the combined effect of reducing aggregation and intramolecular rotation in glycerol−water systems, nearly 300-fold and 310-fold fluorescence enhancement for 266 and 267 in high viscosity environments was achieved. 267 was further demonstrated for viscosity sensing at the cellular level, allowing visualization of different stages during mitosis and highly viscous regions in microtubules.

5. CONCLUDING REMARKS This review summarized and discussed cyanine platforms and related derivatives used as colorimetric and fluorescent sensors for various analytes. Particular attention was given to their design strategies, detection mechanisms, and their applications as bioimaging agents. For chemosensors derived from Cy7, the most attractive scaffold among cyanine dyes, the modifications were most commonly concentrated on the meso-nitrogen or meso-oxygen of the polymethine chain, which was linked to receptors for targets of interest. A few chemosensors based on Cy3 and Cy5 have been explored, mainly for sensing pH, enzymes, and viscosity. These cyanine chemosensors are essential bioimaging agents, due to their suitable excitation and emission wavelengths as well as their good biocompatibility in biosamples. Quite a number of chemosensors based on hemicyanine scaffolds have been reported through influencing the ICT process within these molecules. Hemicyanine sensors always display large Stokes shifts and ratiometric features toward a variety of analytes such as metal ions, anions, ROS, and biological species. Based on the property that squaraines trend to form aggregates in aqueous medium, excellent sensor candidates for in vitro detection have been devised. Modulating the πconjugated system of squaraine is another noticeable approach for developing thiol or ROS-sensitive chemosensors. Also, polarity-sensitive squarains are among the most popular molecules for designing fluorescent protein chemosensors. Despite great advances that have been made in this area, there is still much scope for improvement, especially for the biological applications including subcellular imaging and in vivo imaging. For instance, only a few examples based on cyanine platforms were reported to realize fluorescence imaging within mitochondria or lysosomes, but are still rare in the endoplasmic reticulum, Golgi apparatus, and others. And chemosensors that are suitable for in vivo imaging are also limited. Moreover, cyanine chemosonsers used as fluorescent indicators for medical diagnosis and disease treatment require further attention. All of these need to further improve their photophysical and chemical properties: (1) Cyanine dyes still suffer from low photostability that needs to be further improved. (2) The relatively short excitation and emission wavelengths of hemicyanines embarrass the biological uses. Thus, future efforts aimed at designing new hemicyanine chemosensors will need to focus on how to red shift the absorption and fluorescence spectra of these sensors. (3) Forming aggregates in aqueous media is not only an important property of squaraines for design of chemosensors, but also an obstacle for medical and biological research. Thus, squaraine candidates with good water solubility will be of great interest. To improve the photostability of cyanine dyes and reduce their cell toxicity, tremendous attention has also been given to cyanineinvolved nanosensors. Such incorporation of the cyanine platform and nanomaterials or polymers has provided opportunities for rapid and efficient detection of metal ions, pH, anions, and biological species. On the other hand, by linking upconversion nanoparticles or quantum dots to the cyanine

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies Wen Sun received his M.S. from Dalian University of Technology (China) in 2013 under the supervision of Prof. Jiangli Fan. Now he is a Ph.D. candidate at the Max Planck Institute for Polymer Research (Germany). His research is focused on the construction of fluorescent materials for detection, bioimaging, and photodynamic therapy. Shigang Guo received his Bachelor of Science degree from Dalian University of Technology in 2014. He is currently a M. S. candidate under the supervision of Prof. Jiangli Fan in the State Key Laboratory of Fine Chemicals, Dalian University of Technology. His research is focused on fluorescent probes for bioimaging. Chong Hu obtained his B.S. degree from Wuhan Institute of Technology (China) in 2011. He graduated from Dalian University of Technology with his M.S. degree under the supervision of Prof. Xiaojun Peng in 2014. His research is focused on the design and application of near-infrared fluorescent chemosensors. Jiangli Fan received her Ph.D. from Dalian University of Technology in 2005. In 2010, she attended the University of South Carolina (USA) as a visiting scholar. She is currently a professor at the State Key Laboratory of Fine Chemicals, Dalian University of Technology. Her research is focused on fluorescent dye based probes and their biological applications. Xiaojun Peng received his Ph.D. from Dalian University of Technology in 1990. After completing a postdoctoral research at Nankai University (China), he worked at Dalian University of Technology in 1992. In 2001 and 2002, he attended Stockholm University (Sweden) and Northwestern University (USA) as a visiting scholar. He is currently the director of the State Key Laboratory of Fine Chemicals of China at the Dalian University of Technology, where he is also a professor. His research interests cover fluorescent dyes for the bioimaging, biolabeling, and photochemistry of supramolecules.

ACKNOWLEDGMENTS This work was financially supported by NSF of China (21422601, 21576037, 21136002, and 21421005) and the National Basic Research Program of China (2013CB733702). ABBREVIATIONS AA ascorbic acid AChE acetylcholinesterase ACP acid phosphatase ACM 2-acetylamino-3-mercaptopropionic acid methyl ester ADP adenosine diphosphate AIE aggregation-induced emission 7808


Chemical Reviews ALP ATCl ATP BETA BHQ-3 BODIPY BSA hCA CB8 CBT CCG CMT CTAB CyK CyQ Cys D−π−A DCP DMP DNBS DNP DPA DPEN DPP EDTA EET FLIM FRET G4s GSH Hcys HSA His ICT LPS MMPs MPA NIR NT NTAs NTR OPA PET PGA PMA PT QDs QRs RET cRGD ROS Sec SNPs TICT TPE UCNPs

Review

Events with Fluorescent Sensors and Switches. Chem. Rev. 1997, 97, 1515−1566. (3) Yang, Y.; Zhao, Q.; Feng, W.; Li, F. Luminescent Chemodosimeters for Bioimaging. Chem. Rev. 2013, 113, 192−270. (4) Fabbrizzi, L.; Poggi, A. Sensors and Switches from Supramolecular Chemistry. Chem. Soc. Rev. 1995, 24, 197−202. (5) Lee, M. H.; Kim, J. S.; Sessler, J. L. Small Molecule-Based Ratiometric Fluorescence Probes for Cations, Anions, and Biomolecules. Chem. Soc. Rev. 2015, 44, 4185−4191. (6) Zhou, X.; Lee, S.; Xu, Z.; Yoon, J. Recent Progress on the Development of Chemosensors for Gases. Chem. Rev. 2015, 115, 7944− 8000. (7) Demchenko, A. P. In Advanced Fluorescence Reporters in Chemistry and Biology I; Wolfbeis, O. S., Demchenko, A. P., Eds.; Springer-Verlag: Berlin, 2010; pp 3−24. (8) Yin, J.; Hu, Y.; Yoon, J. Fluorescent Probes and Bioimaging: Alkali Metals, Alkaline Earth Metals and pH. Chem. Soc. Rev. 2015, 44, 4619− 4644. (9) Ashton, T. D.; Jolliffe, K. A.; Pfeffer, F. M. Luminescent Probes for the Bioimaging of Small Anionic Species in Vitro and in Vivo. Chem. Soc. Rev. 2015, 44, 4547−4595. (10) Kim, H. M.; Cho, B. R. Small-Molecule Two-Photon Probes for Bioimaging Applications. Chem. Rev. 2015, 115, 5014−5055. (11) Zhu, H.; Fan, J.; Wang, B.; Peng, X. Fluorescent, MRI, and Colorimetric Chemical Sensors for the First-Row d-block Metal Ions. Chem. Soc. Rev. 2015, 44, 4337−4366. (12) Xiong, D.; Li, H. Colorimetric Detection of Pesticides Based on Calixarene Modified Silver Nanoparticles in Water. Nanotechnology 2008, 19, 465502−465508. (13) Zhang, X.; Yin, J.; Yoon, J. Recent Advances in Development of Chiral Fluorescent and Colorimetric Sensors. Chem. Rev. 2014, 114, 4918−4959. (14) Zhou, Y.; Zhang, J. F.; Yoon, J. Fluorescence and Colorimetric Chemosensors for Fluoride-Ion Detection. Chem. Rev. 2014, 114, 5511−5571. (15) Zhang, J. F.; Zhou, Y.; Yoon, J.; Kim, J. S. Recent Progress in Gluorescent and Colorimetric Chemosensors for Detection of Precious Metal Ions (Silver, Gold and Platinum Ions). Chem. Soc. Rev. 2011, 40, 3416−3429. (16) Jung, H. S.; Chen, X.; Kim, J. S.; Yoon, J. Recent Progress in Luminescent and Colorimetric Chemosensors for Detection of Thiols. Chem. Soc. Rev. 2013, 42, 6019−6031. (17) Jung, H. S.; Kwon, P. S.; Lee, J. W.; Kim, J.; Hong, C. S.; Kim, J. W.; Yan, S.; Lee, J. Y.; Lee, J. H.; Joo, T.; Kim, J. S. Coumarin-Derived Cu2+-Selective Fluorescence Sensor: Synthesis, Mechanisms, and Applications in Living Cells. J. Am. Chem. Soc. 2009, 131, 2008−2012. (18) Hettie, K. S.; Klockow, J. L.; Glass, T. E. Three-Input Logic Gates with Potential Applications for Neuronal Imaging. J. Am. Chem. Soc. 2014, 136, 4877−4880. (19) Komatsu, K.; Urano, Y.; Kojima, H.; Nagano, T. Development of an Iminocoumarin-Based Zinc Sensor Suitable for Ratiometric Fluorescence Imaging of Neuronal Zinc. J. Am. Chem. Soc. 2007, 129, 13447−13454. (20) Zhou, Y.; Liu, K.; Li, J.-Y.; Fang, Y.; Zhao, T.-C.; Yao, C. Visualization of Nitroxyl in Living Cells by a Chelated Copper(II) Coumarin Complex. Org. Lett. 2011, 13, 1290−1293. (21) Kim, S. K.; Bok, J. H.; Bartsch, R. A.; Lee, J. Y.; Kim, J. S. A Fluoride-Selective PCT Chemosensor Based on Formation of a Static Pyrene Excimer. Org. Lett. 2005, 7, 4839−4842. (22) Zhou, Y.; Jung, J. Y.; Jeon, H. R.; Kim, Y.; Kim, S.; Yoon, J. A Novel Supermolecular Tetrameric Vanadate-Selective Colorimetric and “Off-On” Sensor with Pyrene Ligand. Org. Lett. 2011, 13, 2742−2745. (23) Gai, L.; Chen, H.; Zou, B.; Lu, H.; Lai, G.; Li, Z.; Shen, Z. Ratiometric Fluorescence Chemodosimeters for Fluoride Anion Based on Pyrene Excimer/Monomer Transformation. Chem. Commun. 2012, 48, 10721−10723. (24) Duke, R. M.; Veale, E. B.; Pfeffer, F. M.; Kruger, P. E.; Gunnlaugsson, T. Colorimetric and Fluorescent Anion Sensors: An

alkaline phosphatase acetylthiocholine adenosine triphosphate bis(2-((2-(ethylthio)ethyl)thio)ethyl)amine Black Hole Quencher-3 boron dipyrromethene difluoride bovine serum albumin human carbonic anhydrase cucurbit[8]uril 2-cyano-6-methoxybenzothiazole chemically converted grapheme critical micelle temperature cetyltrimethylammonium bromide cyanine-ketone cyanine-quinone cysteine donor−π−acceptor diethyl chlorophosphate 2,3-dimercaptopropanol 2,4-dinitrobenzenesulfonyl dinitrophenyl 2,2′-dipicolylamine dipicolylethylenediamine diketopyrrolopyrrole ethylenediaminetetraacetic acid electronic energy transfer fluorescence lifetime imaging microscopy fluorescence resonance energy transfer G-quadruplexes glutathione homocysteine human serum albumin histidine intramolecular charge transfer lipopolysaccharide matrix metalloproteinases 3-mercaptopropionic acid near-infrared naphthalene-2-thiol N-acetyltransferases nitroreductase o-phthalaldehyde photoinduced electron transfer penicillin G acylase phorbol myristate acetate propanethiol quantum dots quantum rods resonance energy transfer cyclic arginine-glycine-aspartic acid reactive oxygen species selenocysteine silicon nanoparticles twisted intramolecular charge transfer tetraphenylethene upconversion nanoparticles

REFERENCES (1) Quang, D. T.; Kim, J. S. Fluoro- and Chromogenic Chemodosimters for Heavy Metal Ion Detection in Solution and Biospecimens. Chem. Rev. 2010, 110, 6280−6301. (2) de Silva, A. P.; Gunaratne, H. Q. N.; Gunnlaugsson, T.; Huxley, A. J. M.; McCoy, C. P.; Rademacher, J. T.; Rice, T. E. Signaling Recognition 7809


Chemical Reviews

Review

Overview of Recent Developments in the Use of 1,8-NaphthalimideBased Chemosensors. Chem. Soc. Rev. 2010, 39, 3936−3953. (25) Banerjee, S.; Veale, E. B.; Phelan, C. M.; Murphy, S. A.; Tocci, G. M.; Gillespie, L. J.; Frimannsson, D. O.; Kelly, J. M.; Gunnlaugsson, T. Recent Advances in the Development of 1,8-Naphthalimide Based DNA Targeting Binders, Anticancer and Fluorescent Cellular Imaging Agents. Chem. Soc. Rev. 2013, 42, 1601−1618. (26) Chen, X.; Pradhan, T.; Wang, F.; Kim, J. S.; Yoon, J. Fluorescent Chemosensors Based on Spiroring-Opening of Xanthenes and Related Derivatives. Chem. Rev. 2012, 112, 1910−1956. (27) Boens, N.; Leen, V.; Dehaen, W. Fluorescent Indicators Based on BODIPY. Chem. Soc. Rev. 2012, 41, 1130−1172. (28) Kowada, T.; Maeda, H.; Kikuchi, K. BODIPY-Based Probes for the Fluorescence Imaging of Biomolecules in Living Cells. Chem. Soc. Rev. 2015, 44, 4953−4972. (29) Kaur, M.; Choi, D. H. Diketopyrrolopyrrole: Brilliant Red Pigment Dye-Based Fluorescent Probes and Their Applications. Chem. Soc. Rev. 2015, 44, 58−77. (30) Wu, W.; Sun, X.; Guo, Z.; Tang, J.; Shen, Y.; James, T. D.; Tian, H.; Zhu, W. In Vivo and in Situ Tracking Cancer Chemotherapy by Highly Photostable NIR Fluorescent Theranostic Prodrug. J. Am. Chem. Soc. 2014, 136, 3579−3588. (31) Guo, Z.; Zhu, W.; Tian, He. Dicyanomethylene-4H-pyran Chromophores for OLED Emitters, Logic Gates and Optical Chemosensors. Chem. Commun. 2012, 48, 6073−6084. (32) Sun, W.; Fan, J.; Hu, C.; Cao, J.; Zhang, H.; Xiong, X.; Wang, J.; Cui, S.; Sun, S.; Peng, X. A Two-photon Fluorescent Probe with NearInfrared Emission for Hydrogen Sulfide Imaging in Biosystems. Chem. Commun. 2013, 49, 3890−3892. (33) Mishra, A.; Behera, R. K.; Behera, P. K.; Mishra, B. K.; Behera, G. B. Cyanines during the 1990s: A Review. Chem. Rev. 2000, 100, 1973− 2011. (34) Williams, C. H. G. Trans. - R. Soc. Edinburgh 1857, 21, 377. (35) Ajayaghosh, A. Chemistry of Squaraine-Derived Materials: NearIR Dyes, Low Band Gap Systems, and Cation Sensors. Acc. Chem. Res. 2005, 38, 449−459. (36) Guo, Z.; Park, S.; Yoon, J.; Shin, I. Recent Progress in the Development of Near-Infrared Fluorescent Probes for Bioimaging Applications. Chem. Soc. Rev. 2014, 43, 16−29. (37) König, V. W. Ü ber “Vinylenhomologe” Indol- und PyrrolFarbstoffe. Angew. Chem. 1925, 38, 743−748. (38) Weissleder, R.; Ntziachristos, V. Shedding Light onto Live Molecular Targets. Nat. Med. 2003, 9, 123−128. (39) Weissleder, R. A Clearer Vision for in Vivo Imaging. Nat. Biotechnol. 2001, 19, 316−317. (40) Escobedo, J. O.; Rusin, O.; Lim, S.; Strongin, R. M. NIR Dyes for Bioimaging Applications. Curr. Opin. Chem. Biol. 2010, 14, 64−70. (41) Samanta, A.; Vendrell, M.; Das, R.; Chang, Y. T. Development of Photostable Near-Infrared Cyanine Dyes. Chem. Commun. 2010, 46, 7406−7408. (42) Peng, X.; Song, F.; Lu, E.; Wang, Y.; Zhou, W.; Fan, J.; Gao, Y. Heptamethine Cyanine Dyes with a Large Stokes Shift and Strong Fluorescence: A Paradigm for Excited-State Intramolecular Charge Transfer. J. Am. Chem. Soc. 2005, 127, 4170−4171. (43) Pham, W.; Cassell, L.; Gillman, A.; Koktysh, D.; Gore, J. C. A Near-Infrared Dye for Multichannel Imaging. Chem. Commun. 2008, 16, 1895−1897. (44) Wu, X.; Zhu, W. Stability Enhancement of Fluorophores for Lighting up Practical Application in Bioimaging. Chem. Soc. Rev. 2015, 44, 4179−4184. (45) Wu, X.; Chang, S.; Sun, X.; Guo, Z.; Li, Y.; Tang, J.; Shen, Y.; Shi, J.; Tian, H.; Zhu, W. Constructing NIR Silica−cyanine Hybrid Nanocomposite for Bioimaging in Vivo: A Breakthrough in Photostability and Bright Fluorescence with Large Stokes Shift. Chem. Sci. 2013, 4, 1221−1228. (46) Daly, B.; Ling, J.; de Silva, A. P. Current Developments in Fluorescent PET (Photoinduced Electron Transfer) Sensors and Switches. Chem. Soc. Rev. 2015, 44, 4203−4211.

(47) de Silva, A. P.; Moody, T. S.; Wright, G. D. Fluorescent PET (Photoinduced Electron Transfer) Sensors as Potent Analytical Tools. Analyst 2009, 134, 2385−2393. (48) Loudet, A.; Burgess, K. BODIPY Dyes and Their Derivatives: Syntheses and Spectroscopic Properties. Chem. Rev. 2007, 107, 4891− 4932. (49) Tang, B.; Huang, H.; Xu, K.; Tong, L.; Yang, G.; Liu, X.; An, L. Highly Sensitive and Selective Near-Infrared Fluorescent Probe for Zinc and Its Application to Macrophage Cells. Chem. Commun. 2006, 34, 3609−3611. (50) Tang, B.; Cui, L. J.; Xu, K. H.; Tong, L. L.; Yang, G. W.; An, L. G. A Sensitive and Selective Near-Infrared Fluorescent Probe for Mercuric Ions and Its Biological Imaging Applications. ChemBioChem 2008, 9, 1159−1164. (51) Yang, Y.; Cheng, T.; Zhu, W.; Xu, Y.; Qian, X. Highly Selective and Sensitive Near-Infrared Fluorescent Sensors for Cadmium in Aqueous Solution. Org. Lett. 2011, 13, 264−267. (52) Li, P.; Fang, L.; Zhou, H.; Zhang, W.; Wang, X.; Li, N.; Zhong, H.; Tang, B. A New Ratiometric Fluorescent Probe for Detection of Fe2+ with High Sensitivity and Its Intracellular Imaging Applications. Chem. Eur. J. 2011, 17, 10520−10523. (53) Zeng, L.; Miller, E. W.; Pralle, A.; Isacoff, E. Y.; Chang, J. C. A Selective Turn-On Fluorescent Sensor for Imaging Copper in Living Cells. J. Am. Chem. Soc. 2006, 128, 10−11. (54) Li, P.; Duan, X.; Chen, Z.; Liu, Y.; Xie, T.; Fang, L.; Li, X.; Yin, M.; Tang, B. A Near-Infrared Fluorescent Probe for Detecting Copper (II) with High Selectivity and Sensitivity and Its Biological Imaging Applications. Chem. Commun. 2011, 47, 7755−7757. (55) Cao, X.; Lin, W.; Wan, W. Development of a Near-Infrared Fluorescent Probe for Imaging of Endogenous Cu+ in Live Cells. Chem. Commun. 2012, 48, 6247−6249. (56) Hirayama, T.; Van de Bittner, G. C.; Gray, L. W.; Lutsenko, S.; Chang, C. J. Near-Infrared Fluorescent Sensor for in Vivo Copper Imaging in A Murine Wilson Disease Model. Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 2228−2233. (57) Han, J.; Burgess, K. Fluorescent Indicators for Intracellular pH. Chem. Rev. 2010, 110, 2709−2728. (58) Tang, B.; Yu, F.; Li, P.; Tong, L.; Duan, X.; Xie, T.; Wang, X. A Near-Infrared Neutral pH Fluorescent Probe for Monitoring Minor pH Changes: Imaging in Living HepG2 and HL-7702 Cells. J. Am. Chem. Soc. 2009, 131, 3016−3023. (59) Yu, H.; Sun, M.; Zhang, K.; Zhu, H.; Liu, Z.; Zhang, Y.; Zhao, J.; Wu, L.; Zhang, Z.; Wang, S. A Reversible Near-Infrared pH Probes for Optical Measurements of pH in Complete Water System and Living Cells. Sens. Actuators, B 2015, 219, 294−300. (60) Tang, B.; Liu, X.; Xu, K.; Huang, H.; Yang, G.; An, L. A Dual NearInfrared pH Fluorescent Probe and Its Application in Imaging of HepG2 Cells. Chem. Commun. 2007, 36, 3726−3728. (61) Chen, X.; Tian, X.; Shin, I.; Yoon, J. Fluorescent and Luminescent Probes for Detection of Reactive Oxygen and Nitrogen Species. Chem. Soc. Rev. 2011, 40, 4783−4804. (62) Sasaki, E.; Kojima, H.; Nishimatsu, H.; Urano, Y.; Kikuchi, K.; Hirata, Y.; Nagano, T. Highly Sensitive Near-Infrared Fluorescent Probes for Nitric Oxide and Their Application to Isolated Organs. J. Am. Chem. Soc. 2005, 127, 3684−3685. (63) Wang, R.; Yu, F.; Chen, L.; Chen, H.; Wang, L.; Zhang, W. A Highly Selective Turn-On Near-Infrared Fluorescent Probe for Hydrogen Sulfide Detection and Imaging in Living Cells. Chem. Commun. 2012, 48, 11757−11759. (64) Xu, K.; Wang, L.; Qiang, M.; Wang, L.; Li, P.; Tang, B. A Selective Near-Infrared Fluorescent Probe for Singlet Oxygen in Living Cells. Chem. Commun. 2011, 47, 7386−7388. (65) Zhang, J.; Yu, B.; Ning, L.; Zhu, X.; Wang, J.; Chen, Z.; Liu, X.; Yao, X.; Zhang, X.; Zhang, H. A Near-Infrared Fluorescence Probe for Thiols Based on Analyte-Specific Cleavage of Carbamate and Its Application in Bioimaging. Eur. J. Org. Chem. 2015, 2015, 1711−1718. (66) Yin, J.; Kwon, Y.; Kim, D.; Lee, D.; Kim, G.; Hu, Y.; Ryu, J. H.; Yoon, J. Cyanine-Based Fluorescent Probe for Highly Selective 7810


Chemical Reviews

Review

Detection of Glutathione in Cell Cultures and Live Mouse Tissues. J. Am. Chem. Soc. 2014, 136, 5351−5358. (67) Wang, R.; Chen, L.; Liu, P.; Zhang, Q.; Wang, Y. Sensitive NearInfrared Fluorescent Probes for Thiols Based on Se-N Bond Cleavage: Imaging in Living Cells and Tissues. Chem. - Eur. J. 2012, 18, 11343− 11349. (68) Wang, X.; Lv, J.; Yao, X.; Li, Y.; Huang, F.; Li, M.; Yang, J.; Ruan, X.; Tang, B. Screening and Investigation of A Cyanine Fluorescent Probe for Simultaneous Sensing of Glutathione and Cysteine under Single Excitation. Chem. Commun. 2014, 50, 15439−15442. (69) Lim, S.-Y.; Hong, K.-H.; Kim, D. I.; Kwon, H.; Kim, H.-J. Tunable Heptamethine-Azo Dye Conjugate as an NIR Fluorescent Probe for the Selective Detection of Mitochondrial Glutathione over Cysteine and Homocysteine. J. Am. Chem. Soc. 2014, 136, 7018−7025. (70) Yu, F.; Li, P.; Li, G.; Zhao, G.; Chu, T.; Han, K. A Near-IR Reversible Fluorescent Probe Modulated by Selenium for Monitoring Peroxynitrite and Imaging in Living Cells. J. Am. Chem. Soc. 2011, 133, 11030−11033. (71) Xu, K.; Chen, H.; Tian, J.; Ding, B.; Xie, Y.; Qiang, M.; Tang, B. A Near-Infrared Reversible Fluorescent Probe for Peroxynitrite and Imaging of Redox Cycles in Living Cells. Chem. Commun. 2011, 47, 9468−9470. (72) Xu, K.; Qiang, M.; Gao, W.; Su, R.; Li, N.; Gao, Y.; Xie, Y.; Kong, F.; Tang, B. A Near-Infrared Reversible Fluorescent Probe for RealTime Imaging of Redox Status Changes in Vivo. Chem. Sci. 2013, 4, 1079−1086. (73) Yu, F.; Li, P.; Wang, B.; Han, K. Reversible Near-Infrared Fluorescent Probe Introducing Tellurium to Mimetic Glutathione Peroxidase for Monitoring the Redox Cycles Between Peroxynitrite and Glutathione in Vivo. J. Am. Chem. Soc. 2013, 135, 7674−7680. (74) Yu, F.; Li, P.; Song, P.; Wang, B.; Zhao, J.; Han, K. Facilitative Functionalization of Cyanine Dye by an On-Off-On Fluorescent Switch for Imaging of H2O2 Oxidative Stress and Thiols Reducing Repair in Cells and Tissues. Chem. Commun. 2012, 48, 4980−4982. (75) Yu, F.; Song, P.; Li, P.; Wang, B.; Han, K. Development of Reversible Fluorescence Probes Based on Redox Oxoammonium Cation for Hypobromous Acid Detection in Living Cells. Chem. Commun. 2012, 48, 7735−7737. (76) Wang, X.; Cui, L.; Zhou, N.; Zhu, W.; Wang, R.; Qian, X.; Xu, Y. A Highly Selective and Sensitive Near-Infrared Fluorescence Probe for Arylamine N-acetyltransferase 2 in Vitro and in Vivo. Chem. Sci. 2013, 4, 2936−2940. (77) Battaini, G.; Monzani, E.; Casella, L.; Lonardi, E.; Tepper, A. W. J. W.; Canters, G. W.; Bubacco, L. Tyrosinase-Catalyzed Oxidation of Fluorophenols. J. Biol. Chem. 2002, 277, 44606−44612. (78) Li, X.; Shi, W.; Chen, S.; Jia, J.; Ma, H.; Wolfbeis, O. S. A NearInfrared Fluorescent Probe for Monitoring Tyrosinase Activity. Chem. Commun. 2010, 46, 2560−2562. (79) Xu, K.; Wang, F.; Pan, X.; Liu, R.; Ma, J.; Kong, F.; Tang, B. High Selectivity Imaging of Nitroreductase Using a Near-Infrared Fluorescence Probe in Hypoxic Tumor. Chem. Commun. 2013, 49, 2554− 2556. (80) Okuda, K.; Okabe, Y.; Kadonosono, T.; Ueno, T.; Youssif, B. G. M.; Kizaka-Kondoh, S.; Nagasawa, H. 2-Nitroimidazole-Tricarbocyanine Conjugate as a Near-Infrared Fluorescent Probe for in Vivo Imaging of Tumor Hypoxia. Bioconjugate Chem. 2012, 23, 324−329. (81) Youssif, B. G. M.; Okuda, K.; Kadonosono, T.; Salem, O.O. I. A. R.; Hayallah, A. A. M.; Hussein, M. A.; Nagasawa, H.; Kizaka-Kondoh, S. Development of a Hypoxia-Selective Near-Infrared Fluorescent Probe for Non-invasive Tumor Imaging. Chem. Pharm. Bull. 2012, 60, 402− 407. (82) Li, Y.; Sun, Y.; Li, J.; Su, Q.; Yuan, W.; Dai, Y.; Han, C.; Wang, Q.; Feng, W.; Li, F. Ultrasensitive Near-Infrared Fluorescence-Enhanced Probe for in Vivo Nitroreductase Imaging. J. Am. Chem. Soc. 2015, 137, 6407−6416. (83) Fan, J.; Sun, W.; Hu, M.; Cao, J.; Cheng, G.; Dong, H.; Song, K.; Liu, Y.; Sun, S.; Peng, X. An ICT-Based Ratiometric Probe for Hydrazine and Its Application in Live Cells. Chem. Commun. 2012, 48, 8117−8119.

(84) Zhu, M.; Yuan, M.; Liu, X.; Xu, J.; Lv, J.; Huang, C.; Liu, H.; Li, Y.; Wang, S.; Zhu, D. Visible Near-Infrared Chemosensor for Mercury Ion. Org. Lett. 2008, 10, 1481−1484. (85) Carvalho, C. M.; Chew, E. H.; Hashemy, S. I.; Lu, J.; Holmgren, A. Inhibition of the Human Thioredoxin System. A Molecular Mechanism of Mercury Toxicity. J. Biol. Chem. 2008, 283, 11913−11923. (86) Guo, Z.; Zhu, W.; Zhu, M.; Wu, X.; Tian, H. Near-Infrared CellPermeable Hg2+-Selective Ratiometric Fluorescent Chemodosimeters and Fast Indicator Paper for MeHg+ Based on Tricarbocyanines. Chem. Eur. J. 2010, 16, 14424−14432. (87) Kiyose, K.; Kojima, H.; Urano, Y.; Nagano, T. Development of a Ratiometric Fluorescent Zinc Ion Probe in Near-Infrared Region, Based on Tricarbocyanine Chromophore. J. Am. Chem. Soc. 2006, 128, 6548− 6549. (88) Wang, J.; Song, F.; Wang, J.; Peng, X. A Near-infrared and Ratiometric Fluorescent Chemosensor for Palladium. Analyst 2013, 138, 3667−3672. (89) Myochin, T.; Kiyose, K.; Hanaoka, K.; Kojima, H.; Terai, T.; Nagano, T. Rational Design of Ratiometric Near-Infrared Fluorescent pH Probes with Various pKa Values, Based on Aminocyanine. J. Am. Chem. Soc. 2011, 133, 3401−3409. (90) Yu, F.; Li, P.; Song, P.; Wang, B.; Zhao, J.; Han, K. An ICT-Based Strategy to a Colorimetric and Ratiometric Fluorescence Probe for Hydrogen Sulfide in Living Cells. Chem. Commun. 2012, 48, 2852− 2854. (91) Zhu, D.; Li, G.; Xue, L.; Jiang, H. Development of Ratiometric Near-Infrared Fluorescent Probes Using Analyte-Specific Cleavage of Carbamate. Org. Biomol. Chem. 2013, 11, 4577−4580. (92) Yang, Z.; Lee, J. H.; Jeon, H. M.; Han, J. H.; Park, N.; He, Y.; Lee, H.; Hong, K. S.; Kang, C.; Kim, J. S. Folate-Based Near-Infrared Fluorescent Theranostic Gemcitabine Delivery. J. Am. Chem. Soc. 2013, 135, 11657−11662. (93) Niu, L.-Y.; Zheng, H.-R.; Chen, Y.-Z.; Wu, L.-Z.; Tung, C.-H.; Yang, Q.-Z. Fluorescent Sensors for Selective Detection of Thiols: Expanding the Intramolecular Displacement Based Mechanism to New Chromophores. Analyst 2014, 139, 1389−1395. (94) Hu, X.-X.; Su, Y.-T.; Ma, Y.-W.; Zhan, X.-Q.; Zheng, H.; Jiang, Y.B. A Near Infrared Colorimetric and Fluorometric Probe for Organophosphorus Nerve Agent Mimic by Intramolecular Amidation. Chem. Commun. 2015, 51, 15118−15121. (95) Grabowski, Z. R.; Rotkiewicz, K.; Rettig, W. Structural Changes Accompanying Intramolecular Electron Transfer: Focus on Twisted Intramolecular Charge-Transfer States and Structures. Chem. Rev. 2003, 103, 3899−4032. (96) Xu, K.; Sun, S.; Li, J.; Li, L.; Qiang, M.; Tang, B. A Near-Infrared Fluorescent Probe for Monitoring Ozone and Imaging in Living Cells. Chem. Commun. 2012, 48, 684−686. (97) Kiyose, K.; Aizawa, S.; Sasaki, E.; Kojima, H.; Hanaoka, K.; Terai, T.; Urano, Y.; Nagano, T. Molecular Design Strategies for Near-Infrared Ratiometric Fluorescent Probes Based on the Unique Spectral Properties of Aminocyanines. Chem. - Eur. J. 2009, 15, 9191−9200. (98) Fan, J.; Hu, M.; Zhan, P.; Peng, X. Energy Transfer Cassettes Based on Organic Fluorophores: Construction and Applications in Ratiometric Sensing. Chem. Soc. Rev. 2013, 42, 29−43. (99) dos Remedios, C. G.; Moens, P. D. J. Fluorescence Resonance Energy Transfer Spectroscopy Is a Reliable “Ruler” for Measuring Structural Changes in Proteins: Dispelling the Problem of the Unknown Orientation Factor. J. Struct. Biol. 1995, 115, 175−185. (100) Fan, J.; Zhan, P.; Hu, M.; Sun, W.; Tang, J.; Wang, J.; Sun, S.; Song, F.; Peng, X. A Fluorescent Ratiometric Chemodosimeter for Cu2+ Based on TBET and Its Application in Living Cells. Org. Lett. 2013, 15, 492−495. (101) Chen, G.; Song, F.; Wang, J.; Yang, Z.; Sun, S.; Fan, J.; Qiang, X.; Wang, X.; Dou, B.; Peng, X. FRET Spectral Unmixing: a Ratiometric Fluorescent Nanoprobe for Hypochlorite. Chem. Commun. 2012, 48, 2949−2951. (102) Takahashi, S.; Piao, W.; Matsumura, Y.; Komatsu, T.; Ueno, T.; Terai, T.; Kamachi, T.; Kohno, M.; Nagano, T.; Hanaoka, K. Reversible Off-On Fluorescence Probe for Hypoxia and Imaging of Hypoxia7811


Chemical Reviews

Review

Normoxia Cycles in Live Cells. J. Am. Chem. Soc. 2012, 134, 19588− 19591. (103) Xing, B.; Khanamiryan, A.; Rao, J. Cell-Permeable Near-Infrared Fluorogenic Substrates for Imaging β-Lactamase Activity. J. Am. Chem. Soc. 2005, 127, 4158−4159. (104) Kong, Y.; Yao, H.; Ren, H.; Subbian, S.; Cirillo, S. L. G.; Sacchettini, J. C.; Rao, J.; Cirillo, J. D. Imaging Tuberculosis with Endogenous Beta-Lactamase Reporter Enzyme Fluorescence in Live Mice. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 12239−12244. (105) Kiyose, K.; Hanaoka, K.; Oushiki, D.; Nakamura, T.; Kajimura, M.; Suematsu, M.; Nishimatsu, H.; Yamane, T.; Terai, T.; Hirata, Y.; Nagano, T. Hypoxia-Sensitive Fluorescent Probes for in Vivo Real-Time Fluorescence Imaging of Acute Ischemia. J. Am. Chem. Soc. 2010, 132, 15846−15848. (106) Linder, K. E.; Metcalfe, E.; Nanjappan, P.; Arunachalam, T.; Ramos, K.; Skedzielewski, T. M.; Marinelli, E. R.; Tweedle, M. F.; Nunn, A. D.; Swenson, R. E. Synthesis, in Vitro Evaluation, and in Vivo Metabolism of Fluor/Quencher Compounds Containing IRDye 800CW and Black Hole Quencher-3 (BHQ-3). Bioconjugate Chem. 2011, 22, 1287−1297. (107) Hardt, N.; Hacker, S. M.; Marx, A. Synthesis and Fluorescence Characteristics of ATP-Based FRET Probes. Org. Biomol. Chem. 2013, 11, 8298−8305. (108) Freeman, R.; Willner, I. Optical Molecular Sensing with Semiconductor Quantum Dots (QDs). Chem. Soc. Rev. 2012, 41, 4067−4085. (109) Tang, R.; Lee, H.; Achilefu, S. Induction of pH Sensitivity on the Fluorescence Lifetime of Quantum Dots by NIR Fluorescent Dyes. J. Am. Chem. Soc. 2012, 134, 4545−4548. (110) Huang, X.; Wang, J.; Liu, H.; Lan, T.; Ren, J. Quantum DotBased FRET for Sensitive Determination of Hydrogen Peroxide and Glucose Using Tyramide Reaction. Talanta 2013, 106, 79−84. (111) Albers, A. E.; Chan, E. M.; McBride, P. M.; Ajo-Franklin, C. M.; Cohen, B. E.; Helms, B. A. Dual-Emitting Quantum Dot/Quantum Rod-Based Nanothermometers with Enhanced Response and Sensitivity in Live Cells. J. Am. Chem. Soc. 2012, 134, 9565−9568. (112) Wang, F.; Banerjee, D.; Liu, Y.; Chen, X.; Liu, X. Upconversion Nanoparticles in Biological Labeling, Imaging, and Therapy. Analyst 2010, 135, 1839−1854. (113) Zhou, J.; Liu, Q.; Feng, W.; Sun, Y.; Li, F. Upconversion Luminescent Materials: Advances and Applications. Chem. Rev. 2015, 115, 395−465. (114) Zou, X.; Liu, Y.; Zhu, X.; Chen, M.; Yao, L.; Feng, W.; Li, F. An Nd3+-Sensitized Upconversion Nanophosphor Modified with a Cyanine Dye for the Ratiometric Upconversion Luminescence Bioimaging of Hypochlorite. Nanoscale 2015, 7, 4105−13. (115) Zhou, Y.; Pei, W.; Zhang, X.; Chen, W.; Wu, J.; Yao, C.; Huang, L.; Zhang, H.; Huang, W.; Chye Loo, J. S.; Zhang, Q. A CyanineModified Upconversion Nanoprobe for NIR-Excited Imaging of Endogenous Hydrogen Peroxide Signaling in Vivo. Biomaterials 2015, 54, 34−43. (116) Liu, Y.; Chen, M.; Cao, T.; Sun, Y.; Li, C.; Liu, Q.; Yang, T.; Yao, L.; Feng, W.; Li, F. A Cyanine-Modified Nanosystem for in Vivo Upconversion Luminescence Bioimaging of Methylmercury. J. Am. Chem. Soc. 2013, 135, 9869−9876. (117) Hu, C.; Sun, W.; Cao, J.; Gao, P.; Wang, J.; Fan, J.; Song, F.; Sun, S.; Peng, X. A Ratiometric Near-Infrared Fluorescent Probe for Hydrazine and Its in Vivo Applications. Org. Lett. 2013, 15, 4022−4025. (118) Guo, Z.; Nam, S.; Park, S.; Yoon, J. A Highly Selective Ratiometric Near-Infrared Fluorescent Cyanine Sensor for Cysteine with Remarkable Shift and Its Application in Bioimaging. Chem. Sci. 2012, 3, 2760−2765. (119) Yin, K.; Yu, F.; Zhang, W.; Chen, L. A Near-infrared Ratiometric Fluorescent Probe for Cysteine Detection over Glutathione Indicating Mitochondrial Oxidative Stress in Vivo. Biosens. Bioelectron. 2015, 74, 156−164. (120) Wang, X.; Sun, J.; Zhang, W.; Ma, X.; Lv, J.; Tang, B. A NearInfrared Ratiometric Fluorescent Probe for Rapid and Highly Sensitive

Imaging of Endogenous Hydrogen Sulfide in Living Cells. Chem. Sci. 2013, 4, 2551−2556. (121) Wang, X.; Guo, Z.; Zhu, S.; Tian, H.; Zhu, W. A Naked-Eye and Ratiometric Near-Infrared Probe for Palladium via Modulation of a πConjugated System of Cyanines. Chem. Commun. 2014, 50, 13525− 13528. (122) Guo, Z.; Kim, G. H.; Shin, I.; Yoon, J. A Cyanine-Based Fluorescent Sensor for Detecting Endogenous Zinc Ions in Live Cells and Organisms. Biomaterials 2012, 33, 7818−7827. (123) Guo, Z.; Kim, G. H.; Yoon, J.; Shin, I. Synthesis of a Highly Zn2+Selective Cyanine-Based Probe and Its Use for Tracing Endogenous Zinc Ions in Cells and Organisms. Nat. Protoc. 2014, 9, 1245−1254. (124) Karton-Lifshin, N.; Segal, E.; Omer, L.; Portnoy, M.; SatchiFainaro, R.; Shabat, D. A Unique Paradigm for a Turn-ON NearInfrared Cyanine-Based Probe: Noninvasive Intravital Optical Imaging of Hydrogen Peroxide. J. Am. Chem. Soc. 2011, 133, 10960−10965. (125) Maity, D.; Govindaraju, T. A Turn-On NIR Fluorescence and Colourimetric Cyanine Probe for Monitoring the Thiol Content in Serum and the Glutathione Reductase Assisted Glutathione Redox Process. Org. Biomol. Chem. 2013, 11, 2098−2104. (126) Maity, D.; Raj, A.; Samanta, P. K.; Karthigeyan, D.; Kundu, T. K.; Pati, S. K.; Govindaraju, T. A Probe for Ratiometric Near-Infrared Fluorescence and Colorimetric Hydrogen Sulfide Detection and Imaging in Live Cells. RSC Adv. 2014, 4, 11147−11151. (127) Shi, Y.; Zhang, S.; Zhang, X. A Novel Near-Infrared Fluorescent Probe for Selectively Sensing Nitroreductase (NTR) in an Aqueous Medium. Analyst 2013, 138, 1952−1955. (128) Li, P.; Tang, B.; Xing, Y.; Li, P.; Yang, G.; Zhang, L. A NearInfrared Fluorescent Probe for Lipid Hydroperoxides in Living Cells. Analyst 2008, 133, 1409−1415. (129) Kundu, K.; Knight, S. F.; Lee, S.; Taylor, W. R.; Murthy, N. A Significant Improvement of the Efficacy of Radical Oxidant Probes by the Kinetic Isotope Effect. Angew. Chem., Int. Ed. 2010, 49, 6134−6138. (130) Kundu, K.; Knight, S. F.; Willett, N.; Lee, S.; Taylor, W. R.; Murthy, N. Hydrocyanines: A Class of Fluorescent Sensors That Can Image Reactive Oxygen Species in Cell Culture, Tissue, and in Vivo. Angew. Chem., Int. Ed. 2009, 48, 299−303. (131) Lou, Z.; Li, P.; Song, P.; Han, K. Ratiometric Fluorescence Imaging of Cellular Hypochlorous Acid Based on Heptamethine Cyanine Dyes. Analyst 2013, 138, 6291−6295. (132) Sun, M.; Yu, H.; Zhu, H.; Ma, F.; Zhang, S.; Huang, D.; Wang, S. Oxidative Cleavage-Based Near-Infrared Fluorescent Probe for Hypochlorous Acid Detection and Myeloperoxidase Activity Evaluation. Anal. Chem. 2014, 86, 671−677. (133) Niu, H.; Jiang, X.; He, J.; Cheng, J. Cyanine Dye-Based Chromofluorescent Probe for Highly Sensitive and Selective Detection of Cyanide in Water. Tetrahedron Lett. 2009, 50, 6668−6671. (134) He, L.; Lin, W.; Xu, Q.; Ren, M.; Wei, H.; Wang, J. A Simple and Effective “Capping” Approach to Readily Tune the Fluorescence of Near-Infrared Cyanines. Chem. Sci. 2015, 6, 4530−4536. (135) Hilderbrand, S. A.; Weissleder, R. Optimized pH-Responsive Cyanine Fluorochromes for Detection of Acidic Environments. Chem. Commun. 2007, 26, 2747−2749. (136) Briggs, M. S.; Burns, D. D.; Cooper, M. E.; Gregory, S. J. A pH Sensitive Fluorescent Cyanine Dye for Biological Applications. Chem. Commun. 2000, 23, 2323−2324. (137) Cooper, M. E.; Gregory, S.; Adie, E.; Kalinka, S. pH-Sensitive Cyanine Dyes for Biological Applications. J. Fluoresc. 2002, 12, 425− 429. (138) Patrick, M. J.; Janjic, J. M.; Teng, H.; O’Hear, M. R.; Brown, C. W.; Stokum, J. A.; Schmidt, B. F.; Ahrens, E. T.; Waggoner, A. S. Intracellular pH Measurements Using Perfluorocarbon Nanoemulsions. J. Am. Chem. Soc. 2013, 135, 18445−18457. (139) Hilderbrand, S. A.; Kelly, K. A.; Niedre, M.; Weissleder, R. Near Infrared Fluorescence-Based Bacteriophage Particles for Ratiometric pH Imaging. Bioconjugate Chem. 2008, 19, 1635−1639. (140) Zhang, Z.; Achilefu, S. Design, Synthesis and Evaluation of NearInfrared Fluorescent pH Indicators in a Physiologically Relevant Range. Chem. Commun. 2005, 47, 5887−5889. 7812


Chemical Reviews

Review

(141) Lee, H.; Akers, W.; Bhushan, K.; Bloch, S.; Sudlow, G.; Tang, R.; Achilefu, S. Near-Infrared pH-Activatable Fluorescent Probes for Imaging Primary and Metastatic Breast Tumors. Bioconjugate Chem. 2011, 22, 777−784. (142) Zhao, X.; Li, Y.; Jin, D.; Xing, Y.; Yan, X.; Chen, L. A NearInfrared Multifunctional Fluorescent Probe with an Inherent TumorTargeting Property for Bioimaging. Chem. Commun. 2015, 51, 11721− 11724. (143) Behera, G. B.; Behera, P. K.; Mishra, B. K. Cyanine Dyes: Self Aggregation and Behaviour in Surfactants. J. Surf. Sci. Technol. 2007, 23, 1−31. (144) Zheng, H.; Yan, M.; Fan, X.-X.; Sun, D.; Yang, S.-Y.; Yang, L.-J.; Li, J.-D.; Jiang, Y.-B. A Heptamethine Cyanine-Based Colorimetric and Ratiometric Fluorescent Chemosensor for the Selective Detection of Ag+ in an Aqueous Medium. Chem. Commun. 2012, 48, 2243−2245. (145) Zheng, H.; Zhang, X.-J.; Cai, X.; Bian, Q.-N.; Yan, M.; Wu, G.H.; Lai, X.-W.; Jiang, Y.-B. Ratiometric Fluorescent Chemosensor for Hg2+ Based on Heptamethine Cyanine Containing a Thymine Moiety. Org. Lett. 2012, 14, 1986−1989. (146) Cheng, G.; Fan, J.; Sun, W.; Cao, J.; Hu, C.; Peng, X. A NearInfrared Fluorescent Probe for Selective Detection of HClO Based on Se-Sensitized Aggregation of Heptamethine Cyanine Dye. Chem. Commun. 2014, 50, 1018−1020. (147) Lee, S. Y.; Lee, S.; Youn, I.-C.; Yi, D. K.; Lim, Y. T.; Chung, B. H.; Leary, J. F.; Kwon, I. C.; Kim, K.; Choi, K. A Near-Infrared Fluorescence-Based Optical Thermosensor. Chem. - Eur. J. 2009, 15, 6103−6106. (148) Oushiki, D.; Kojima, H.; Terai, T.; Arita, M.; Hanaoka, K.; Urano, Y.; Nagano, T. Development and Application of a Near-Infrared Fluorescence Probe for Oxidative Stress Based on Differential Reactivity of Linked Cyanine Dyes. J. Am. Chem. Soc. 2010, 132, 2795−2801. (149) Hou, T.-C.; Wu, Y.-Y.; Chiang, P.-Y.; Tan, K.-T. Near-Infrared Fluorescence Activation Probes Based on Disassembly-Induced Emission Cyanine Dye. Chem. Sci. 2015, 6, 4643−4649. (150) Peng, X.; Yang, Z.; Wang, J.; Fan, J.; He, Y.; Song, F.; Wang, B.; Sun, S.; Qu, J.; Qi, J.; Yan, M. Fluorescence Ratiometry and Fluorescence Lifetime Imaging: Using a Single Molecular Sensor for Dual Mode Imaging of Cellular Viscosity. J. Am. Chem. Soc. 2011, 133, 6626−6635. (151) Jiang, N.; Fan, J.; Zhang, S.; Wu, T.; Wang, J.; Gao, P.; Qu, J.; Zhou, F.; Peng, X. Dual Mode Monitoring Probe for Mitochondrial Viscosity in Single Cell. Sens. Actuators, B 2014, 190, 685−693. (152) Zhao, Y.; Li, Y.; Wang, Y.; Zheng, J.; Yang, R. A New Strategy for Fluorometric Detection of Ascorbic Acid Based on Hydrolysis and Redox Reaction. RSC Adv. 2014, 4, 35112−35115. (153) Gatzogiannis, E.; Chen, Z.; Wei, L.; Wombacher, R.; Kao, Y. T.; Yefremov, G.; Cornish, V. W.; Min, W. Mapping Protein-Specific MicroEnvironments in Live Cells by Fluorescence Lifetime Imaging of a Hybrid Genetic-Chemical Molecular Rotor Tag. Chem. Commun. 2012, 48, 8694−8696. (154) Konuk, R.; Cornelisse, J.; McGlynn, S. P. Fluorescence Quenching of Pyrene by Cu2+ and Co2+ in Sodium Dodecyl Sulfate Micelles. J. Phys. Chem. 1989, 93, 7405−7408. (155) Han, Z.; Yang, Q.; Liang, L.; Zhang, X. A New Heptamethine Cyanine-Based Near-Infrared Fluorescent Probe for Divalent Copper Ions with High Selectivity. Adv. Mater. Phys. Chem. 2013, 3, 314−319. (156) Chen, X.; Nam, S. W.; Kim, G. H.; Song, N.; Jeong, Y.; Shin, I.; Kim, S. K.; Kim, J.; Park, S.; Yoon, J. A Near-Infrared Fluorescent Sensor for Detection of Cyanide in Aqueous Solution and Its Application for Bioimaging. Chem. Commun. 2010, 46, 8953−8955. (157) Cao, X.; Lin, W.; He, L. A Near-Infrared Fluorescence Turn-On Sensor for Sulfide Anions. Org. Lett. 2011, 13, 4716−4719. (158) Michel, B. W.; Lippert, A. R.; Chang, C. J. A Reaction-Based Fluorescent Probe for Selective Imaging of Carbon Monoxide in Living Cells Using a Palladium-Mediated Carbonylation. J. Am. Chem. Soc. 2012, 134, 15668−15671. (159) Kawagoe, R.; Takashima, I.; Usui, K.; Kanegae, A.; Ozawa, Y.; Ojida, A. Rational Design of a Ratiometric Fluorescent Probe Based on

Arene-Metal-Ion Contact for Endogenous Hydrogen Sulfide Detection in Living Cells. ChemBioChem 2015, 16, 1608−1615. (160) Kong, F.-T.; Dai, S.-Y.; Wang, K.-J. Review of Recent Progress in Dye-Sensitized Solar Cells. Adv. OptoElectron. 2007, 2007, 1−13. (161) Chen, Y.-S.; Li, C.; Zeng, Z.-H.; Wang, W.-B.; Wang, X.-S.; Zhang, B.-W. Efficient Electron Injection Due to a Special Adsorbing Group’s Combination of Carboxyl and Hydroxyl: Dye-Sensitized Solar Cells Based on New Hemicyanine Dyes. J. Mater. Chem. 2005, 15, 1654−1661. (162) Armitage, B. A. In Heterocyclic Polymethine Dyes; Lucjan, S., Ed.; Springer-Verlag: Berlin, 2008; pp 11−29. (163) Rosania, G. R.; Lee, J. W.; Ding, L.; Yoon, H.-S.; Chang, Y.-T. Combinatorial Approach to Organelle-Targeted Fluorescent Library Based on the Styryl Scaffold. J. Am. Chem. Soc. 2003, 125, 1130−1131. (164) Yuan, L.; Lin, W.; Zhao, S.; Gao, W.; Chen, B.; He, L.; Zhu, S. A Unique Approach to Development of Near-Infrared Fluorescent Sensors for in Vivo Imaging. J. Am. Chem. Soc. 2012, 134, 13510−13523. (165) Richard, J.-A.; Massonneau, M.; Renard, P.-Y.; Romieu, A. 7Hydroxycoumarin-Hemicyanine Hybrids: A New Class of Far-Red Emitting Fluorogenic Dyes. Org. Lett. 2008, 10, 4175−4178. (166) Yuan, L.; Lin, W.; Yang, Y.; Chen, H. A Unique Class of NearInfrared Functional Fluorescent Dyes with Carboxylic-Acid-Modulated Fluorescence ON/OFF Switching: Rational Design, Synthesis, Optical Properties, Theoretical Calculations, and Applications for Fluorescence Imaging in Living Animals. J. Am. Chem. Soc. 2012, 134, 1200−1211. (167) Li, Y.; He, S.; Lu, Y.; Zeng, X. Novel Hemicyanine Dye as Colorimetric and Fluorometric Dual-Modal Chemosensor for Mercury in Water. Org. Biomol. Chem. 2011, 9, 2606−2609. (168) Xu, J.-F.; Chen, H.-H.; Chen, Y.-Z.; Li, Z.-J.; Wu, L.-Z.; Tung, C.H.; Yang, Q.-Z. A Colorimetric and Fluorometric Dual-modal Chemosensor for Cyanide in Water. Sens. Actuators, B 2012, 168, 14− 19. (169) Lee, D.-N.; Jo, A.; Park, S. B.; Hong, J.-I. Colorimetric and Orange Light-Emitting Fluorescent Probe for Pyrophosphate in Water. Tetrahedron Lett. 2012, 53, 5528−5530. (170) Gao, X.; Zheng, H.; Shang, G.-Q.; Xu, J.-G. Colorimetric Detection of Fluoride in an Aqueous Solution Using Zr(IV)-EDTA Complex and a Novel Hemicyanine Dye. Talanta 2007, 73, 770−775. (171) Du, J.; Hu, M.; Fan, J.; Peng, X. Fluorescent Chemodosimeters Using ‘‘Mild’’ Chemical Events for the Detection of Small Anions and Cations in Biological and Environmental Media. Chem. Soc. Rev. 2012, 41, 4511−4535. (172) Chan, J.; Dodani, S. C.; Chang, C. J. Reaction-Based SmallMolecule Fluorescent Probes for Chemoselective Bioimaging. Nat. Chem. 2012, 4, 973−984. (173) Chen, X.; Li, H.; Jin, L.; Yin, B. A Ratiometric Fluorescent Probe for Palladium Detection Based on an Allyl Carbonate Group Functionalized Hemicyanine Dye. Tetrahedron Lett. 2014, 55, 2537− 2540. (174) Chen, H.; Lin, W.; Yuan, L. Construction of a Near-Infrared Fluorescence Turn-On and Ratiometric Probe for Imaging Palladium in Living Cells. Org. Biomol. Chem. 2013, 11, 1938−1941. (175) Chen, Y.; Yang, C.; Yu, Z.; Chen, B.; Han, Y. A Highly Sensitive Hemicyanine-Based Fluorescent Chemodosimeter for Mercury Ions in Aqueous Solution and Living Cells. RSC Adv. 2015, 5, 82531−82534. (176) Yang, S.; Liu, Y.; Feng, G. Rapid and Selective Detection of Fluoride in Aqueous Solution by a New Hemicyanine-Based Colorimetric and Fluorescent Chemodosimeter. RSC Adv. 2013, 3, 20171−20178. (177) Zhang, J.; Ning, L.; Liu, J.; Wang, J.; Yu, B.; Liu, X.; Yao, X.; Zhang, Z.; Zhang, H. Naked-Eye and Near-Infrared Fluorescence Probe for Hydrazine and Its Applications in in Vitro and in Vivo Bioimaging. Anal. Chem. 2015, 87, 9101−9107. (178) Han, Q.; Shi, Z.; Tang, X.; Yang, L.; Mou, Z.; Li, J.; Shi, J.; Chen, C.; Liu, W.; Yang, H.; Liu, W. A Colorimetric and Ratiometric Fluorescent Probe for Distinguishing Cysteine from Biothiols in Water and Living Cells. Org. Biomol. Chem. 2014, 12, 5023−5030. 7813


Chemical Reviews

Review

(179) Li, H.; Jin, L.; Kan, Y.; Yin, B. A Visual and “Turn-On” Fluorescent Probe for Rapid Detection of Cysteine over Homocysteine and Glutathione. Sens. Actuators, B 2014, 196, 546−554. (180) Wang, S. P.; Deng, W. J.; Sun, D.; Yan, M.; Zheng, H.; Xu, J. G. A Colorimetric and Fluorescent Merocyanine-Based Probe for Biological Thiols. Org. Biomol. Chem. 2009, 7, 4017−4020. (181) Rayman, M. P. The Importance of Selenium to Human Health. Lancet 2000, 356, 233−241. (182) Schrauzer, G. N. Anticarcinogenic Effects of Selenium. Cell. Mol. Life Sci. 2000, 57, 1864−1873. (183) Kong, F.; Hu, B.; Gao, Y.; Xu, K.; Pan, X.; Huang, F.; Zheng, Q.; Chen, H.; Tang, B. Fluorescence Imaging of Selenol in HepG2 Cell Apoptosis Induced by Na2SeO3. Chem. Commun. 2015, 51, 3102−3105. (184) Chen, H.; Dong, B.; Tang, Y.; Lin, W. Construction of a NearInfrared Fluorescent Turn-On Probe for Selenol and Its Bioimaging Application in Living Animals. Chem. - Eur. J. 2015, 21, 11696−11700. (185) Kong, F.; Ge, L.; Pan, X.; Xu, K.; Liu, X.; Tang, B. A Highly Selective Near-Infrared Fluorescent Probe for Imaging H2Se in Living Cells and in Vivo. Chem. Sci. 2016, 7, 1051−1056. (186) Li, L.; Li, Z.; Shi, W.; Li, X.; Ma, H. Sensitive and Selective NearInfrared Fluorescent Off-On Probe and Its Application to Imaging Different Levels of β-lactamase in Staphylococcus Aureus. Anal. Chem. 2014, 86, 6115−6120. (187) Li, Z.; He, X.; Wang, Z.; Yang, R.; Shi, W.; Ma, H. In Vivo Imaging and Detection of Nitroreductase in Zebrafish by a New NearInfrared Fluorescence Off-On Probe. Biosens. Bioelectron. 2015, 63, 112−116. (188) Miao, J.-T.; Fan, C.; Shi, X.-Y.; Sun, R.; Xu, Y.-J.; Ge, J.-F. Colorimetric and Ratiometric pH Responses by the Protonation of Phenolate within Hemicyanine. Analyst 2014, 139, 6290−6297. (189) Li, Y.; Wang, Y.; Yang, S.; Zhao, Y.; Yuan, L.; Zheng, J.; Yang, R. Hemicyanine-Based High Resolution Ratiometric Near-Infrared Fluorescent Probe for Monitoring pH Changes in Vivo. Anal. Chem. 2015, 87, 2495−2503. (190) Wang, B.-L.; Jiang, C.; Li, K.; Liu, Y.-H.; Xie, Y.; Yu, X.-Q. Molecular Engineering of a Dual Emission Near-Infrared Ratiometric Fluorophore for the Detection of pH at the Organism Level. Analyst 2015, 140, 4608−4615. (191) Wan, Q.; Chen, S.; Shi, W.; Li, L.; Ma, H. Lysosomal pH Rise during Heat Shock Monitored by a Lysosome-Targeting Near-Infrared Ratiometric Fluorescent Probe. Angew. Chem. 2014, 126, 11096−11100. (192) Lin, V. S.; Chang, C. J. Fluorescent Probes for Sensing and Imaging Biological Hydrogen Sulfide. Curr. Opin. Chem. Biol. 2012, 16, 595−601. (193) Lin, V. S.; Chen, W.; Xian, M.; Chang, C. J. Chemical Probes for Molecular Imaging and Detection of Hydrogen Sulfide and Reactive Sulfur Species in Biological Systems. Chem. Soc. Rev. 2015, 44, 4596− 4618. (194) Yang, Y.; Yin, C.; Huo, F.; Zhang, Y.; Chao, J. A Ratiometric Colorimetric and Fluorescent Chemosensor for Rapid Detection Hydrogen Sulfide and Its Bioimaging. Sens. Actuators, B 2014, 203, 596−601. (195) Chen, Y.; Zhu, C.; Yang, Z.; Chen, J.; He, Y.; Jiao, Y.; He, W.; Qiu, L.; Cen, J.; Guo, Z. A Ratiometric Fluorescent Probe for Rapid Detection of Hydrogen Sulfide in Mitochondria. Angew. Chem., Int. Ed. 2013, 52, 1688−1691. (196) Zhou, Y.; Chen, W.; Zhu, J.; Pei, W.; Wang, C.; Huang, L.; Yao, C.; Yan, Q.; Huang, W.; Loo, J. S. C.; Zhang, Q. Inorganic-Organic Hybrid Nanoprobe for NIR-Excited Imaging of Hydrogen Sulfide in Cell Cultures and Inflammation in a Mouse Model. Small 2014, 10, 4874−4885. (197) Sun, Y.-Q.; Liu, J.; Zhang, J.; Yang, T.; Guo, W. Fluorescent Probe for Biological Gas SO2 Derivatives Bisulfite and Sulfite. Chem. Commun. 2013, 49, 2637−2639. (198) Peng, M. J.; Yang, X. F.; Yin, B.; Guo, Y.; Suzenet, F.; En, D.; Li, J.; Li, C. W.; Duan, Y. W. A Hybrid Coumarin-Thiazole Fluorescent Sensor for Selective Detection of Bisulfite Anions in Vivo and in Real Samples. Chem. - Asian J. 2014, 9, 1817−1822.

(199) Sun, M.; Yu, H.; Zhang, K.; Zhang, Y.; Yan, Y.; Huang, D.; Wang, S. Determination of Gaseous Sulfur Dioxide and Its Derivatives via Fluorescence Enhancement Based on Cyanine Dye Functionalized Carbon Nanodots. Anal. Chem. 2014, 86, 9381−9385. (200) Niu, L.-Y.; Chen, Y.-Z.; Zheng, H.-R.; Wu, L.-Z.; Tung, C.-H.; Yang, Q.-Z. Design Strategies of Fluorescent Probes for Selective Detection among Biothiols. Chem. Soc. Rev. 2015, 44, 6143−6160. (201) Liu, X.-D.; Sun, R.; Xu, Y.; Xu, Y.-J.; Ge, J.-F.; Lu, J.-M. A Benzoxazine−Hemicyanine Based Probe for the Colorimetric and Ratiometric Detection of Biothiols. Sens. Actuators, B 2013, 178, 525− 531. (202) Liu, J.; Sun, Y.-Q.; Zhang, H.; Huo, Y.; Shi, Y.; Shi, H.; Guo, W. A Carboxylic Acid-Functionalized Coumarin-Hemicyanine Fluorescent Dye and Its Application to Construct a Fluorescent Probe for Selective Detection of Cysteine over Homocysteine and Glutathione. RSC Adv. 2014, 4, 64542−64550. (203) Liu, J.; Sun, Y.-Q.; Huo, Y.; Zhang, H.; Wang, L.; Zhang, P.; Song, D.; Shi, Y.; Guo, W. Simultaneous Fluorescence Sensing of Cys and GSH from Different Emission Channels. J. Am. Chem. Soc. 2014, 136, 574−577. (204) Lv, X.; Liu, J.; Liu, Y.; Zhao, Y.; Sun, Y. Q.; Wang, P.; Guo, W. Ratiometric Fluorescence Detection of Cyanide Based on a Hybrid Coumarin-Hemicyanine Dye: the Large Emission Shift and the High Selectivity. Chem. Commun. 2011, 47, 12843−12845. (205) Yang, Z.; Liu, Z.; Chen, Y.; Wang, X.; He, W.; Lu, Y. A New Ratiometric and Colorimetric Chemosensor for Cyanide Anion Based on Coumarin-Hemicyanine Hybrid. Org. Biomol. Chem. 2012, 10, 5073−5076. (206) Peng, M.-J.; Guo, Y.; Yang, X.-F.; Wang, L.-Y.; An, J. A Highly Selective Ratiometric and Colorimetric Chemosensor for Cyanide Detection. Dyes Pigm. 2013, 98, 327−332. (207) Goswami, S.; Paul, S.; Manna, A. Carbazole Based Hemicyanine Dye for Both “Naked Eye” and ‘NIR’ Fluorescence Detection of CN− in Aqueous Solution: from Molecules to Low Cost Devices (TLC Plate Sticks). Dalton Trans. 2013, 42, 10682−10686. (208) Zhou, C.; Sun, M.; Yan, C.; Yang, Q.; Li, Y.; Song, Y. A New Colorimetric and Fluorescent Chemodosimeter for Fast Detection of Cyanide. Sens. Actuators, B 2014, 203, 382−387. (209) Huo, F.; Kang, J.; Yin, C.; Chao, J.; Zhang, Y. A Turn on Fluorescent Sensor for Cyanide Based on ICT off in Aqueous and Its Application for Bioimaging. Sens. Actuators, B 2015, 215, 93−98. (210) Zhou, X.; Kwon, Y.; Kim, G.; Ryu, J.-H.; Yoon, J. A Ratiometric Fluorescent Probe Based on a Coumarin-Hemicyanine Scaffold for Sensitive and Selective Detection of Endogenous Peroxynitrite. Biosens. Bioelectron. 2015, 64, 285−291. (211) Liu, F.; Wu, T.; Cao, J.; Zhang, H.; Hu, M.; Sun, S.; Song, F.; Fan, J.; Wang, J.; Peng, X. A Novel Fluorescent Sensor for Detection of Highly Reactive Oxygen Species, and for Imaging Such Endogenous hROS in the Mitochondria of Living Cells. Analyst 2013, 138, 775−778. (212) Chan, M. S.; Xu, D.; Guo, L.; Tam, D. Y.; Liu, L. S.; Chen, Y.; Wong, M. S.; Lo, P. K. Cyanine Fluorophores for Cellular Protection Against ROS in Stimulated Macrophages and Two-Photon ROS Detection. Org. Biomol. Chem. 2015, 13, 7307−7312. (213) Wu, X.; Lin, B.; Yu, M.; Yang, L.; Han, J.; Han, S. A Carbohydrate-Grafted Nanovesicle with Activatable Optical and Acoustic Contrasts for Dual Modality High Performance Tumor Imaging. Chem. Sci. 2015, 6, 2002−2009. (214) Yu, M.; Wu, X.; Lin, B.; Han, J.; Yang, L.; Han, S. Lysosomal pH Decrease in Inflammatory Cells Used To Enable Activatable Imaging of Inflammation with a Sialic Acid Conjugated Profluorophore. Anal. Chem. 2015, 87, 6688−6695. (215) Liu, F.; Wu, T.; Cao, J.; Cui, S.; Yang, Z.; Qiang, X.; Sun, S.; Song, F.; Fan, J.; Wang, J.; Peng, X. Ratiometric Detection of Viscosity Using a Two-Photon Fluorescent Sensor. Chem. - Eur. J. 2013, 19, 1548−1553. (216) Reja, S. I.; Khan, I. A.; Bhalla, V.; Kumar, M. A TICT based NIRFluorescent Probe for Human Serum Albumin: A Pre-clinical Diagnosis in Blood Serum. Chem. Commun. 2016, 52, 1182−1185. (217) Jiang, N.; Fan, J.; Xu, F.; Peng, X.; Mu, H.; Wang, J.; Xiong, X. Ratiometric Fluorescence Imaging of Cellular Polarity: Decrease in 7814


Chemical Reviews

Review

Mitochondrial Polarity in Cancer Cells. Angew. Chem., Int. Ed. 2015, 54, 2510−2514. (218) Chen, S.; Liu, J.; Liu, Y.; Su, H.; Hong, Y.; Jim, C. K. W.; Kwok, R. T. K.; Zhao, N.; Qin, W.; Lam, J. W. Y.; Wong, K. S.; Tang, B. Z. An AIEActive Hemicyanine Fluorogen with Stimuli-Responsive Red/Blue Emission: Extending the pH Sensing Range by “Switch + Knob” Effect. Chem. Sci. 2012, 3, 1804−1809. (219) Huang, X.; Gu, X.; Zhang, G.; Zhang, D. A Highly Selective Fluorescence Turn-On Detection of Cyanide Based on the Aggregation of Tetraphenylethylene Molecules Induced by Chemical Reaction. Chem. Commun. 2012, 48, 12195−12197. (220) Kricka, L. J.; Fortina, P. Analytical Ancestry: “Firsts” in Fluorescent Labeling of Nucleosides, Nucleotides, and Nucleic Acids. Clin. Chem. 2009, 55, 670−683. (221) Erve, A.; Saoudi, Y.; Thirot, S.; Guetta-Landras, C.; Florent, J. C.; Nguyen, C. H.; Grierson, D. S.; Popov, A. V. BENA435, a New CellPermeant Photoactivated Green Fluorescent DNA Probe. Nucleic Acids Res. 2006, 34, e43. (222) Peng, X.; Wu, T.; Fan, J.; Wang, J.; Zhang, S.; Song, F.; Sun, S. An Effective Minor Groove Binder as a Red Fluorescent Marker for LiveCell DNA Imaging and Quantification. Angew. Chem., Int. Ed. 2011, 50, 4180−4183. (223) Feng, X. J.; Wu, P. L.; Bolze, F.; Leung, H. W. C.; Li, K. F.; Mak, N. K.; Kwong, D. W. J.; Nicoud, J.-F.; Cheah, K. W.; Wong, M. S. Cyanines as New Fluorescent Probes for DNA Detection and TwoPhoton Excited Bioimaging. Org. Lett. 2010, 12, 2194−2197. (224) Guo, L.; Chan, M. S.; Xu, D.; Tam, D. Y.; Bolze, F.; Lo, P. K.; Wong, M. S. Indole-Based Cyanine as a Nuclear RNA-Selective TwoPhoton Fluorescent Probe for Live Cell Imaging. ACS Chem. Biol. 2015, 10, 1171−1175. (225) Treibs, A.; Jacob, D.-C. Cyclotrirnethine Dyes Derived from Squaric Acid. Angew. Chem., Int. Ed. Engl. 1965, 4, 694. (226) Hu, L.; Yan, Z.; Xu, H. Advances in Synthesis and Application of Near-Infrared Absorbing Squaraine Dyes. RSC Adv. 2013, 3, 7667− 7676. (227) Song, X.; Foley, J. W. A New Water-soluble Near-infrared Croconium Dye. Dyes Pigm. 2008, 78, 60−64. (228) Law, K. Y. Squaraine Chemistry: Effects of Structural Changes on the Absorption and Multiple Fluorescence Emission of Bis[4(dimethylamino)phenyl]squaraine and Its Derivatives. J. Phys. Chem. 1987, 91, 5184−5193. (229) Makowski, B. T.; Valle, B.; Singer, K. D.; Weder, C. A MeltProcessable Squaraine-Based Organic Glass for Nonlinear Optics. J. Mater. Chem. 2012, 22, 2848−2850. (230) Chen, G.; Sasabe, H.; Igarashi, T.; Hong, Z.; Kido, J. Squaraine Dyes for Organic Photovoltaic Cells. J. Mater. Chem. A 2015, 3, 14517− 14534. (231) Gonçalves, M. S. Fluorescent Labeling of Biomolecules with Organic Probes. Chem. Rev. 2009, 109, 190−212. (232) Ramaiah, D.; Joy, A.; Chandrasekhar, N.; Eldho, N.; Das, S.; George, M. Halogenated Squaraine Dyes as Potential Photochemotherapeutic Agents. Synthesis and Study of Photophysical Properties and Quantum Efficiencies of Singlet Oxygen Generation. Photochem. Photobiol. 1997, 65, 783−790. (233) Ramaiah, D.; Eckert, I.; Arun, K. T.; Weidenfeller, L.; Epe, B. Squaraine Dyes for Photodynamic Therapy: Mechanism of Cytotoxicity and DNA Damage Induced by Halogenated Squaraine Dyes Plus Light (>600 nm). Photochem. Photobiol. 2004, 79, 99−104. (234) Arunkumar, E.; Chithra, P.; Ajayaghosh, A. A Controlled Supramolecular Approach toward Cation-Specific Chemosensors: Alkaline Earth Metal Ion-Driven Exciton Signaling in Squaraine Tethered Podands. J. Am. Chem. Soc. 2004, 126, 6590−6598. (235) Sreejith, S.; Divya, K. P.; Ajayaghosh, A. A Near-Infrared Squaraine Dye as a Latent Ratiometric Fluorophore for the Detection of Aminothiol Content in Blood Plasma. Angew. Chem., Int. Ed. 2008, 47, 7883−7887. (236) Fan, J.; Wang, Z.; Zhu, H.; Fu, N. A Fast Response SquaraineBased Colorimetric Probe for Detection of Thiols in Physiological Conditions. Sens. Actuators, B 2013, 188, 886−893.

(237) Kim, S. H.; Hwang, S. H.; Kim, J. J.; Yoon, C. M.; Keum, S. R. Syntheses and Properties of Functional Aminosquarylium Dyes. Dyes Pigm. 1998, 37, 145−154. (238) Jisha, V. S.; Arun, K. T.; Hariharan, M.; Ramaiah, D. SiteSelective Interactions: Squaraine Dye-Serum Albumin Complexes with Enhanced Fluorescence and Triplet Yields. J. Phys. Chem. B 2010, 114, 5912−5919. (239) Jisha, V. S.; Arun, K. T.; Hariharan, M.; Ramaiah, D. SiteSelective Binding and Dual Mode Recognition of Serum Albumin by a Squaraine Dye. J. Am. Chem. Soc. 2006, 128, 6024−6025. (240) Wang, B.; Fan, J.; Sun, S.; Wang, L.; Song, B.; Peng, X. 1(Carbamoylmethyl)-3H-indolium Squaraine Dyes: Synthesis, Spectra, Photo-Stability and Association with BSA. Dyes Pigm. 2010, 85, 43−50. (241) Geddes, C. D. Reviews in Fluorescence; Springer: New York, 2009; p 86. (242) McKerrow, A. J.; Buncel, E.; Kazmaier, P. M. Aggregation of Squaraine Dyes: Structure-Property Relationships and Solvent Effects. Can. J. Chem. 1995, 73, 1605−1615. (243) Chen, H.; Farahat, M. S.; Law, K.-Y.; Whitten, D. G. Aggregation of Surfactant Squaraine Dyes in Aqueous Solution and Microheterogeneous Media: Correlation of Aggregation Behavior with Molecular Structure. J. Am. Chem. Soc. 1996, 118, 2584−2594. (244) Chen, H.; Law, K.-Y.; Perlstein, J.; Whitten, D. G. Amphiphilic Squaraine Dye Aggregates: Evidence for a Cyclic Chiral Structure as a General Supramolecular Structure for Aggregates of Dyes and Aromatic Molecules. J. Am. Chem. Soc. 1995, 117, 7257−7258. (245) de Miguel, G.; Ziółek, M.; Zitnan, M.; Organero, J. A.; Pandey, S. S.; Hayase, S.; Douhal, A. Photophysics of H- and J-Aggregates of Indole-Based Squaraines in Solid State. J. Phys. Chem. C 2012, 116, 9379−9389. (246) Xu, Y.; Li, Z.; Malkovskiy, A.; Sun, S.; Pang, Y. Aggregation Control of Squaraines and Their Use as Near-Infrared Fluorescent Sensors for Protein. J. Phys. Chem. B 2010, 114, 8574−8580. (247) Li, X.-H.; Zhang, B.-W.; Cao, Y. Aggregation of bis(2,4,6trihydroxyphenyl) squaraine in different solutions. Dyes Pigm. 2000, 45, 209−217. (248) Yagi, S.; Fujie, Y.; Hyodo, Y.; Nakazumi, H. Synthesis, Structure, and Complexation Properties with Transition Metal Cations of a Novel Methine-Bridged Bisquarylium Dye. Dyes Pigm. 2002, 52, 245−252. (249) Basheer, M. C.; Alex, S.; George Thomas, K.; Suresh, C. H.; Das, S. A Squaraine-Based Chemosensor for Hg2+ and Pb2+. Tetrahedron 2006, 62, 605−610. (250) Avirah, R. R.; Jyothish, K.; Ramaiah, D. Infrared Absorbing Croconaine Dyes: Synthesis and Metal Ion Binding Properties. J. Org. Chem. 2008, 73, 274−279. (251) Wang, S.; Cong, T.; Liang, Q.; Li, Z.; Xu, S. Dual Colorimetric and Fluorescent Chemosensor of Fe3+ and Cu2+ based on 2,5-bis[(4carboxylic-piperidylamino)thiophenyl]-croconine. Tetrahedron 2015, 71, 5478−5483. (252) Ros-Lis, J. V.; Martínez-Máñez, R.; Rurack, K.; Sancenón, F.; Soto, J.; Spieles, M. Highly Selective Chromogenic Signaling of Hg2+ in Aqueous Media at Nanomolar Levels Employing a Squaraine-Based Reporter. Inorg. Chem. 2004, 43, 5183−5185. (253) Chen, C.; Wang, R.; Guo, L.; Fu, N.; Dong, H.; Yuan, Y. A Squaraine-Based Colorimetric and “Turn on” Fluorescent Sensor for Selective Detection of Hg2+ in an Aqueous Medium. Org. Lett. 2011, 13, 1162−1165. (254) Chen, C.; Dong, H.; Chen, Y.; Guo, L.; Wang, Z.; Sun, J. J.; Fu, N. Dual-Mode Unsymmetrical Squaraine-Based Sensor for Selective Detection of Hg2+ in Aqueous Media. Org. Biomol. Chem. 2011, 9, 8195−8201. (255) Zhu, H.; Lin, Y.; Wang, G.; Chen, Y.; Lin, X.; Fu, N. A Coordination Driven Deaggregation Approach Toward Hg2+-Specific Chemosensors Based on Thioether Linked Squaraine-Aniline Dyads. Sens. Actuators, B 2014, 198, 201−209. (256) Zhu, H.; Fan, J.; Chen, H.; Tang, Z.; Wang, G.; Fu, N. An EDTA Promoted Coordination Induced Disaggregation for Specific Hg2+ Detection. Dyes Pigm. 2015, 113, 181−188. 7815


Chemical Reviews

Review

(257) Fu, N.; Chen, Y.; Fan, J.; Wang, G.; Lin, S. A Bifunctional “Turn On” Fluorescent Probe for Trace Level Hg2+ and EDTA in Aqueous Solution via Chelator Promoted Cation Induced Deaggregation Signalling. Sens. Actuators, B 2014, 203, 435−443. (258) Xu, Y.; Panzner, M. J.; Li, X.; Youngs, W. J.; Pang, Y. Host-Guest Assembly of Squaraine Dye in Cucurbit[8]uril: Its Implication in Fluorescent Probe for Mercury Ions. Chem. Commun. 2010, 46, 4073− 4075. (259) Ajayaghosh, A.; Arunkumar, E.; Daub, J. A Highly Specific Ca2+Ion Sensor: Signaling by Exciton Interaction in a Rigid-Flexible-Rigid Bichromophoric “H” Foldamer. Angew. Chem., Int. Ed. 2002, 41, 1766− 1769. (260) Arunkumar, E.; Ajayaghosh, A.; Daub, J. Selective Calcium Ion Sensing with a Bichromophoric Squaraine Foldamer. J. Am. Chem. Soc. 2005, 127, 3156−3164. (261) Chithra, P.; Varghese, R.; Divya, K. P.; Ajayaghosh, A. SolventInduced Aggregation and Cation-Controlled Self-Assembly of Tripodal Squaraine Dyes: Optical, Chiroptical and Morphological Properties. Chem. - Asian J. 2008, 3, 1365−1373. (262) Wang, G.; Zhu, H.; Lin, Y.; Chen, Y.; Fu, N. A Ca2+ Controlled Thioether Linked Bichromophoric Squaraine Foldamer for “Turn on” Fluorescent Sensing of Oxalate. Sens. Actuators, B 2015, 206, 624−629. (263) Xu, Y.; Malkovskiy, A.; Pang, Y. A Graphene Binding-Promoted Fluorescence Enhancement for Bovine Serum Albumin Recognition. Chem. Commun. 2011, 47, 6662−6664. (264) He, Q.; Fan, X.; Sun, S.; Li, H.; Pei, Y.; Xu, Y. Highly Selective Turn-On Detection of (Strept)Avidin Based on Self-Assembled NearInfrared Fluorescent Probes. RSC Adv. 2015, 5, 38571−38576. (265) Jin, B.; Zhang, X.; Zheng, W.; Liu, X.; Zhou, J.; Zhang, N.; Wang, F.; Shangguan, D. Dicyanomethylene-Functionalized Squaraine as a Highly Selective Probe for Parallel G-Quadruplexes. Anal. Chem. 2014, 86, 7063−7070. (266) Karpenko, I. A.; Collot, M.; Richert, L.; Valencia, C.; Villa, P.; Mely, Y.; Hibert, M.; Bonnet, D.; Klymchenko, A. S. Fluorogenic Squaraine Dimers with Polarity-Sensitive Folding as Bright Far-Red Probes for Background-Free Bioimaging. J. Am. Chem. Soc. 2015, 137, 405−412. (267) Xu, Y.; Malkovskiy, A.; Wang, Q.; Pang, Y. Molecular Assembly of a Squaraine Dye with Cationic Surfactant and Nucleotides: Its Impact on Aggregation and Fluorescence Response. Org. Biomol. Chem. 2011, 9, 2878−2884. (268) Xu, Y.; Li, B.; Xiao, L.; Li, W.; Zhang, C.; Sun, S.; Pang, Y. The Sphere-to-Rod Transition of Squaraine-Embedded Micelles: a SelfAssembly Platform Displays a Distinct Response to Cysteine and Homocysteine. Chem. Commun. 2013, 49, 7732−7734. (269) Xu, Y.; Li, B.; Xiao, L.; Ouyang, J.; Sun, S.; Pang, Y. A Colorimetric and Near-Infrared Fluorescent Probe with High Sensitivity and Selectivity for Acid Phosphatase and Inhibitor Screening. Chem. Commun. 2014, 50, 8677−8680. (270) Xu, Y.; Li, B.; Han, P.; Sun, S.; Pang, Y. Near-Infrared Fluorescent Detection of Glutathione via Reaction-Promoted Assembly of Squaraine-Analyte Adducts. Analyst 2013, 138, 1004−1007. (271) Wu, N.; Lan, J.; Yan, L.; You, J. A Sensitive Colorimetric and Fluorescent Sensor Based on Imidazolium-Functionalized Squaraines for the Detection of GTP and Alkaline Phosphatase in Aqueous Solution. Chem. Commun. 2014, 50, 4438−4441. (272) Ananda Rao, B.; Kim, H.; Son, Y.-A. Synthesis of Near-Infrared Absorbing Pyrylium-Squaraine Dye for Selective Detection of Hg2+. Sens. Actuators, B 2013, 188, 847−856. (273) Huang, Y.; Lin, Q.; Wu, J.; Fu, N. Design and Synthesis of a Squaraine Based Near-Infrared Fluorescent Probe for the Ratiometric Detection of Zn2+ Ions. Dyes Pigm. 2013, 99, 699−704. (274) Chandrasekaran, Y.; Dutta, G. K.; Kanth, R. B.; Patil, S. Tetrahydroquinoxaline Based Squaraines: Synthesis and Photophysical Properties. Dyes Pigm. 2009, 83, 162−167. (275) Wang, W.; Fu, A.; You, J.; Gao, G.; Lan, J.; Chen, L. SquaraineBased Colorimetric and Fluorescent Sensors for Cu2+-Specific Detection and Fluorescence Imaging in Living Cells. Tetrahedron 2010, 66, 3695−3701.

(276) Luo, C.; Zhou, Q.; Zhang, B.; Wang, X. A New Squaraine and Hg2+-Based Chemosensor with Tunable Measuring Range for ThiolContaining Amino Acids. New J. Chem. 2011, 35, 45−48. (277) Fan, J.; Chen, C.; Lin, Q.; Fu, N. A Fluorescent Probe for the Dual-Channel Detection of Hg2+/Ag+ and Its Hg2+-Based Complex for Detection of Mercapto Biomolecules with a Tunable Measuring Range. Sens. Actuators, B 2012, 173, 874−881. (278) Lin, Q.; Huang, Y.; Fan, J.; Wang, R.; Fu, N. A Squaraine and Hg2+-Based Colorimetric and “Turn On” Fluorescent Probe for Cysteine. Talanta 2013, 114, 66−72. (279) Ros-Lis, J. V.; García, B.; Jiménez, D.; Martínez-Máñez, R.; Sancenón, F.; Soto, J.; Gonzalvo, F.; Valldecabres, M. C. Squaraines as Fluoro-Chromogenic Probes for Thiol-Containing Compounds and Their Application to the Detection of Biorelevant Thiols. J. Am. Chem. Soc. 2004, 126, 4064−4065. (280) Sreejith, S.; Divya, K. P.; Ajayaghosh, A. A Near-Infrared Squaraine Dye as a Latent Ratiometric Fluorophore for the Detection of Aminothiol Content in Blood Plasma. Angew. Chem., Int. Ed. 2008, 47, 7883−7887. (281) Fan, J.; Wang, Z.; Zhu, H.; Fu, N. A Fast Response Squarainebased Colorimetric Probe for Detection of Thiols in Physiological Conditions. Sens. Actuators, B 2013, 188, 886−893. (282) Liao, S.; Han, W.; Ding, H.; Xie, D.; Tan, H.; Yang, S.; Wu, Z.; Shen, G.; Yu, R. Modulated Dye Retention for the Signal-On Fluorometric Determination of Acetylcholinesterase Inhibitor. Anal. Chem. 2013, 85, 4968−4973. (283) Ros-Lis, J. V.; Marcos, M. D.; Martínez-Máñez, R.; Rurack, K.; Soto, J. A Regenerative Chemodosimeter Based on Metal-Unduced Dye Formation for the Highly Selective and Sensitive Optical Determination of Hg2+ Ions. Angew. Chem., Int. Ed. 2005, 44, 4405−4407. (284) Hewage, H. S.; Anslyn, E. V. Pattern-Based Recognition of Thiols and Metals Using a Single Squaraine Indicator. J. Am. Chem. Soc. 2009, 131, 13099−13106. (285) Ros-Lis, J. V.; Martínez-Máñez, R.; Soto, J. A Selective Chromogenic Reagent for Cyanide Determination. Chem. Commun. 2002, 19, 2248−2249. (286) Zhang, X.; Li, C.; Cheng, X.; Wang, X.; Zhang, B. A NearInfrared Croconium Dye-based Colorimetric Chemodosimeter for Biological Thiols and Cyanide Anion. Sens. Actuators, B 2008, 129, 152− 157. (287) Yu, H.; Fu, M.; Xiao, Y. Switching off FRET by Analyte-Induced Decomposition of Squaraine Energy Acceptor: A Concept to Transform ‘Turn off’ Chemodosimeter into Ratiometric Sensors. Phys. Chem. Chem. Phys. 2010, 12, 7386−7391. (288) Wang, W.; Fu, A.; Lan, J.; Gao, G.; You, J.; Chen, L. Rational Design of Fluorescent Bioimaging Probes by Controlling the Aggregation Behavior of Squaraines: A Special Effect of Ionic Liquid Pendants. Chem. - Eur. J. 2010, 16, 5129−5137. (289) Jisha, V. S.; Arun, K. T.; Hariharan, M.; Ramaiah, D. SiteSelective Binding and Dual Mode Recognition of Serum Albumin by a Squaraine Dye. J. Am. Chem. Soc. 2006, 128, 6024−6025. (290) Suzuki, Y.; Yokoyama, K. A Protein-Responsive Chromophore Based on Squaraine and Its Application to Visual Protein Detection on a Gel for SDS-PAGE. Angew. Chem., Int. Ed. 2007, 46, 4097−4099. (291) Wang, B.; Fan, J.; Sun, S.; Wang, L.; Song, B.; Peng, X. 1(Carbamoylmethyl)-3H-indolium Squaraine Dyes: Synthesis, Spectra, Photo-Stability and Association with BSA. Dyes Pigm. 2010, 85, 43−50. (292) Lynch, D. E.; Chowdhury, M. Z. H.; Luu, N.-L.; Wane, E. S.; Heptinstall, J.; Cox, M. J. Water soluble bis(indolenine)squaraine salts for use as fluorescent protein-sensitive probes. Dyes Pigm. 2013, 96, 116−124. (293) Zhang, Y.; Yue, X.; Kim, B.; Yao, S.; Bondar, M. V.; Belfield, K. D. Bovine Serum Albumin Nanoparticles with Fluorogenic Near-IR Emitting Squaraine Dyes. ACS Appl. Mater. Interfaces 2013, 5, 8710− 8717. (294) Volkova, K. D.; Kovalska, V. B.; Losytskyy, M. Y.; Bento, A.; Reis, L. V.; Santos, P. F.; Almeida, P.; Yarmoluk, S. M. Studies of benzothiazole and benzoselenazole squaraines as fluorescent probes for albumins detection. J. Fluoresc. 2008, 18, 877−882. 7816


Chemical Reviews

Review

(295) Volkova, K. D.; Kovalska, V. B.; Losytskyy, M. Y.; Bento, A.; Reis, L. V.; Santos, P. F.; Almeida, P.; Lynch, D. E.; Yarmoluk, S. M. AzaSubstituted Squaraines for the Fluorescent Detection of Albumins. Dyes Pigm. 2011, 90, 41−47. (296) Volkova, K. D.; Kovalska, V. B.; Tatarets, A. L.; Patsenker, L. D.; Kryvorotenko, D. V.; Yarmoluk, S. M. Dyes Pigm. 2007, 72, 285−292. (297) Oushiki, D.; Kojima, H.; Takahashi, Y.; Komatsu, T.; Terai, T.; Hanaoka, K.; Nishikawa, M.; Takakura, Y.; Nagano, T. Near-Infrared Fluorescence Probes for Enzymes Based on Binding Affinity Modulation of Squarylium Dye Scaffold. Anal. Chem. 2012, 84, 4404− 4410. (298) Xu, Y.; Liu, Q.; Li, X.; Wesdemiotis, C.; Pang, Y. A Zwitterionic Squaraine Dye with a Large Stokes Shift for in Vivo and Site-Selective Protein Sensing. Chem. Commun. 2012, 48, 11313−11315. (299) Povrozin, Y. A.; Markova, L. I.; Tatarets, A. L.; Sidorov, V. I.; Terpetschnig, E. A.; Patsenker, L. D. Near-Infrared, Dual-Ratiometric Fluorescent Label for Measurement of pH. Anal. Biochem. 2009, 390, 136−140. (300) Snee, P. T.; Somers, R. C.; Nair, G.; Zimmer, J. P.; Bawendi, M. G.; Nocera, D. G. A Ratiometric CdSe/ZnS Nanocrystal pH Sensor. J. Am. Chem. Soc. 2006, 128, 13320−13321. (301) Zhang, Y.; Yue, X.; Kim, B.; Yao, S.; Belfield, K. D. Deoxyribonucleoside-Modified Squaraines as Near-IR Viscosity Sensors. Chem. - Eur. J. 2014, 20, 7249−7253.

7817


Recent Development of Chemosensors Based on Cyanine Platforms

Recommend Documents