Long-Lived Emissive Probes for Time-Resolved ... - ACS Publications

Review Cite This: Chem. Rev. XXXX, XXX, XXX−XXX

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Long-Lived Emissive Probes for Time-Resolved Photoluminescence Bioimaging and Biosensing Kenneth Yin Zhang,†,∥ Qi Yu,†,∥ Huanjie Wei,† Shujuan Liu,† Qiang Zhao,*,† and Wei Huang*,†,‡,§ †

Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors, Institute of Advanced Materials (IAM), Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing University of Posts & Telecommunications, 9 Wenyuan Road, Nanjing 210023, P. R. China ‡ Shaanxi Institute of Flexible Electronics (SIFE), Northwestern Polytechnical University (NPU), Xi’an 710072, P. R. China § Key Laboratory of Flexible Electronics (KLOFE) and Institute of Advanced Materials (IAM), Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing Tech University (NanjingTech), Nanjing 211800, P. R. China S Supporting Information *

ABSTRACT: In this Review article, we systematically summarize the design and applications of various kinds of long-lived emissive probes for bioimaging and biosensing via time-resolved photoluminescence techniques. The probes reviewed, including lanthanides, transition-metal complexes, organic dyes, carbon and silicon nanoparticles, metal clusters, and persistent phosphores, exhibit longer luminescence lifetimes than that of autofluorescence from biological tissue and organs. When these probes are internalized into living cells or animals, time-gated photoluminescence imaging selectively collects long-lived signals for intensity analysis, while photoluminescence lifetime imaging reports the decay details of each pixel. Since the long-lived signals are differentiated from autofluorescence in the time domain, the imaging contrast and sensing sensitivity are remarkably improved. The future prospects and challenges in this rapidly growing field are addressed.

CONTENTS 1. Introduction 2. Long-Lived Luminescent Probes 2.1. Lanthanides 2.2. Transition-Metal Complexes 2.3. Organic Compounds 2.4. Inorganic Nanomaterials 2.5. Persistent Phosphors 3. Time-Resolved Photoluminescence Techniques 3.1. Time-Gated Luminescence Technique 3.2. Photoluminescence Lifetime Imaging Microscopy 3.3. General Comparison between Time-Gated Luminescence Microscopy and Photoluminescence Lifetime Imaging Microscopy 4. Long-Lived Luminescent Probes for Time-Resolved Photoluminescence Bioimaging and Biosensing 4.1. Lanthanides for Time-Resolved Photoluminescence Bioimaging and Biosensing 4.1.1. Lanthanides for Cell Staining 4.1.2. Lanthanides for Time-Resolved Photoluminescence Sensing 4.1.3. Lanthanides for Time-Resolved Photoluminescence Imaging of Organisms, Tissues, and Laboratory Animals

4.2. Transition-Metal Complexes for Time-Resolved Photoluminescence Bioimaging and Biosensing 4.2.1. Transition-Metal Complexes for Cell Staining 4.2.2. Transition-Metal Complexes for TimeResolved Photoluminescence Sensing 4.2.3. Transition-Metal for Time-Resolved Photoluminescence Imaging of Tissues and Laboratory Animals 4.3. Long-Lived Luminescent Organic Compounds for Cell Staining and Time-Resolved Photoluminescence Sensing 4.4. Inorganic Nanomaterials for Time-Resolved Photoluminescence Bioimaging and Biosensing 4.4.1. Inorganic Nanomaterials for Cell Staining 4.4.2. Inorganic Nanomaterials for Time-Resolved Photoluminescence Sensing 4.4.3. Inorganic Nanomaterials for Time-Resolved Photoluminescence Imaging of Tissues, Organs, and Laboratory Animals 5. Conclusions and Outlook Associated Content Supporting Information Author Information

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Received: July 14, 2017

© XXXX American Chemical Society

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DOI: 10.1021/acs.chemrev.7b00425 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews Corresponding Authors ORCID Author Contributions Notes Biographies Acknowledgments Abbreviations References

Review

straightforward to relate this intensity to the analyte concentration in solution. However, when the probes are used in complicated biological environments, the accuracy and precision of the detection are reduced because the detected luminescence intensity is also affected by the uncertain intracellular or in vivo probe concentrations, fluctuated excitation laser power, and autofluorescence from endogenous fluorophores. Table 1 lists

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Table 1. Representative Endogenous Fluorophores fluorophore

1. INTRODUCTION Medical imaging refers to technologies that create visual representations of the inside of a human body to provide precise positional and morphologic information for clinical diagnosis.1−3 It allows identification of abnormalities according to a database of normal anatomy and physiology.4 Traditional diagnostic imaging technologies capture images and report qualities such as water content and density of specific areas.5,6 Molecular imaging has emerged as a modern imaging technology, which focuses on tracking biomarkers, collecting information on their surroundings, and giving fundamental molecular pathways and functions in cells, tissues, organs, and organisms.7−13 While traditional diagnostic imaging directly visualizes pathological tissues, molecular imaging allows early diagnosis at molecular and cellular level before tissue damage occurs or typical symptoms of a disease are observed.14,15 The major modalities of molecular imaging for clinical diagnosis include positron emission tomography, single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), and medical optical imaging, each of which has its own strengths and weaknesses in regard to spatial resolution, temporal resolution, sensitivity, and cost. For example, positron emission tomography using radioactive isotopes as tracers possesses very high sensitivity, but expensive cyclotrons are needed to produce radionuclides.16−19 SPECT are significantly less expensive than positron emission tomography, but the spatial resolution is reduced because of less radiation event localization information analyzed.20−22 MRI offers high spatial resolution with low sensitivity.23−26 Luminescence imaging has attracted fastgrowing interest owing to the high sensitivity and specificity.27 The rapid development of luminescence imaging microscopes and availability of a variety of emissive probes and labels,28 such as organic compounds,29−32 transition-metal complexes,33−38 lanthanide chelates,39−48 quantum dots,49−55 nanoparticles,56−61 and fluorescent proteins,62−65 facilitate visualization of physiological and pathophysiological processes at cellular,66−70 subcellular,71−77 and molecular levels.78−80 A luminescence signal is characterized by its intensity, wavelength, lifetime, and polarization. In luminescence imaging, intensity is usually used to create images, since it simply reflects the localization and concentration of a probe.81−83 Wavelength can be used to differentiate probes that display different luminescence colors in multicolor imaging.84,85 To avoid photobleaching of emissive dyes86−88 and deepen penetration depths during luminescence imaging,89,90 efforts have been made to increase the photostability of dyes and tune the emission into near-infrared (NIR) region, where the absorption coefficient of biological samples is considerably lower and hence deeper penetration is achieved.30,32,91,92 In addition to tracking the probe, photoluminescence imaging allows detecting analytes of interest based on sensitive optical response of probes to specific analyte.93−102 In many cases, luminescence intensity of a probe is proportional to the analyte and it appears simple and

emission (nm)

lifetime (ns)

NAD(P)H

excitation (nm) 310−370

410−510

0.3

flavine collagen

380−500 270−370

500−600 305−450

5.2 5.3

elastin

300−370

420−460

∼2.0

lipofuscin tryptophan tyrosine phenylalanine melanin

410−470 280−340 273 (max) 258 (max) 340−400

500−695 300−400 303 (max) 280 (max) 440, 520, 570

1.3 2.6 3.6 7.5 0.1/1.9/8.0

ref 104, 106, 109, 114, 116, and 117 103 and 109 116, 110, and 112 109, 110, and 118 118 105 112 118 109

representative endogenous fluorophores and their excitation and emission data. For example, flavins and flavoproteins in mitochondria are excitable at 450−500 nm and emit at 500− 600 nm. Heterogeneous complexes of lipids and proteins in brain tissue absorb at 400−550 nm, and the emission covers the yellow and extends to NIR regions.103−118 The absorption and emission of the endogenous fluorophores cover the full visible region, which disturbs the collection of luminescence signal of probes during imaging and causes fluctuation of the results. Luminescence lifetime is an average time that an excited luminophore remains in its excited state.119 It is denoted as the Greek letter τ and quantified as the time for the intensity to drop to 1/e. The luminescence lifetime is neglectably affected by concentration variation of the intracellular luminophore or the excitation laser power. Additionally, luminophores that absorb or emit at similar wavelengths can be distinguished based on their different emission decay rates. Therefore, utilization of long-lived luminophores for bioimaging via time-resolved imaging techniques is particularly useful in minimizing interference from autofluorescence. There are two typical imaging techniques that analyze luminescence signals in time domains. The first one is time-gated photoluminescence imaging,120 in which the detector is on the off state until the decay of the unwanted short-lived signals finished. Therefore, short-lived autofluorescence and photon scattering in thick layers of samples are minimized, and only long-lived signals are collected for further analysis. The other one is photoluminescence lifetime imaging microscopy (PLIM).121,122 Luminescence lifetimes of each pixel are measured to create a PLIM image, in which different lifetime values are usually represented by different colors. Although the short-lived luminescence signals are hardly differentiated from autofluorescence in the time domain, it is fast and efficient to image short-lived fluorescent probes with high fluorescence intensity but short lifetime under excitation by a high-frequency laser pulse.123,124 In most cases, long-lived luminescent probes are less bright than short-lived fluorescent dyes, but long-lived luminescence signals can be easily differentiated from shortedlived autofluorescence in the time domain. Compared to upconversion luminescence imaging125−131 and two-photon B


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luminescence imaging techniques,132 which involve NIR excitation and avoid autofluorescence during excitation, timeresolved luminescence imaging filters off autofluorescence during signal analysis and treatment. Owing to the highresolution in the time domain, time-resolved photoluminescence techniques have been widely employed as a significantly useful tool to improve the accuracy and precision in bioimaging. In this review article, we summarize long-lived luminescent probes that show emission lifetimes longer than 10 ns, which is almost the maximum of autofluorescence lifetimes in biological samples and review their applications in bioimaging via timeresolved photoluminescence techniques including time-gated photoluminescence imaging and PLIM. To date, many long-lived luminescent probes have been used for this application, and in this article we will review more than 250 of them. These probes include lanthanides, transition-metal complexes, organic dyes, and inorganic nanomaterials. Their photophysical properties and working conditions are listed in Table S1. In addition to imaging cellular structures, time-resolved photoluminescence imaging, similar to intensity-based imaging, produces images that provide information about intracellular environment. We summarize the utilization of long-lived luminescent probes to detect intracellular metal cations, halogen anions, reactive oxygen, nitrogen and sulfur species, and biomolecules and to monitor intracellular pH values, temperature, and hypoxia, where time-gated photoluminescence imaging and PLIM are used to improve the detection sensitivity and accuracy. Furthermore, we describe the tissue and small animal imaging via time-resolved photoluminescence techniques, which improve the contrast through elimination of the autofluorescence and scattering interference. At last, the future prospects and challenges in this rapidly growing field are addressed.

Figure 1. Simplified Jablonski diagram illustrating the photophysical processes in lanthanide(III) chelates. ISC = intersystem crossing and ET = energy transfer.

cence with lifetimes in the microsecond and millisecond time scales. Selection of antennae and chelators is very important when designing luminescent lanthanide chelates. Possible energy transfer and photoinduced redox quenching should be taken into consideration.136 Perfuorination of the sensitizing ligand strikingly enhances the luminescence efficiency and elongates the lifetimes.137 Among all the lanthanide ions, Eu(III) and Tb(III) are mostly used owing to their high intrinsic quantum yields and emission in the visible region.39−42,138−140 As lanthanide ions exhibit characteristic narrow-line emission, which is well-separated in wavelength, different lanthanide ions can be used simultaneously for multicolor imaging.141 Additionally, the large difference in the excited-state lifetimes of lanthanide ions enables lifetime-based multiplexing for unambiguous identification of different lanthanide ions.136 Lanthanide-doped nanocrystals with rare earth oxide, oxysulfide, fluoride, phosphate, and vanadate as the host lattices and lanthanide ions as the emitters display the characteristic sharp and long-lived luminescence primarily originating from electronic transitions within the [Xe]4f n configuration of the lanthanide dopants.128,129,142−145 The luminescence properties of lanthanide-doped nanocrystals are similar to the chelate analogues but are also influenced by the phonon energy and crystal-field strength of the host lattice. Therefore, the emission of lanthanide-doped nanocrystals can be tuned by varying the host materials and lanthanide emitters. Interestingly, nanocrystals doped with Er3+, Tm3+, or Ho3+ as emitters and Yb3+ as the sensitizer readily undergo luminescence upconversion which yields high-energy anti-Stokes luminescence through subsequent absorption of multiple low energy photons.125−130 Doping with Mn2+ into upconversion nanoparticles as the energy acceptor achieved upconversion luminescence of Mn2+ with ultralong lifetimes in tens of milliseconds at room temperature.146−154 Low-energy excitation in the NIR region minimizes the photodamage to biological samples and allows deep tissue penetration facilitating in vivo bioimaging and biosensing.

2. LONG-LIVED LUMINESCENT PROBES In order to obtain high-quality time-resolved photoluminescence images of biological samples with minimized autofluorescence interference, luminescent imaging reagents are required to exhibit a luminescence lifetime that is sufficiently long compared to that of autofluorescence generated from biological samples. Lanthanides and transition-metal complexes are famous for their long luminescence lifetimes owing to the spin-forbidden nature of their luminescence. Others probes such as fluorescent dyes, quantum dots, and luminescent nanoparticles have also been reported to exhibit long luminescence lifetimes and be suitable for time-resolved photoluminescence measurements. 2.1. Lanthanides

The trivalent lanthanide ions are characterized by a gradual filling of the 4f orbitals, from 4f 0 (for La3+) to 4f14 (for Lu3+).39,133,134 They display luminescence from transitions involving a redistribution of electrons within 4f orbitals because of the effective shielding by 6s and 5p orbitals that minimizes the influence of external ligand fields. As the transitions within 4f orbitals are in violation of the Laporte rule which states that electronic transitions that conserve parity are forbidden, lanthanide ions display very small molar absorption coefficients (10 ns) can be easily distinguishable from that of autofluorescence.190 Silicon nanoparticles (Si NPs) are indirect band gap semiconductors and exhibit much longer-lived emissive states compared to direct gap semiconductors such as CdS.193,194

2.3. Organic Compounds

Organic compounds with the extended conjugation systems are usually emissive because of the π−π* transitions. Compounds with separated electron donor and acceptor can emit from a charge-transfer state. The emission lifetimes of these compounds are usually very short (1 s) at room temperature.202 Crystal-induced phosphorescence with aggregation-enhanced emission properties also contributes to the longlived organic afterglow. Compared to inorganic counterparts, organic persistent compounds showed lower production costs, easier structure modification, but relatively shorter afterglow lifetimes. At the end of this section, the lifetime ranges of different classes of luminophores were listed in Table 2.

3.1. Time-Gated Luminescence Technique

Common luminescence analysis and microscopy techniques are based on steady-state emission intensity at certain wavelengths which is indicative of the presence of a specific analyte or the occurrence of an event. However, when the analyte is low in concentration or the event has rarely occurred, the target luminescence signal is hardly recognized from naturally occurring autofluorescent substances. Time-gated luminescence (TGL) technique is an efficient approach to solving this problem. In a typical TGL measurement, a pulsed light source is used to excite the target probe, which exhibits comparatively long luminescence lifetimes. The detector is maintained in the offstate until short-lived signals fade beyond detection. Thus, only long-lived events fall into the signal collection window (Figure 3).210−217 These signals are distinguished from short-lived

Table 2. Lifetime Ranges of Different Classes of Long-Lived Luminophores luminophores

lifetimes

lanthanide chelates lanthanide-doped nanocrystals transition-metal complexes 2,3-diazabicyclo[2.2.2]oct-2-ene aza/oxa triangulenium compounds organic compounds with delayed fluorescence QDs doped with Mn or In thiol-capped metal nanoclusters nanodiamonds silicon nanoparticles persistent phosphors

μs ∼ ms μs ∼ ms hundreds ns ∼ μs up to 1 μs ∼20 ns hundreds ns ∼ μs ∼μs ∼μs >10 ns >10 ns >1 s

Figure 3. Principle of TGL technique to suppress autofluorescence.

unwanted noise in time domain even if they are weak in intensity, which considerably enhances the detection accuracy and sensitivity. The signal-to-noise ratio is remarkably related to the delay time of the detector. It increases when the decay of the short-lived noise proceeds and reaches to the maximum when the decay is completely finished. After that, the value drops because of the collectable long-lived signals becoming fewer. Long-lived luminophores have also been employed as energy donors in a Förster resonance energy transfer (FRET) system for bioanalysis. Luminescent lanthanides have received particular attention as the donors because of their advantageous properties including long luminescence lifetimes, large Stokes shifts, extremely narrow emission bands, and resistance toward photobleaching.46,120,218,219 The acceptors are usually shortlived fluorescent quantum dots or organic dyes with lifetimes of several nanoseconds. The excited-state lifetimes of the acceptors are remarkably elongated when FRET occurs, allowing timegated FRET (TG-FRET) biosensing. Since lanthanides exhibit well-separated emission bands, which can respectively sensitize several different acceptors, this allows multiplexed TG-FRET with reduced operational costs.46,120 Terbium(III) chelates are the most popular donors in multiplexed TG-FRET biosensing because of their four relatively strong emission bands at about 495, 545, 575, and 620 nm. Green- and red-emitting dyes are frequently used as the acceptors in a duplex mode. Adequate correction procedures to account for spectral crosstalk are necessary in the multiplex mode. These TG-FRET techniques have already been used in commercial and clinical applications.

3. TIME-RESOLVED PHOTOLUMINESCENCE TECHNIQUES Fluorescence microscopy, especially confocal microscopy, has been widely employed for luminescence bioimaging.203−208 The emission intensity of various luminescent probes is used to reflect the concentration and the microenvironment of the probes. However, the variation of excitation laser power and probe concentration reduces the precision of the imaging and quantification analysis. Additionally, when the emission of the probe occurs at the same wavelength as that of autofluorescence or the emission of two or more probes significantly overlaps, it is difficult to recognize the signal of interest based on the intensity. Time-resolved photoluminescence techniques provide a new E


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Time-resolved fluorometry has been widely used in analytical biochemistry and clinical chemistry.220,221 Introducing the timegated concept into microscopes requires modification of the standard microscope setups. The available pulsed excitation sources include chopper-interrupted continuous Hg lamp, He− Cd laser, argon-ion laser, pulsed Xenon flashlamp, and currentswitched ultraviolet (UV) light-emitting diode (LED).222 The selection of the pulsed laser source depends on the luminophore of interest. The wavelength of the excitation source should match the absorption of the luminophore. For example, an argon-ion laser with visible output at 514 nm is suitable for exciting platinum and palladium porphyrins which possess the absorption maximum at 530 nm.223 The pulse length of the excitation source should be as short as possible to ensure the detection efficiency but be sufficiently long to allow completed decay of the luminophore.216 For example, a laser source with a high repetition rate of 1 MHz is not suitable for the luminophore with decay lifetimes longer than 1 μs since another excitation pulse takes place before the previous decay is finished. Additionally, excitation source with high power and low cost is preferable. With respect to photon detection, a rotating mechanical chopper has been employed to block the excitation and short-lived luminescence signals and only allow long-lived signals to reach the detector.214,224 Mechanical choppers allow naked-eye observation of true-color TGL images in real time215,225 but high-speed rotation induces instability of the equipment. An electric shutter is an alternative electronic device. Photons are blocked by the shutter under a negative voltage and detected when a positive voltage is applied.213 Charge-coupled device (CCD) is the mostly used device that converts the photon signals into digital ones.226 In the TGL imaging, CCD is used to create high-resolution images based on the received long-lived luminescence photons with the aid of mechanical choppers or electric shutters.227 Intensified CCD (ICCD) cameras provide another effective means of shuttering luminescence signals, as the image intensifier can be turned on/off with nanosecond resolution.215,228 Very recently, the application of TGL imaging has been expanded in bioimaging and sensing for different purposes. In an FRET system with a long-lived luminescent donor, time-gated detection efficiently suppressed the fluorescence from directly excited acceptors.229,230 Incorporation of the time-gated concept into stimulated emission depletion (STED) microscopy produced super-resolution images by breaking the diffractionlimited resolution for a given system.231 Extending the application of TGL to the second biological window (corresponding to the 1000−1350 nm spectral range) highly improved the resolution and penetration in in vivo imaging.232 Combination of time-gate detection technique with terahertz imaging allowed analysis in the frequency range of 0.1−10 THz with time resolution of 40 fs facilitating deep content extraction.233

independent of its concentration, a variation in lifetime is usually indicative of differences in microenvironments of the probe or interactions with surroundings. Therefore, with probes that display lifetime responses to the environment, PLIM produces images that provide information such as ion concentrations,237,238 oxygen contents,239 pH values,240 and temperature.241 Additionally, electronic communications between the probe and its surroundings such as energy/electron transfer that leads to lifetime changes can be reflected in the PLIM images.242−244 At present, there are two common methods widely used for lifetime measurement in PLIM. They are frequency domain phase modulation and time-correlated single photon counting (TCSPC).245−254 In frequency domain measurement, a sample is excited with sinusoidally modulated light. The luminescence of the sample shows a decreased modulation degree and a phase shift (Δϕ) compared to the excitation (Figure 4a), which allows

Figure 4. (a) Scheme of luminescence lifetime detection in the frequency domain phase modulation measurements. (b) Scheme of luminescence lifetime detection in the TCSPC measurements.

the reconstruction of luminescence decay. TCSPC is another well-established and commonly used technique for photoluminescence lifetime measurements. It is a histogramming process that measures the time of each individual photons of probes after probes are excited with a laser pulse (Figure 4b). After excitation of the sample by a high repetitive light source, a sufficient number of photon events can be fit to an exponential function that gives lifetime parameters. Imaging of fluorescence lifetimes in the picosecond and nanosecond ranges is fast and efficient. It takes longer time to image luminescence lifetimes in microseconds or milliseconds because the pulse excitation with a very low repetition rate, and a much higher pulse power is required to ensure sufficient photon events for data analysis. For example, Mycek and co-workers presented a PLIM system for the detection of intracellular oxygen with [Ru(bpy)3]2+.255 A nitrogen (N2) pumped dye laser

3.2. Photoluminescence Lifetime Imaging Microscopy

TGL techniques discriminate target luminescence signals against nonspecific background autofluorescence by using a “time gate”. Once the “time gate” is applied, the techniques analyze the intensity of the photons collected beyond the gate. In contrast, PLIM measures the luminescence lifetime of a probe to map its spatial distribution in cells, tissues, and small animal modes, where signals from the probe can be easily distinguished from short-lived autofluorescence and light scattering based on their different lifetimes.234−236 As the emission lifetime of a probe is F


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Figure 5. Principle to simultaneously image the lifetimes of fluorescence and phosphorescence. Blue bars represent the excitation pulse. The yellow emission decays are detected from short-lived fluorescence analyzing, and the green decays are detected from long-lived phosphorescence analyzing.

3.3. General Comparison between Time-Gated Luminescence Microscopy and Photoluminescence Lifetime Imaging Microscopy

with a high output and a repetition rate as low as 10 Hz was used as the excitation source and a wide-field ICCD allowed fast data collection. Incorporation of confocal scanning technique into PLIM improves the spatial resolution remarkably. A novel approach has been developed to simultaneously image the lifetimes of short-lived fluorescence and long-lived phosphorescence.256 A fast-repetition pulsed laser is used to excite fluorescence and build up phosphorescence (Figure 5). After sufficient photons are detected to calculate the fluorescence lifetime, the laser is turned off and pure phosphorescence is obtained for analysis. Recently, Grichine, Maury, and co-workers developed pinhole shifting lifetime imaging microscopy (PSLIM) and temporal sampling lifetime imaging microscopy (TSLIM) for lifetime imaging in the μs−ms range. The PSLIM significantly reduced the signal acquisition time with sacrifice of precision due to selective detection of long-lived species, while the TSLIM analyzed most of the photons and maximized the photon efficiency at the expense of the overall acquisition time.208 Multiphoton imaging enables improved spatial resolution and deep tissue penetration.131,132,257−260 Combination of twophoton excitation and long-lifetime imaging is challenging since the excitation requires a femtosecond laser which typically has a time interval of around 10 ns between pulses. To adapt for long-lived photoluminescence imaging, one alternative method is to add a laser modulator to build up phosphorescence over a period of femtosecond laser pulses before monitoring the decay.210 For example, Vinogradov and co-workers used a femtosecond laser (typically Ti:sapphire, 100 fs at 840 nm) for two-photon phosphorescence lifetime imaging.261 In the microscope system, an acousto-optical modulator (AOM) was used to control the on/off state of the excitation source. Long-lived phosphorescence was analyzed when the excitation was turned off. The two-photon PLIM techniques have been used for imaging of oxygen and blood flow in deep cerebral vessels.

Both TGLM and PLIM are used to obtain high quality images with minimized autofluorescence interference. In TGLM, shortlived emission is filtered off and only long-lived luminescence is collected for analysis, resulting in much higher signal-to-noise ratios (SNRs) but with sacrifice of intensity. As same as prompt luminescence intensity, the TGL intensity is linear to the probe concentration in a certain concentration range. In PLIM, all photons are collected for calculation of lifetimes and signals of interest and autofluorescence are differentiated based on their different decay rates. The lifetimes are independent of probe concentration and used to create images. To use probes with extremely long emission lifetimes such as persistent phosphors for bioimaging, TGLM is more suitable because the SNR can maintain a high value even if long gate time is applied but PLIM requires a very long photon acquiring duration. With respect to resolution in time domain, PLIM is better than TGLM, since TGLM only recognizes long-lived signals from short-lived ones using a “time gate” while PLIM distinguishes the lifetimes of every individual pixel. When these techniques are applied to biological sensing, PLIM is suitable for analysis of analytes that are able to induce a significant alteration in the luminescence lifetime, while TGLM is more suitable for long-lived probes that display significant intensity response to analyses.

4. LONG-LIVED LUMINESCENT PROBES FOR TIME-RESOLVED PHOTOLUMINESCENCE BIOIMAGING AND BIOSENSING As the basic building block of life, a cell contains genetic and reproductive information for cellular differentiation and proliferation and is responsible for the maintenance of regular metabolic processes. Cellular imaging is helpful and important in the study of cell structures and the investigation of intracellular activity. Luminescence imaging provides high sensitivity and specificity and has been attracting increasing research interest. Luminescence intensity is commonly used to create images that G


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Chart 1. Lanthanide Chelates (1−22) for Cell Imaging

show the intracellular localization of the emissive compounds and reflect intracellular interactions and biological activities. However, in this case, autofluorescence from biological samples is indistinguishable and also included to produce the images,

which reduces the sensitivity and accuracy. Although the autofluorescence covers almost the whole visible region and extends to the NIR region, it is readily distinguishable in the time domain as its decay rate is very fast. Thus, the background H


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spacer-arm. The BSA layer reduced the steric hindrance and facilitated the binding of surface transferrin to transferrin receptors on the cell membrane. These transferrin-conjugated nanoparticles showed the excitation and emission maxima at 334 and 611 nm, respectively, and the luminescence lifetime was in the submillisecond scale. Fluorescence microscopy imaging revealed that the cell membrane of live HeLa cells was impermeable to the unconjugated nanoparticles, while the transferrin-conjugated nanoparticles readily entered cells through receptor-mediated endocytosis. The SNR was increased by about four times when a delay time of 100 μs and a gate time of 1 ms was applied in the TGLM imaging. Apoferritin (AFt) is a cytoplasmic protein and pass across cell membranes via a receptor-mediated endocytosis process. It consists of 24 polypeptide subunits, which form a hollow cage structure with internal and external diameters of 8 and 12 nm, respectively. The encapsulation of lanthanide chelates into AFt significantly increases their bioaffinity and biocompatibility. For example, Eu(III) chelate 5 was embedded into AFt through a dissociation−reassembly route, forming an artificial luminescent protein (5@AFt).267 The excitation and emission maxima of 5@ AFt occurred at 331 and 611 nm, respectively. And the lifetime of 5@AFt was determined to be 1.29 ms. 5@AFt internalized into HepG2 cells through an apoferritin-receptor-mediated endocytic pathway and accumulated in the cytoplasm. The prompt imaging showed a slightly stronger background noise. Upon applying a delay time of 100 μs and a gate time of 1 ms, as the autofluorescence from the cells had been completely suppressed, highly specific and background-free TGL images were obtained. In a related work, another Eu(III) chelate, 6 was employed to fabricate the luminescent protein, 6@AFt, to reduce the excitation energy.268 6@AFt exhibited the excitation maximum at 420 nm, and the emission maximum occurred at 613 nm with a lifetime of 365 μs. HeLa cells incubated with 6@AFt for 3 h were used for cellular imaging. The prompt images only showed the blue autofluorescence, while TGLM images revealed the characteristic red luminescence of 6@AFt. Utilization of Ir(III) complexes as sensitizers for lanthanide chelates red-shifts the excitation wavelength to the visible region owing to their low energy absorption. For example, in a series of Ir(III)−Eu(III) complexes (7 − 11), the Ir(III) unit with relatively high triplet energy level acts as an energy donor to sensitize the intense emission of the Eu3+ ion, and the excitation wavelengths are about 400 nm.269,270 Additionally, Ir(III) complexes are reported to be two-photon excitable, which allows occurrence of lanthanide emission upon NIR excitation.271−273 A water-soluble dinuclear Ir(III)−Eu(III) complex 12 was two-photon excitable at 780 nm.274 Partial energy transfer from the Ir(III) complex to Eu(III) ion allowed simultaneous detection of the green Ir(III)-based and the red Eu(III)-based emission from the same probe. Internalization of the complex into live human dermal fibroblast (HDF) cells resulted in the cytoplasmic staining. The TGLM imaging revealed that the luminescence of cells treated with this complex was still visible after a delay time of 75 μs. Similarly, two dinuclear Ir(III)-Ln(III) complexes 13 and 14 where the phosphorescent Ir(III) unit was connected to a Ln(III) unit via an alkynyl linkage were designed and synthesized.275 The IrIII → EuIII energy-transfer rate constant in complex 14 was an order of magnitude faster than that of complex 12, which can be ascribed to the conjugated pathway facilitating energy transfer. Both complexes were used for twophoton confocal and PLIM imaging. From two-photon confocal imaging results, they were observed to enter cells and localized

interference can be easily removed by using long-lived luminescent probes via time-resolved photoluminescence imaging techniques. Luminescent molecular probes have attracted much research interest owing to their high sensitivity with broad dynamic range in the detection of specific analytes. The presence of the analyte is usually reflected by a change in the luminescence intensity or wavelength. When the detection is applied to biological samples such as live cells, tissues, and animal modes, it exclusively avoids the post-mortem processing or destruction of samples. However, the accuracy of the detection is reduced because the autofluorescence from biological samples is also collected for analysis without discrimination. In contrast, time-resolved photoluminescence detection, in which the reporting signals are readily differentiated from the short-lived autofluorescence, shows much higher sensitivity. In this section, we summarize recent developments of longlived luminescent probes for imaging cellular structures and detecting different analytes including metal cations, halogen anions, reactive oxygen, nitrogen and sulfur species, gas molecules, biological macromolecules, and microenvironments. 4.1. Lanthanides for Time-Resolved Photoluminescence Bioimaging and Biosensing

4.1.1. Lanthanides for Cell Staining. Lanthanide ions show weak absorption limiting their applications in optical sensing and imaging. When lanthanide ions are coordinated with organic ligands to form lanthanide chelates, they can be efficiently sensitized owing the strong absorptivity of the ligands. Due to the Laporte-forbidden nature of the 4f−4f transition, lanthanide chelates display luminescence lifetimes in the microsecond and millisecond scales. Owing to their extremely long luminescence lifetimes, lanthanide chelates and nanoparticles are the most commonly used luminophores in TGL applications.262,263 For example, Nagano and co-workers prepared two Eu(III) chelates (1 and 2, see Chart 1), both of which showed luminescence lifetimes of around 0.60 ms in water.264 Their internalization into live different human cervical carcinoma (HeLa) cells was aided by physical injection with an Eppendorf injection system. The cell images were recorded via TGLM, in which an image intensifier was employed to control the delay and gate time and to improve the uniformity of the emission light. In the prompt imaging, cells injected with the chelates displayed intense luminescence throughout the whole cells, while cells without injection were weakly emissive due to the autofluorescence. In the TGLM imaging with a delay time of 52 or 70 μs and a gate time of 808 μs, the autofluorescence was efficiently minimized and the chelate-injected cells were clearly distinguished. Additionally, TGLM can be combined with multicolor imaging techniques by using long-lived materials with different luminescence colors. For example, Eu(III) and Tb(III) chelates (2, 3) were injected into HeLa cells. In the TGLM imaging, only the luminescence of the Eu-injected cell was detected through a wavelength window of 617 ± 37 nm, whereas the luminescence of the Tb-injected cell was selectively recorded through a window of 528 ± 19 nm. Receptor-mediated endocytosis provides a new uptake pathway for molecules that bind to membrane receptors.265 Luminescent silica nanoparticles were prepared by covalent immobilization of a Eu(III) chelate 4 into silica shell of poly(vinylpyrrolidone) (PVP) stabilized Fe3O4 nanoparticles.266 The silica nanoparticles were modified with transferrin on the surface with a flexible bovine serum albumin (BSA) layer as the I


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SA and the cell surface receptor EpCAM. Flow cytometry investigation showed that MCF-7 cells incubated with Pdot−SA in the presence of the biotinylated primary antibody exhibited much more intense luminescence than those treated with Pdot− SA in the absence of the biotinylated primary antibody. The membrane labeling was confirmed by fluorescence microscopy. To demonstrate that the Pdots can be distinguished from the autofluorescence, the Pdots was mixed with commercial red fluorescent nanoparticles, R300 NPs for imaging. In the imaging experiment, the R300 NPs served as an interference signal source. The luminescence signals of the Pdots and R300 NPs could not be differentiated based on their wavelengths due to the spectral overlap. As the luminescence lifetime of these Pdots (509 μs) was much longer than that of R300 NPs (3.6 ns), TGLM imaging with a delay time of 200 μs selectively collected the signals from Pdots. In the cell imaging experiment of human breast carcinoma (MCF-7) cells incubated with Pdots, the SNR of TGLM imaging was improved from 85 to 232 compared to the prompt imaging. With the use of a similar strategy, a mutant TEM-1 β-lactamase (BL-tag) was fused to the extracellular region (N terminus) of epidermal growth factor receptor (EGFR) on the surface of human embryonic kidney (HEK293T) cells via gene transfection using Lipofectamine 2000 as the gene carrier.281 A long-lived luminescent Eu(III) chelate 19 (τ = 1.25 ms) modified with an ampicillin moiety can bind to BL-tag. TGLM imaging showed the transfected HEK193T cells were efficiently labeled with the Eu(III)−ampicillin conjugate (19) on the cell membrane, and the long-lived luminescence was absent when the nontransfected cells were used. The visualization of cell membrane proteins was resistant to fetal bovine serum (FBS) containing various shortlived fluorescent components because the TGLM image showed only long-lived luminescence of the Eu(III) signals on the cell surface. Furthermore, a costaining experiment involving conjugate 19 and MitoTracker Orange (MTO), which is a rhodamine-based fluorescent dye that stains mitochondria, was performed. The transfected cells were labeled with the Eu(III) chelate and MTO. TGLM images with no delay time and a gate time of 10 μs selectively showed the short-lived fluorescence of MTO since it is much more intense than the luminescence of the Eu(III) chelate. When a delay time of 85 μs and a gate time of 10 ms were applied, the long-lived luminescence on the cell surface was selectively visualized. Similarly, a Eu(III) chelate 20 containing a benzylguanine moiety was used to label the surface of HEK293 cells that expressed the SNAP-tagged CCK2 membrane receptor.282 Negligible nonspecific cell labeling was observed owing to the negative charge and hydrophilic nature of the chelate, which suppressed cellular uptake or adsorption to living cells. This chelate was applied to monitor fluorescent ligand binding on cell-surface proteins with time-resolved energy transfer assays. Upon addition of a red-fluorescent agonist of the CCK2 receptor, energy transfer from Eu(III) to the fluorophore gave rise to quenching of the TGL of the Eu(III) ion. 4.1.1.2. Lanthanides for Lysosome Staining. Lysosomes are acidic organelles with a pH value of about five.283,284 There is an array of hydrolytic enzymes in lysosomes for degradation of various cellular macromolecules, including proteins, nucleic acids, carbohydrates, lipids, and cellular debris.285−287 Lysosome trackers usually contain an amino group, and the protonated form readily accumulates in the lysosomes. For example, Bünzli and co-workers developed a bimetallic Eu(III) chelate 21 containing the benzimidazole group.288 Chelate 21 was noncytotoxic and internalized into normal and cancer cells through

into the cell cytoplasm. Lifetime mapping of the Ir(III)-based emission from both complexes were also carried out via PLIM imaging. A longer emission lifetime was observed for complex 13. In another study, Ir(III) complex 15 and Eu(III) chelate 16 were covalently embedded into mesoporous silica nanoparticles.276 The Ir-based luminescence of the nanoparticles at 470 nm exhibited biexponential decay with the lifetimes of the two components to be 1203 ns (49%) and 102 ns (51%), respectively. The Eu-based luminescence at 615 nm showed lifetimes of 1021 μs (46%) and 499 μs (54%). The nanoparticles entered cells through energy-dependent endocytosis and were localized in the cytoplasm. TGLM imaging showed that the luminescence from the nanoparticles was observable with a delay time of 1500 ns. A Eu(III) chelate 17 was used to detect prostate cancer cells based on specific antibody−antigen recognition via time-gated immunoluminescence.277 Direct labeling of the chelate to primary antibody MIL38 allowed sensitive and selective recognition of prostate cancer DU145 cells. Indirect labeling involving 17 modified streptavidin/biotin pair or secondary antibody has also been comparative investigated. Compared to the direct labeling, the indirect detection platforms were less sensitive but retained the high selectivity. Compared to conventional FITC labeling, the Eu(III) chelate 17 facilitated the time-gated detection, which completely suppressed the cellular autofluorescence and produced vivid and high contrast images of immune-stained cancer cells. 4.1.1.1. Lanthanides for Cell Membrane Staining. Luminescent dyes that can label the cell membrane are important for cellsurface demarcation and integral to studying cellular functions. The cell membrane is a semipermeable plasma membrane that controls the migration of substances into and out of cells. It is composed of phospholipid bilayers and embedded proteins. Some of membrane proteins aid the structural stability of the membrane, and the others act as passages through the membrane for molecules and ions.278 Over 50% of modern medicinal drugs are designed to target membrane proteins.279 The incorporation of a substrate of membrane proteins into luminescent compounds brings about strong affinity of these compounds to the cell membrane. Luminescent polymer dots (Pdots) were prepared by nanoprecipitation of a mixture of a Eu(III) chelate 18, poly(9vinylcarbozole) (PVK), and a block copolymer PS-polyethylene glycol (PEG)-COOH (Figure 6).280 Streptavidin was attached to the surface of the Pdots, giving Pdot−SA conjugate. A biotinylated primary antibody was employed to connect Pdot−

Figure 6. Preparation procedure of Pdots containing Eu(III) chelate 18, PVK and PS−PEG−COOH; the procedure for labeling MCF-7 cells by using Pdot−streptavidin bioconjugates. Reprinted with permission from ref 280. Copyright 2013 John Wiley & Sons. J


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Chart 2. Lanthanide Chelates (23−28) for Metal Ions Sensing

binds metal cations with different affinities depending on cation sizes. Diaza-18-crown-6 receptors bind K+ with the selectivity of 5- to 10-fold over Na+. However, such selectively is not sufficiently high for detection of K+ in the biological system, where the typical concentration of K+ (3.5−5.3 mM) is much lower than that of Na+ (135−148 mM). Investigation has revealed that involvement of a selective cation−π interaction significantly improves the selectivity of K+ recognition over Na+. When the crown-ether is used to bridge a lanthanide ion and an organic antenna, the sensitization efficiency depends on the complexation of the crown-ether unit with K+, which provides a design strategy for luminescent lanthanide probes for K+. For example, Pierre and co-workers designed a Tb(III) chelate 23 (see Chart 2) that contained an azaxanthone unit as a sensitizing antenna, a diaza-18-crown-6 moiety for K+ recognition, and an aryl-ether for cooperative metal cation binding.300 In the absence of K+, this chelate displayed weak luminescence because of low sensitization efficiency due to a long distance between the Tb(III) center and the antenna. Complexation of K+ by the azacrown-ether favored a cation−π interaction with the aryl-ether, leading to a close proximity between the Tb(III) center and the antenna, resulting in significant luminescence enhancement of chelate 23 (Figure 7). Although Na+ could be complexed by the aza-crown-ether, its smaller size sterically limited formation of the cation-π interaction, which brought about apparent selectivity for K+ over Na+. TGL titration (delay time = 0.2 ms) showed that chelate 23 exhibited a 22-fold enhancement in the Tb(III) luminescence at 545 nm upon complexation with K+.

an energy-dependent and viability-dependent endocytosis pathway. TGLM imaging showed that HeLa cells incubated with chelate 21 (100 μM) for 24 h substantially stained endosomes and lysosomes, which was confirmed by the costaining experiment involving LysoTracker Blue. 4.1.1.3. Lanthanides for Mitochondrion Staining. Mitochondria are cytoplasmic organelles and known as the energy factory where adenosine triphosphate (ATP) is produced to power most cellular processes.289 The outer membrane of mitochondria is structurally similar to the eukaryotic plasma membrane, and positively charged lipophilic compounds such as triphenyl phosphine have a high potential to accumulate in the mitochondria.290−292 Maury, Parker, and co-workers synthesized a series of neutral Eu(III) chelates which displayed intense luminescence.293 These chelates entered live NIH 3T3 cells via macropinocytosis. The luminescence spectrum of the Eu(III) (22)-loaded cells recorded via time-resolved spectral imaging, where the autofluorescence was filtered off, definitely showed the characteristic Eu(III) spectral signature, indicative of internalization of the intact chelates. The specific mitochondrion staining was confirmed by costaining experiments involving MitoTracker Green. 4.1.2. Lanthanides for Time-Resolved Photoluminescence Sensing. 4.1.2.1. Lanthanides for Metal Ion Sensing. Many luminescent probes have been developed for metal-cation sensing. The target metal cations include those of the essential metals such as potassium and trace essential metals such as zinc, which play biological important roles in living system. Sensing of heavy metal cations that are deleterious, such as mercury, has also attracted much interest. Since coordinatively unsaturated metal cations often serve as a Lewis acid, the design strategy of probes for metal cations is usually to incorporate Lewis base species into the molecular structures of luminophores. The formation of Lewis adducts usually affects the electronic communication between the luminophores and the binding sites, resulting in luminescence response. 4.1.2.1.1. Lanthanides for K+ Sensing. K+ is one of alkali metal ions and involved in many biological processes including regulation of membrane polarization and osmotic pressure.294−298 The sensitive detection of K+ is essential to biomedical diagnosis since failures in homeostasis of K+ have been associated with hypertension, stroke, and seizures.299 The design of probes for alkali metal ions has been focused on the employment of a macrocyclic ring such as crown-ether which

Figure 7. Chemical structure of chelate 23 and the sensing mechanism toward K+. Reprinted from ref 300. Copyright 2009 American Chemical Society. K


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The selectivity of the K+ detection is 93, 260, 105, and 61 fold over Na+, Li+, Mg2+, and Ca2+, respectively. In a similar design, with diaza-18-crown-6 as the receptor for K+, the Eu(III) chelate 24 was employed as the emissive center and phenanthridine was used as the antenna.301 Complexation of this chelate 24 with K+ modified the excited energy levels of the antenna, which thereby resulted in a change in the excitation spectral profile of chelate 24. The Eu(III) luminescence was independent of the K+ concentration when chelate 24 was excited at 400 nm, while excitation at shorter wavelengths such as 265 nm yielded a K+-induced emission enhancement. As a result, the emission intensities when the chelate was excited at these two wavelengths facilitated the ratiometric detection of K+ in biological systems, in which the autofluorescence can be efficiently gated off by TGL detection. 4.1.2.1.2. Lanthanides for Zn2+ Sensing. Zn2+ is the secondmost abundant essential transition-metal cation in the human body and plays a key role in biological systems. It is associated with various intracellular procedures, such as neural signal transmission and enzymatic catalysis.302,303 Uncontrolled doses of Zn2+ ion have been proved to be associated with neurological diseases such as Alzheimer’s disease,304 Parkinson’s disease,305 and ischemia.306 Thus, it is very important to design sensitive and selective sensors for Zn2+. 2,2′-Dipicolylamine (DPA) and its derivatives are the most commonly used Zn2+ receptors307−310 not only due to their strong affinity to Zn2+ but also because the complexation with Zn2+ inhibits the efficient photoinduced electron transfer (PET) from the tertiary amine of DPA to the luminophore, resulting in significant enhancement of luminescence intensity and elongation of luminescence lifetime. Although the PET-based Zn2+ detection showed high sensitivity, protonation of the tertiary amine or forming hydrogen bonding with intracellular biological molecules can also inhibit the PET process, leading to emission enhancement of the luminophores. Nagano and co-workers designed an alternative Eu(III) chelate 25 that contained a DPA unit.311 Chelate 25 exhibited a pHindependent luminescence behavior; the luminescence was not affected by pH values between 3.6 and 8.8, although the pKa values of DPA have been reported to be 6.10, 4.28, and 2.49. Therefore, the binding of Zn2+ cannot suppress the PET process. Interestingly, upon complexation with Zn2+, the Eu3+-based luminescence displayed enhancement in intensity, which has been ascribed to the trigger of efficient intramolecular energy transfer which sensitized the Eu(III) luminescence. To explore the utility of the long luminescence lifetime of chelate 25, the emission titration was repeated in the presence of rhodamine 6G using a time-gated mode (Figure 8). In the prompt spectra, the titration results were disturbed by three short-lived signals that were the scattered light (300 nm) and the fluorescence of the chelate (400 nm) and rhodamine 6G (550 nm). The delayed spectra recorded with delay and gate times to be 0.05 and 1.00 ms, respectively, revealed a significant enhancement of the Eu3+based luminescence without fluorescent noise. Chelate 25 was also used to detect intracellular Zn2+ via TGLM imaging with a delay time of 70 μs and a gate time of 808 μs.264 A single HeLa cell was injected with chelate 25, but the luminescence was hardly observed. Incubation of the cell with Zn2+ in the presence of an ionophore efficiently switched on the luminescence of the cell. In another study, the same group designed a long-lived luminescent Tb(III) chelate 26 that contained two DPA units. 312 Interestingly, the two DPA units bound the same Zn2+, which led to emission enhancement of the Tb3+ ion because of the efficient intracellular energy transfer in the Zn2+-bound chelate.

Figure 8. Photoluminescence spectra of chelate 25 (a) without and (b) with a gate time of 1.00 ms in the presence of Zn2+ with different concentrations and rhodamine 6G under excitation at 320 nm. Reprinted from ref 311. Copyright 2004 American Chemical Society.

4.1.2.1.3. Lanthanides for Cu+ Sensing. Copper, as an essential element, plays important roles in various biological processes and its misregulation is related to many diseases including Menkes, Wilson, and Parkinson’s.313,314 While extracellular copper is in the +II oxidation state, intracellular mobile copper is in the reduced +I state. The design of luminescent sensors for Cu+ is challenging because of the efficient quenching of luminescence by Cu+. Many luminescent sensors for metal cations are designed based on a PET mechanism. Cation-binding inhibits the PET process turning on luminescence. A Tb(III)-peptide conjugate (27) has been designed as a luminescent sensor, in which the peptide is able to bind Cu+ via four amino acids (two methionines (M), a histidine (H), and a tryptophan (W)).315 The cation−π interaction between Cu+ and the tryptophan increased the population of the triplet excited states of the tryptophan, subsequently quenching the indole fluorescence and improving the sensitization of Tb(III) luminescence. In the TGL measurements, the Tb(III) luminescence was enhanced by 6 fold upon binding of Cu+ when the sensor was excited at 280 nm. The enhancement factor was increased to 58 when the excitation wavelength was 310 nm because Cu+-binding red-shifted the π−π* absorption band of the indole moieties. 4.1.2.1.4. Lanthanides for Hg2+ Sensing. Mercury(II) ion is one of the most deleterious global pollutants, and its bioaccumulation causes serious health problems, such as neurological diseases, mitosis impairment, brain damage, kidney failure, and various cognitive and motion disorders.316−320 Thus, it is of great importance to develop efficient sensors for Hg2+. Hg2+ sensing is mainly based on the soft−soft interaction between a mercury(II) ion and a sulfur atom. For example, a Tb(III) chelate 28 was designed to contain a 3,6,12,15-tetrathiaL


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Chart 3. Lanthanide Chelates (29−47) for Reactive Oxygen Species Sensing

9-monoazaheptadecane unit as both a Hg2+ binding site and an electron donor to quench the luminescence of Tb3+ through PET.321 The complexation with Hg2+ inhibited the PET, leading to luminescence enhancement by about 5 fold. The turn-on luminescence response was selectively toward Hg2+ over other common metal cations including Co2+, Mn2+, Cd2+, Pd2+, Zn2+, Ni2+, Pb2+, Mg2+, Ca2+, Ba2+, Sn2+, Cu2+, Fe2+, and Fe3+. The detection sensitivity toward Hg2+ showed strong dependence on the pH values and reached a maximum at pH = 6−7. A quantitative TGL titration, in which the background noise was minimized to increase the accuracy, was performed. A linear

correlation between the Tb3+ luminescence intensity and the Hg2+ concentration (0.1−10 μM) with R2 = 0.999 was observed, and the detection limit was determined to be 17 nM. 4.1.2.2. Lanthanides for Reactive Oxygen Species Sensing. Reactive oxygen species (ROS) are produced during the metabolism of oxygen and play critical roles in cell signaling and homeostasis.322−324 They are also implicated in oxidative defense mechanisms responsible for killing of bacteria and pathogen.325,326 Excessive ROS can damage cell structures and biomolecules including proteins, lipids, and DNA,327,328 causing several diseases such as cancer,329,330 neurodegenerative M


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diseases,331 and cardiovascular diseases.332−334 The design strategy of probes for ROS is usually to incorporate a reductive luminescence quencher into the chemical structures of the luminophores. Upon oxidized by a specific ROS, the luminescence is recovered. 4.1.2.2.1. Lanthanides for Hydrogen Peroxide Sensing. Hydrogen peroxide (H2O2) is one of the most important ROS and plays an important role in host defense,335 oxidative biosynthetic reactions,336 and signal transduction.337 Controlled H2O2 can mediate beneficial cellular processes including cell proliferation, differentiation, and migration,338,339 while the failure of H2O2 homeostasis in the cells can cause pathological states that contribute to aging, oxidative stress, and vascular diseases.340−342 Chang and co-workers prepared two Tb(III) chelates 29 and 30 (see Chart 3), containing a boronate protecting group to uncage a pendant aniline and phenol groups, respectively.343 Both chelates were readily and selectively oxidized by H2O2 over other ROS. The luminescence response of the chelates to H2O2 was examined via TGL techniques with a delay time of 100 μs and a gate time of 10 ms. Luminescence enhancement of the chelates was observed in the presence of H2O2 because the chemoselective H2O2-mediated oxidation resulted in a red-shift of the absorption maxima of the chelates, which significantly improved the sensitization of the Tb(III) center by the antenna groups. Chelate 30 was further applied for detection of endogenous H2O2 in RAW 264.7 macrophages. Incubation of 30-treated cells with phorbol myristate acetate (PMA), which can stimulate the generation of H2O2, led to an increase of Tb(III) luminescence in the time-gated spectra. In another study, a boronate-containing Eu(III) chelate 31 displayed a turn-off response to H2O2 under basic conditions.344 Chelate 31 exhibited intense Eu(III) luminescence at pH > 7, which was efficiently quenched through intramolecular charge transfer when the boronate group was converted to a hydroxyl group by H2O2. To avoid background fluorescence, the use of chelate 31 for H2O2 detection was conducted in time-gated mode with a delay time of 0.2 ms and a gate time of 0.4 ms. The luminescence intensity of chelate 31 was gradually decreased with increased concentration of H2O2. The conversion of the boronate group to the hydroxyl analogue was confirmed by electrospray-ionization mass-spectrometry (ESI-MS). A Tb(III) chelate 32 was nonemissive because of PET-based quenching by the electron-rich diaminophenyl moiety.345 Reaction with H2O2 in the presence of peroxidase led to cleavage of the diaminophenyl ether, resulting in a 39-fold increase in the luminescence quantum yield of chelate 32 accompanied by lifetime elongation from 1.95 to 2.76 ms. TGL titration revealed a linear relation of the luminescence intensity against the H2O2 concentration in the range from 10−8 to 10−6 M, and the detection limit was calculated to be as low as 3.7 × 10−9 M. This chelate was used to detect oligosaccharide-induced H2O2 generation in tobacco leaf epidermal tissues, where peroxidase was produced endogenously. In Figure 9, TGLM imaging revealed that cells treated with the acetoxymethyl ester analogue of chelate 32 did not display observable long-lived luminescence. Further incubation of the cells with oligosaccharide turned on intense Tb(III) luminescence because the oligosaccharide induced the plant cells to generate H2O2. In a control experiment, where catalase was added to the incubation medium as a H2O2 scavenger, the luminescence was hardly observed. 4.1.2.2.2. Lanthanides for Hydroxyl Radical Sensing. Hydroxyl radical (•OH) is the neutral form of the hydroxide

Figure 9. Luminescence images of the tobacco leaf epidermal tissues (left: bright-field images; right: luminescence images) labeled with chelate 32. (a) TGLM image of the tissue incubated with the chelate 32. (b and c) Prompt and TGLM images of the chelate 32-labeled tissues treated with oligosaccharide. (d) TGLM image of the chelate 32-loaded tissue treated with oligosaccharide and catalase. Scale bar: 40 μm; excitation filter 330−380 nm; emission filter >420 nm; gate time 1.00 ms. Reprinted from ref 345. Copyright 2011 American Chemical Society.

anion. It is the most reactive member in the family of ROS, and the cellular half-life of •OH is about 1 ns.346−351 Endogenous generation of •OH is during the reduction of H2O2 by reducing metals such as Cu(I) and Fe(II). Pierre and co-workers designed a •OH sensing system involving a coordinatively unsaturated Tb(III) chelate 33 and trimesate which is an aromatic acid that is readily oxidized by •OH, affording 2-hydroxytrimesic acid.352,353 Since trimesate is a poor lanthanide chelator and sensitizer, chelate 33 emitted weakly. Upon oxidation by •OH, 2hydroxytrimesic acid coordinated the Tb(III) in a bidentate manner and acted as an efficient sensitizer (Scheme 1), resulting in significant luminescence enhancement. The luminescence response toward •OH was extremely sensitive; a steady-state concentration of •OH in the femtomole scale caused remarkable increase (about 11-fold) in the time-gated Tb(III) luminescence with a gate time of 0.2 ms. The increase in luminescence intensity did not correlate with a decrease in the hydration number (q) of the Tb(III) center for chelate 33. The 2-hydroxytrimesic acid may coordinate the Tb(III) center either via displacing two carboxylate arms or via a second sphere coordination environment. Additionally, the sensing system showed a good selectivity toward •OH over other ROS. Similarly, sensing systems, where trimesamide was used instead of trimesate as the preantenna, N


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A β-diketonate-Eu(III) chelate 40 readily reacted with HClO resulting in rapid, selective, and sensitive luminescence quenching because the carbonyl group of β-diketonate was oxidized to a carboxylic acid, leading to decomposition.368 This chelate was immobilized on the surface of silica nanoparticles, in which a reference Tb(III) chelate 41 was embedded in the core. The silica nanoparticles exhibited both green and red luminescence corresponding to the Tb(III) and Eu(III) chelates, respectively. In the presence of HClO, the red luminescence was selectively quenched, giving ratiometric luminescence response. Since both the responsive and reference chelates exhibited longlived luminescence in the millisecond or submillisecond scales, the nanoparticles have been used for time-gated imaging of intracellular exogenous and endogenous HClO (Figure 10). Macrophage cells infected by Escherichia coli also displayed ratiometric TGL response because HClO was produced in the cytoplasm to kill the bacteria. Incorporation of organelletargeting groups, triphenyl phosphonium and morpholine, into 40, afforded chelates 42 and 43, respectively, which were turn-off probes for TGL detection of HClO in mitochondria and lysosomes.369 4.1.2.2.4. Lanthanides for Singlet Oxygen Sensing. Singlet oxygen (1O2) is an excited state of molecular oxygen. It is often generated in photochemical reactions including photosynthesis.370 1O2 is much more reactive than ground-state oxygen and can oxidize a variety of biological molecules, such as DNA, proteins, and lipids, causing cytotoxicity and pathogenesis. Additionally, it is the active species to kill cancer cells in photodynamic therapy (PDT), where photosensitizers were usually employed to produce 1O2.371,372 Anthracene and its derivatives are capable of trapping 1O2 to yield the corresponding endoperoxides, accompanied by the decrease in absorbance of the π → π* transition.373 A Eu(III) chelate 44 equipped with a 9anthryl moiety was designed and synthesized as a luminescent 1 O2 probe.374 This chelate exhibited a 12.5-fold luminescence enhancement in response to 1O2, because the luminescence was efficiently quenched by anthracene but not by the endoperoxide. The concentration of 1O2 in solutions was quantitatively measured via TGL titrations with a delay time of 0.2 ms and a gate time of 0.4 ms. The detection limit was established to be as low as 2.8 nM. The 10-methyl-9-anthryl analogue 45, which displayed a detection limit of 3.8 nM in the 1O2 quantification, was used for measurement of intracellular 1O2 with HeLa cells as a model cell line.375 The chelate 46 contained three 9,10dimethyl-2-anthryl moieties reacted with 1O2 stepwise, but the detection limit (10 μM) was much higher because higher concentration of 1O2 was required to convert all the anthracene units to endoperoxide for reaching the instrumental detection limit.376 A water-soluble cationic porphyrin, 5,10,15,20-tetrakis(1-methyl-4-pyridinio)porphyrin tetra(p-toluenesulfonate) (TMPyP), was employed not only as an efficient 1 O 2 photosensitizer but also to facilitate the internalization of chelate 45 by forming cation−anion pairs. HeLa cells were first loaded with chelate 45 and TMPyP. The generation of intracellular 1O2 under continuous irradiation with a 100 W mercury lamp (λ = 450−490 nm) was monitored via TGLM where a delay time of 400 μs was set to eliminate the emission from TMPyP and cell components. Results showed that both the nucleic and the cytoplasm of the cells displayed luminescence enhancement. A faster response in the nuclei was observed because TMPyP was principally accumulated in the nuclei where more 1O2 was produced. A structurally similar Eu(III) chelate 47 was used to track the intracellular 1O2 generation induced by two PDT

Scheme 1. Sensing Mechanism of the System Involving Chelate 33 and Trimesate

exhibited selective TGL response toward •OH with an increased sensitivity.353 Detection of •OH based on PET elimination was reported. A weakly emissive Tb(III) chelate (34) exhibited a 49-fold enhancement of the TGL in response to •OH due to the •OH-induced cleavage of the p-aminophenoxy ether (Scheme 2) Scheme 2. Sensing Mechanism of Chelate 34

which is a PET-based quencher.354 The •OH sensing was insensitive to pH values in the physiological pH range. The intracellular •OH detection was demonstrated using HeLa cells as a model cell line. TGLM imaging with a delay time of 100 μs and gate time of 1000 μs revealed that HeLa cells incubated with the acetoxymethyl ester analogue of chelate 34 for 2 h showed weak luminescence which was hardly observed. Further treatment of the cells with H2O2 and Fe3+ for another 1 h lighted up the cells since •OH was generated. 4.1.2.2.3. Lanthanides for Hypochlorous Acid Sensing. Intracellular hypochlorous acid (HClO) plays an important role in the destruction of pathogens in the immune system.355 It is produced endogenously in leukocytes by myeloperoxidase (MPO) which catalyzes the oxidation of chloride to HClO by H2O2.356−358 Unregulated HClO production may cause various cardiovascular diseases,359 neuron degeneration,360−362 arthritis,363 and cancer.364 Lanthanide [Tb(III) and Eu(III)] chelates 35−39 were designed to detect HClO.365−367 These chelates were weakly emissive due to PET process in which a 4-amino-3nitrophenyl, 4-aminophenyl, or nitrophenyl moiety served as the electron donor or acceptor. Reaction with HClO yielded strongly emissive analogues due to the cleavage of the electron donor/ acceptor. These lanthanide chelates were used for the detection of endogenous HClO in RAW 264.7 macrophage cells via TGLM. The cells were first simulated with lipopolysaccharide (LPS)/interferon-γ (IFN-γ)/PMA, which induced rapid production of HClO, and then incubated with the esterized chelates. Red and green TGL were observed in the cells treated with the Eu(III) and Tb(III) chelates, respectively. In control experiments, where an MPO inhibitor was added to the incubation medium of the cells, the luminescence disappeared.366 O


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Figure 10. TGLM images of the RAW 264.7 cells (1: collected at the red channel; 2: collected at the green channel; 3: overlap of luminescence and bright field images; 4: Igreen/Ired ratiometric images). (a) The cells incubated with 40, 41 loaded nanoparticles. (b) Cells with 40, 41 loaded nanoparticle in the presence of HClO. (c) Cells were treated with LPS and IFN-γ, PMA, and 40, 41 loaded nanoparticles. (d) Cells were treated with LPS, IFN-γ, PMA, and 4-ABAH, and 40, 41 loaded nanoparticles. (e) Cells were pretreated with E. coli, followed by incubation with 40, 41 loaded nanoparticles. Scale bar: 20 μm; excitation filter 330−380 nm; emission filter >590 nm; gate time 1.00 ms. Reprinted with permission from ref 368. Copyright 2017 The Royal Society of Chemistry.

drugs.377 HeLa cells incubated with chelate 47 and the PDT drug displayed emission enhancement when the intracellular production of 1O2 was triggered by irradiation of the cells. Similar luminescence change was not observed when sodium azide, which is a 1O2 quencher, was initially present in the cell culture medium. 4.1.2.3. Lanthanides for Reactive Nitrogen Species Sensing. 4.1.2.3.1. Lanthanides for Nitric Oxide Sensing. Reactive nitrogen species (RNS) are a family of compounds derived from nitric oxide (NO). As same as ROS, RNS not only function in host defense as antimicrobial factors but also regulate diverse physiological signaling pathways.378 When excess RNS are generated, nitrosative stress occurs and results in the alternation of protein structures, thus inhibiting their biological functions.379 NO is the origin of RNS. It is endogenously generated during the

conversion of L-arginine to L-citrulline by nitric oxide synthase (NOS)380 and involved in the regulation of transcription factors, endocytic pathways, and tyrosine kinases.381−383 It can also inhibit leukocyte adhesion, which is associated with inflammatory diseases.384,385 For these reasons, the development of probes to detect intracellular NO is of paramount importance. Luminophores containing an electron-rich o-diaminophenyl moiety are commonly used as NO probes, in which the luminescence is quenched via PET. Reaction with NO converts the o-diaminophenyl to the electron-deficient benzotriazole derivative, accompanied by emission enhancement. For example, a weakly emissive Eu(III) chelate 48 (see Chart 4) equipped with an o-diaminophenyl moiety was designed according to the abovementioned mechanism (Scheme 3).386 Addition of NO to a solution of chelate 48 caused a 47-fold enhancement of the timeP


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Chart 4. Lanthanide Chelate (48−53) for Reactive Nitrogen Species Sensing

When the cells were pretreated with 2-(4-carboxyphenyl)4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO), which is a NO scavenger, luminescence was undetectable, which indicated that the luminescence observed in the absence of cPTIO was attributed to the reaction product of the chelate with endogenous NO. Additionally, in a quantification analysis using the luminescence intensity of chelate 48 as an indicator, the intracellular NO concentration in the 60 min’s incubation solution of the onion inner-layer epidermal peels (50 mg) was measured to be about 50 nM. A Eu(III) chelate containing a ringclosed rhodamine derivative 49 exhibited intense and long-lived Eu(III) luminescence upon photoexcitation.387 Reaction of 49 with NO led to a rhodamine ring open, favoring the luminescence resonance energy transfer from Eu(III) to rhodamine (Figure 12), giving rise to ratiometric luminescence response. Additionally, the average luminescence lifetime decreased from 484.3 to 48.7 μs upon reaction with NO, providing a ca. 10-fold contrast window for the detection of NO using luminescence lifetime as the signal. In a similar design, a Tb(III) chelate 50 and a ring-closed rhodamine derivative 51 were assembled using apoferritin as a carrier.388 Upon reaction with NO, the luminescence ratio of rhodamine over Tb(III) was increased by ca. 24.5 fold. Detection of intracellular NO was demonstrated via time-gated ratiometric luminescence imaging. 4.1.2.3.2. Lanthanides for Peroxynitrite Sensing. Peroxynitrite (ONOO−) is a short-lived oxidant species generated by a reaction between NO and superoxide (O2−).389 It is a potent cytotoxic mediator and capable of inducing damage to a wide range of biomolecules.390 Yuan, Guan, and co-workers have designed and synthesized Tb(III) chelate 52 containing a 2,4dimethoxyphenyl group as a long-lived luminescent probe for ONOO−.391 This chelate exhibited intense luminescence in the absence of ONOO−, and the luminescence was selectively and efficiently quenched by ONOO − via electron transfer. Interestingly, the Eu(III) analogue displayed negative response to ONOO− due to its lower excited state energy level. As the luminescence of Eu(III) is well-separated from that of Tb(III) in wavelength, simply mixing of the Eu(III) and Tb(III) chelates gave a ratiometric sensing system where the emission ratio of Eu(III) over Tb(III) (I612 nm/I541 nm) increased with increasing concentration of ONOO−. In the detection of intracellular ONOO−, TGLM imaging revealed that the intracellular luminescence of the Tb(III) chelate 52 was quenched when

Scheme 3. Sensing Mechanism of Chelate 48

gated Eu(III) luminescence and an elongation of luminescence lifetime from 1.08 to 1.30 ms. The limit of detection for NO was established to be 8.4 nM. The intracellular detection of NO was also performed via TGLM using onion inner-layer epidermal peels which can produce a substantial amount of NO (Figure 11). Intense intracellular luminescence was observed upon incubation of the cells with the acetoxymethyl ester of chelate 48.

Figure 11. (a) Bright-field and (b) TGLM images of the chelate 48loaded onion inner-layer epidermal peels before and after addition of cPTIO. Scale bar: 100 μm, excitation filter 330−380 nm; emission filter >420 nm; gate time 1.00 ms. Reprinted with permission from ref 386. Copyright 2011 Royal Society of Chemistry. Q


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Figure 12. Chemical structure of Tb(III) chelate 49 and the sensing mechanism toward NO. Reprinted with permission from ref 387. Copyright 2017 Royal Society of Chemistry.

the cells were incubated with a ONOO− stimulant, 3-morpholinosydnonimine (SIN-1). In the ratiometric detection, cells were loaded with both Tb(III) and Eu(III) chelates. Luminescence microscopy imaging showed that addition of SIN-1 clearly changed the intracellular luminescence to red color due to the selective quenching of the Tb(III) luminescence. In the design of chelate 53, the 2,4-dimethoxyphenyl group was incorporated into a β-diketonate ligand to enhance the luminescence quantum yield and a triazine analogue with extended planar structure was employed as a coligand to lower the excitation energy.392 Detection of intracellular ONOO− was demonstrated via TGLM imaging. 4.1.2.4. Lanthanides for Reactive Sulfur Species Sensing. 4.1.2.4.1. Lanthanides for Hydrogen Sulfide Sensing. Reactive sulfur species (RSS) are sulfur-containing molecules that participate in redox reactions among biomolecules.393−399 Intracellular RSS include sulfides, thiols, and sulfates, which are important components of many amino acids and proteins, and functionalize as essential ingredients in physiology. The biological role of hydrogen sulfide has received increasing attention owing to its significant role as an endogenous gasotransmitter in signaling processes.400,401 Intracellular production of H2S is catalyzed by cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE).402 Failure of H2S homeostasis has been linked to the pathogenesis of Alzheimer’s disease,403 Down’s syndrome,404 and diabetic complications.401 Lanthanide chelates equipped with organic azides (54−56, see Chart 5) have been designed for H2S detection since azido groups are readily reduced to amino groups by H2S.405−407 Chelate 54 was used to sense sulfide in water.405 The reduction of the azido group to an amino group by sulfide (Scheme 4)

Scheme 4. Sensing Mechanism of Chelate 54

increased the efficiency of energy transfer from the antenna to the Eu(III) center, thus resulting in emission enhancement. The reaction between chelate 54 and NaHS is complete in about 30 min with a 6-fold enhancement after just 5 min, suggesting a rapid reaction rate for the sensing system. Given the long emission lifetime in the submillisecond scale, the luminescence response of chelate 54 toward NaHS was examined in serum. While the signal originating from chelate 54 is subsumed by the much stronger signal of fluorescent species present in serum, a pure Eu(III) luminescence was observed in a TGL spectrum. Chelate 55 was used as an ink and printed onto test paper, which was able to clearly visualize trace H2S gas exhaled by mice.406 The Eu(III)/Tb(III) chelate 57 responded to hydrogen sulfide based on a PET mechanism.408 The chelate was weakly emissive due to PET-based quenching by the appended 2,4dinitrophenyl unit. Reaction with hydrogen sulfide cleaved the dinitrophenyl group, terminating the PET process and turning on the luminescence. Interestingly, while the green Tb(III) luminescence was remarkably increased, the red Eu(III) luminescence was slightly decreased due to efficient intramolecular charge transfer. Thus, the intensity ratio of Igreen/Ired was analyzed to reflect the presence and the concentration of hydrogen sulfide. TGL detection of hydrogen sulfide has been demonstrated in aqueous media. The Igreen/Ired value was significantly increased by about 220 fold upon addition of hydrogen sulfide. The Tb(III) chelate was used to image intracellular hydrogen sulfide. Living HepG2 cells loaded with the chelate emitted weak blue autofluorescence and no timegated luminescene signal was observed (Figure 13). Upon further incubation with NaHS, time-gated image showed intense green luminescence without autofluorescence. Time-gated ratiometric imaging involving both Eu(III) and Tb(III) chelates revealed that the reaction products with NaHS preferred accumulation in the nucleolus. 4.1.2.4.2. Lanthanides for Biothiol Sensing. Thiols are organic sulfur compounds that contain a carbon-bonded sulfhydryl group. They are reductive and can be oxidized to form disulfide bonds in the course of protein folding.393,396,397 They are also involved in the regulation of redox environments to avoid or repair oxidative damage to organisms.395,398 A Tb(III) chelate 58 containing a 2,4-dinitrobenzenesulfonyl (DNBS)

Chart 5. Lanthanide Chelate (54−58) for Reactive Sulfur Species Sensing

R


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Figure 13. Prompt (left), and TGLM (right) images of HepG2 cells treated with chelate 57 in the (a) absence and (b) presence of NaHS. Excitation filter 330−380 nm. Reprinted from ref 408. Copyright 2014 American Chemical Society.

moiety exhibited weak luminescence due to efficient quenching of the Tb(III) luminescence by the dinitrobenzene moiety.409 Reaction with thiol-containing amino acids such as cysteine (Cys) and homocysteine (Hcy) cleaved the linkage between the complex core and the electron-accepting quencher, affording the alcohol analog and switching on the long-lived TGL. The Eu(III) analogue can also react with thiols which cleaved the DNBS moiety, but the luminescence was almost unaffected. The mixture of both chelates was used to ratiometrically detect total biothiols in live cells (Figure 14). Results showed that the average amounts of total biothiols in a single PC-12, HeLa, MCF-7, and A-673 cell was about 5.5, 20.9, 24.1, 18.6 fmol, respectively. Additionally, treatment of HeLa cells with R-lipoic acid, which was metabolized intracellularly to a dithiol to induce fast synthesis of GSH, led to a significant increase in the amount of total biothiols to 104.8 fmol. 4.1.2.5. Lanthanides for Biomolecule Sensing. 4.1.2.5.1. Lanthanides for Nucleoside Triphosphate Sensing. Nucleoside triphosphates are a family of biological molecules containing a nucleoside bound to triphosphates. They play important roles in cell metabolism and regulation. For example, ATP is one of a major source of cellular energy and guanosine triphosphate (GTP) acts as a cofactor in many biochemical processes.410−412 The luminescence of Tb(III) chelate 59 (see Chart 6) was selectively quenched by purine nucleotides due to PET from the purine unit to the phenanthridine antenna (Figure 15).413,414 The ATP/GTP sensing was conducted in a time-gated mode with a delay time of 0.1 ms to minimize the autofluorescence interference. Interestingly, this chelate exhibited preferable response to ATP/GTP over their diphosphate (ADP/GDP) and monophosphate (AMP/GMP) counterparts, which was ascribed to the different attractive forces between these negatively charged nucleotides and the positively charged chelate 59. This was further supported by the observation that the neutrally charged Eu(III) analogue 60 did not distinguish

Figure 14. (a) TGL spectra of Tb(III) chelate 58 and its Eu(III) analogue after adding with different volume of the extraction solution of HeLa cells under excitation at 340 nm with a gate time of 0.40 ms. (b) Amount of biothiols in a single HeLa, MCF-7, A-673, and PC-12 cell. Reprinted from ref 409. Copyright 2013 American Chemical Society.

triphosphate nucleotides from di- and monophosphate nucleotides. Since chelate 59 can distinguish between GTP and GDP, but chelate 60 cannot, a mixture of both chelates was used to monitor the GTP to GDP conversion. The Eu(III) luminescence indicated the total concentration of guanine nucleotide, while the Tb(III) luminescence reflected the amount of GTP. 4.1.2.5.2. Lanthanides for Nucleic Acid Sensing. Nucleic acids including DNA and RNA are the most important biomolecules and function to create, encode, store genetic information in the nucleus of living cells. The primary structure of nucleic acids is the sequence of nucleotides. The design of luminescent probes for nucleic acids is usually based on the specific complementary hybridization of base pairs. For example, an oligonucleotide was labeled with a lanthanide [Tb(III) or Eu(III)] chelate (61 and 62) containing an o-azide−o-ester biphenyl group as a poor sensitizing antenna.415 The other oligonucleotide was modified with a reducing phosphine moiety. When a target sequence was present, hybridization led to the reduction of the azide group by the phosphine, yielding an amine group which underwent cyclization with the ester group giving a phenanthridinone ring, which was an active antenna to excite the lanthanide chelate, thus turning on the luminescence. The binary probes were designed to target 23S rRNA in crude solution of living E. coli cells. The lanthanide luminescence was hardly observed in prompt spectra due to the intense autofluorescence throughout the whole visible region. In contrast, in time-gated spectra with a delay time of 0.1 ms, the autofluorescence was reduced to a negligible level and the long-lived lanthanide S


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Chart 6. Lanthanide Chelates (59−62, 64, 69, 72, 74−83, 91, 92, 94, and 95) for Biomolecules Sensing

sequence were immobilized on fluorescent QDs to probe AlexaFluor 647 labeled target oligonucleotide.416 Upon hybridization, two step FRET from 64 to QD to AlexaFluor 647 occurred efficiently. The detection limits were as low as 16 nM owing to the lower signal-to-noise for the AlexaFluor fluorescence within the time-gated measurements. This sensing system was further used for orthogonal two-plex hybridization sensing. Two independent oligonucleotides were immobilized on the QDs, and the two complementary sequences were labeled with AlexaFluor 647 and 64, respectively. The nongated luminescence ratio of AlexaFluor 647/QDs was used for quantification of the AlexaFluor 647 labeled sequence while the 64 labeled one was reflected by the gated luminescence of both QDs and AlexaFluor 647. Hildebrandt and co-workers developed a series of Tb(III) (donor)-acceptor sensing systems for multiplexed TG-FRET detection of nucleic acid hybridization.417−419 In the presence of target nucleic acids, hybridization led to a close proximity to enable FRET from Tb(III) to fluorescent acceptors giving longlived acceptor luminescence for time-gated detection. By choosing multiple FRET-sensitizable acceptors, either QDs (in 65)417 or organic dyes (in 66),418 with separated luminescence maxima, more than one nucleic acid molecules can be detected and quantified simultaneously. Taking advantages of time-gated detection of long-lived luminescence, the detection limit reached as low as 0.2 nM in serum samples. Using a single Tb(III)acceptor FRET pair for multiplexed nucleic acid detection (67) can also be realized by tuning the distance between the donor [Tb(III)] and the acceptor (QDs or dyes), which determines the efficiency of FRET and hence the decay rate of the acceptors.419 By analyzing the luminescence intensity of the acceptor in different time windows (e.g., 0−2 ms, 2−4 ms, 4−8 ms), nucleic acids with different lengths of nucleotides can be detected simultaneously.

Figure 15. Chemical structure of Tb(III) chelate 59 and the sensing mechanism toward ATP. Reprinted from ref 414. Copyright 2012 American Chemical Society.

luminescence was selectively collected for analysis. The results revealed that the binary probes exhibited specific luminogenic response toward 23S rRNA. Donor−acceptor binary FRET sensing systems have been widely used to develop luminescent probes for nucleic acids. Employing long-lived luminescent lanthanide donors can substantially extend the excited-state lifetime of the short-lived acceptor, facilitating TG-FRET detections. For example, in sensing system 63, the commercially available green-emissive Tb(III) probe 64, and an oligonucleotide with complementary T


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4.1.2.5.3. Lanthanides for Protein Sensing. Immunoassays relying on specific antibody−antigen have been widely used in detection of protein biomarkers. FRET-based sandwich immunoassays involving luminescent lanthanide donors and fluorescent acceptors have been recently developed.420−427 Upon binding of the donor and acceptor antibodies to the same biomarker, FRET from long-lived luminescent lanthanides to QDs/dyes not only turns on the acceptor fluorescence but also significantly elongates the excited-state lifetime of the short-lived acceptor, allowing time-gated detection to improve the sensitivity and lower the detection limits. By employing several acceptor dyes with different fluorescence colors, multiple biomarkers can be detected simultaneously. In an example involving the Lumi4-Tb donor (64) and five acceptor dyes (OG488, AF555, AF568, Cy5, and AF700), the multiplexed sensory system (68) demonstrated clinically relevant detection limits in the low picomolar (ng/mL) concentration range for five different markers via time-gated detection with a sophisticated spectral crosstalk correction.428 Enzymes are a family of special proteins that are capable of catalysis for lots of metabolic processes. For example, lysozymes are glycoside hydrolases that damage bacterial cell walls. A carbon nanotube-based lysozyme sensing system involving an antilysozyme aptamer and a luminescent Eu(III) chelate 69 was reported.429 In this system, the Eu(III) luminescence was quenched due to the adsorption of the Eu(III) chelate into the noncovalent assembly of the carbon nanotube and the aptamer. Addition of lysozyme dispersed the assembly because of the much stronger aptamer-lysozyme interaction, resulting in luminescence enhancement. In Tris-HCl buffer, addition of 10 μM lysozyme led to enhancement of the Eu(III) luminescence at 612 nm by about 735 fold. However, when the lysozyme sensing was performed in 1640 cell growth media, intense background fluorescence reduced the sensitivity to 6%. The high sensitivity was recovered to about 78% by using TGL with a delay time of 50 μs. Protein probes can also be designed based on the catalyst activity of enzymes. Lanthanide chelates containing active sites in their sensitizing antenna have been designed. Enzyme catalyzes the specific modification of the antenna at the active site, which alters the sensitization efficiency, thus leading to luminescence response of the lanthanide ions. Parker and co-workers designed an artificial substrate peptide (SAStide) for specific detection of the spleen tyrosine kinase (Syk).430 SAStide can be phosphorylated yielding pSAStide. Both SAStide and pSAStide can coordinate with Tb3+. Interestingly, the Tb(III)-pSAStide chelate 70 displayed a more intense luminescence with a longer lifetime compared to the Tb(III)-SAStide chelate 70 due to reduced inner-sphere hydration number of the Tb(III) center upon phosphorylation of SAStide. Additionally, the optimal excitation wavelength was 266 and 275 nm for pSAStide and SAStide, respectively. Upon excitation at 266 nm, the prompt spectra showed that the luminescence ratio of pSAStide over SAStide was 2:1, which was increased to 32:1 in the time-gated spectra with a delay time of 50 μs. The sharp ratio difference gave the possibility of quantitative detection of Syk activity via TGL measurements. Moreover, the utilization of Tb(III)-SAStide to detect Syk activity in vitro was performed using enhanced green fluorescent protein (EGFP)-conjugated Syk which was immunoprecipitated from engineered DT40 chicken B-cells. The TGL of the Tb(III) was directly associated with the enzymatic phosphorylation degree. Furthermore, owing to the high sensitivity of the TGL of Tb(III)-SAStide to the catalyst activity

of Syk, the probe was used for inhibitor screening. Addition of a Syk inhibitor piceatannol led to luminescence quenching of the probe. With the same strategy, a probe 71 was also designed to detect anaplastic lymphoma kinase (ALK) activity.431 Proteases begin protein catabolism by hydrolysis of the peptide bonds. Kikuchi and co-workers synthesized Tb(III)peptide (Suc-LY) conjugate 72 which displayed weak luminescence.432 Addition of calpains resulted in the cleavage of the specific Suc-LY residue leading to luminescence enhancement. TGL measurements remarkably increased the signal-to-noise ratio of the detection. The nucleic acid sensing system 63 has also been used for detecting trypsin, which is a protease that can cleave on the C-terminal side of arginine and lysine residues.416 The commercially available luminescent Tb(III) chelate 64, and fluorescent AlexaFluor 647 were immobilized on the surface of QDs by two peptide linkers. Upon photoexcitation of the chelate, the excited state of AlexaFluor 647 was slowly populated through QD-bridged two-step energy transfer. Since the peptide linking AlexaFluor 647 contained one lysine and two arginine, while that linking the Tb(III) chelate did not, the presence of trypsin cuts off the second step of the energy transfer. Therefore, the long-lived emission in the TGL showed ratiometric response to trypsin. The detection limit was estimated to be 200 nM. In a related work, the Tb(III)-QDs-AlexaFluor 647 system (73) was used for multiplexed tracking of protease activity.433 The activity of two proteases that catalyze cleave the peptide linking Tb(III) and AlexaFluor 647, respectively, remarkably affected the Tb(III)-to QDs and QDs-to-AlexaFluor 647 FRET processes, enabling multiplexed time-gated detection. In another study, a series of lanthanide chelates (74−83) which displayed weak luminescence were designed for detection of enzymatic activity.434 Addition of different analytes cleaved the specific caging group through hydrolysis, resulting in enhancement of the luminescence (Figure 16). For example, an over 50-

Figure 16. Sensing mechanism of chelate 74−83 toward enzymatic activity. Reprinted with permission from ref 434. Copyright 2015 John Wiley & Sons.

fold increase in the emission was recorded via TGL measurement for the β-Gal probe 78. Additionally, the Ln-based probes can be combined with an organic-based fluorophore that owned little overlap of absorption and emission wavelengths with the probes to achieve three-color analyte detection. 4.1.2.5.4. Lanthanides in Biotin−Avidin Sensing System. Many protein probes have been designed based on specific protein−substrate interactions. The noncovalent binding of biotin to avidin is the strongest protein−substrate interaction with a first dissociation constant Kd of about 10−15 M.435 A timeresolved FRET system involving biotinylated NaYF4:Ce/Tb nanocrystals (84)436 to detect FITC labeled avidin was developed. Upon avidin−biotin binding, energy transfer from the nanocrystals to fluorescein apparently elongated the U


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nm (ca. 261 μs). The detection has been demonstrated in lysed blood and urine, which generated high absorbance and high autofluorescence, respectively. NIR excitation and TGL detection avoided the autofluorescence, ensuring the high detection limit. The specificity of biotin−avidin interaction provides the basis for developing assays to detect or quantify analytes. The biotin− avidin system is commonly applied in different bioanalytical technologies such as immunoassays. The antigen (analyte) is recognized by the immobilized antibody. The biotinylated antibody provides the bridging capability to link the antigen and avidin. In a simplest assay design, the avidin is labeled with a reporter, which provides the detectability required to quantify the antigen. Ye, Yuan, and co-workers labeled streptavidin with long-lived luminescent Eu(III) chelate 92 and used these conjugates to detect human prostate specific antigen and image pathogenic microorganism Cryptosporidium muris.450 Chen and co-workers developed Eu(III) doped Lu6O5F8 (93) nanoparticles with ultrasmall particle sizes (100 ns) was recognized from the background signals (600 nm) windows were collected

investigated in more detail using HeLa cells in different phases during a cell cycle. The results showed that the cluster distributed throughout the whole cells in the mitotic (M) phase when nuclear and cytoplasmic division occurs and the cells do not have the nucleolus but exhibited stronger affinity to the nucleoli of the cells in the other phases during cell division cycles. Both TGLM and PLIM imaging revealed that a long emission lifetime was observed from the nucleoli of the cells loaded with cluster 141. 4.2.1.3. Transition-Metal Complexes for Lysosome Staining. Autophagy is a basic lysosomal degradation pathway, involving degradation of unnecessary cytoplasmic macromolecules and damaged organelles, which maintains cellular energy levels and promotes cellular survival during starvation.506−510 Two phosphorescent Ir(III) complexes 142 and 143 were designed to stain lysosomes.511 Complexes 142 and 143 emitted at 600 and 645 nm in aqueous buffer, respectively, and the emission intensity was very sensitive to the pH values of the solvent due to the presence of the protonable indole moiety. Upon reducing the pH value from 8.2 to 3.0, both complexes displayed significant emission enhancement. Additionally, complexes 142 and 143 were two-photon excitable; in buffer solution at pH 5.4, they exhibited two-photon absorption action cross sections of about 73 and 62 GM, respectively, at 810 nm. Both complexes readily entered human lung adenocarcinoma (A549) cells and were well-colocalized with LysoTracker Green, which is a commercially available fluorescent dye that stains lysosomes. PLIM imaging revealed that the average phosphorescence lifetimes of complexes 142 and 143 in cells were about 111 and 140 ns, respectively (Figure 28), which was consistent

Figure 28. PLIM images of A549 cells incubated with (a) complexes 142 and (b) 143 under excitation at 405 nm. Reprinted with permission from ref 511. Copyright 2014 John Wiley & Sons.

with their lifetimes at lysosomal pH. Lysosome staining images without background noise were obtained via TGLM and twophoton imaging experiments, in which either the autofluorescence was filtered off or the fluorescent biomolecules were unexcitable. Additionally, transmission electron microscopy (TEM) images showing the cellular ultrastructure and morphology indicated that both complexes induced autophagy in A549 cells. Although autophagy and apoptosis are extensively interconnected, investigation using Annexin V as the apoptotic marker showed that the complexes did not cause apoptosis. 4.2.1.4. Transition-Metal Complexes for Mitochondrion Staining. Cationic and lipophilic mitochondrial penetrating peptides are a family of synthetic peptides that undergo efficient cellular uptake and specifically accumulate in mitochondria. The incorporation of a mitochondrial penetrating peptide into luminescent compounds brings about strong affinity of these compounds to mitochondria. For example, a luminescent AD


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Chart 10. Transition-Metal Complexes (145−153) for Metal Ion Sensing

which emits at 590 nm with a lifetime of 2.1 ns. Since the red phosphorescence of complex 148 at 635 nm was embedded into the intense fluorescence band of rhodamine B, addition of Hg2+ to the mixture only caused a slight decrease in intensity at 635 nm of the total emission. The decrease factor was increased to 2.8 fold when the spectra were recorded after a 99 ns-delay, during which the fluorescence from rhodamine decayed to a negligible level. Three phosphorescent probes 149−152 have been designed to sense Hg2+ based on Hg2+-promoted desulfation and intramolecular cyclic guanylation of the thiourea reaction.517−519 In the absence of Hg2+, the complexes displayed weak emission. Addition of Hg2+ allowed interaction with the thiourea group and induced desulfation followed by intramolecular cyclic guanylation (Scheme 6) and caused emission enhancement. The turn-on emission response was selective for Hg2+ and unaffected in the pH range of 4−10, demonstrating the potential of the complexes for Hg2+ detection in biological samples, where the pH values were mainly about 5.25−8.93. Before intracellular application, the detection of Hg2+ was performed in the presence of rhodamine 6G, which acted as a typical signal interference. The prompt emission titration showed that addition of Hg2+ did not induce considerable changes in the emission spectra, indicating the strong interference of background fluorescence to the Hg2+ sensing. In contrast, the time-gated spectra acquired after a delay time efficiently removed most of the background noise generated by rhodamine 6G, and an obvious enhancement of the emission was observed upon addition of Hg2+. An optimal SNR was obtained for complex 150 when a delay time was set to be 1.2 μs.518 Live human hepatoma (SMMC-7721) cells were used as a model to demonstrate the detection of intracellular Hg2+ using complexes. Confocal luminescence microscopy images showed that cells treated with complexes exhibited a weak cytoplasmic emission, the intensity of which was significantly increased upon

Scheme 5. Sensing Mechanism of Complex 147

separately. Cu2+ treatment of the complex-loaded fixed cells selectively quenched the emission from the red window. 4.2.2.1.3. Transition-Metal Complexes for Hg2+ Sensing. The design of transition-metal-complex-based mercury(II) sensor is mainly relied on the strong Hg−S interaction. A cationic Ir(III) complex 148 containing a sulfur atom in each cyclometalating ligand exhibited red phosphorescence at 635 nm, which was selectively quenched upon Hg2+ binding through Hg−S interaction.516 This complex formed a dual-emissive system upon electrostatic attraction with blue-fluorescent poly(4,4′-(2-phenyl-9H-fluorene-9,9-diyl)dibutane-1-sulfonate sodium) (PFB-SO3Na), which is an anionic conjugated polyelectrolyte. As the blue fluorescence was independent of Hg2+, the hybrid system responded to Hg2+ in a ratiometric manner; the emission intensity ratio of I425 nm/I635 nm was changed from 0.29 to 2.57 upon interaction with Hg2+. To demonstrate the resistance of the long-lived-phosphorescence sensing toward short-lived background noise, the Hg2+ sensing was performed in the presence of rhodamine B (Figure 29), AE


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Figure 29. PL spectra of complex 148 in the presence of PFB and rhodamine B upon addition of Hg2+ in (a) prompt and (b) TGL spectra under excitation at 380 nm with at delay time of 99 ns. Time-resolved emission spectra of complex 148 containing PFB and rhodamine B (c) before and (d) after addition of Hg2+ under excitation at 380 nm. Reprinted with permission from ref 516. Copyright 2013 John Wiley & Sons.

upon chemical transformation from the thiourea unit to the imidazoline moiety. The Hg2+-induced red-shift of the emission maximum allowed wavelength-ratiometric intracellular sensing. 4.2.2.1.4. Transition-Metal Complexes for Cr3+ Sensing. The chromium(III) ion is required in trace amounts for carbohydrate and lipid metabolism in mammals. It has also been demonstrated that Cr3+ facilitates regulation of insulin action.521−523 However, in large amounts or on different oxidation states [such as Cr(V) and Cr(VI)],524−526 chromium is highly toxic and carcinogenic. The first phosphorescent probe 153 for Cr3+ was designed by incorporation of a sulfur-rich Cr 3+ receptor, bis(2-(2(methylthio)ethylthio)ethyl)amino (BTTA), into the diimine ligand of a cyclometalated Ir(III) complex.527 In the absence of Cr3+, complex 153 displayed weak green emission at 515 nm in acetonitrile, which was assigned to the intraligand excited state. Addition of Cr3+ to the complex 153 immediately tuned the emission color to orange (557 nm) with an 8-fold emission enhancement, which has been attributed to the elimination of the PET process (Scheme 7) from the tertiary amine of BTTA to the excited complex core and the enhanced MLCT character in the emissive state. Subsequent addition of a strong metal chelator, N,N,N′,N′-tetrakis(2-picolyl)ethylenediamine (TPEN), led to a

Scheme 6. Sensing Mechanism of Complexes (149−152)

incubation of the cells with Hg2+. Interestingly, when the thiourea substituent of Ir(III) complex 149 on the 5-position of phenanthroline was changed to the 4-position, the resultant complex 151 displayed a different luminescence response to Hg2+.520 In the absence of Hg2+, complex 151 showed a broad emission with a maximum peak at about 560 nm, while addition of Hg2+ tuned the emission wavelength to 620 nm. This was ascribed to the modulation of the intramolecular charge-transfer Scheme 7. Sensing Mechanism of Complex 153

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Chart 11. Transition-Metal Complexes (154−156) for Anion Sensing

constant of about 9.17 × 104 M−1.546 Since the binding of the electron-rich F− perturbed the pπ−π* conjugation through the empty 2p-orbital of the boron atoms, the emission color of complex 154 changed from bluish-green (512 nm) to orange (567 nm) upon addition of two equivalents of F−. In the meantime, the emission lifetime was elongated from 0.56 to 1.2 μs, which was sufficiently long for elimination of background emissions via TGL acquisition. The F− sensing was also performed in the presence of FITC, which produced green background fluorescence. The sensitivity of the sensing was increased by 4.3 fold via TGL acquisition with a delay time of 100 ns. Additionally, complex 154 was doped into poly(methyl methacrylate) polymer to demonstrate the detection of F− in aqueous solution. An Ir(III) complex 155 containing a formamide group exhibited intense luminescence with long lifetime in the microsecond scale in organic solvents, but the luminescence was significantly quenched by F− which induced deprotonation of the complex at the nitrogen atom of the formamide.547 Further addition of water recovered the long-lived luminescence of complex 155 due to reprotonation, which allowed detection of trace amounts of water in organic solvents. The long luminescence lifetime of complex 155 favored the water detection in the presence of fluorescent compounds via the TGL technique. An Ir(III) complex containing tert-butyldiphenylsilyl groups as F− responsive units was incorporated into conjugated polyelectrolytes, affording a biocompatible ratiometric sensor (156) for intracellular F−.548 While the blue emission of the polymer backbone was insensitive toward F−, the butyldiphenylsilyl groups was released in the presence of F−, leading to PET-induced quenching of the orange luminescence of the Ir(III) complex. The ratiometric luminescence response was also observed upon incubation of the 156-loaded living HeLa cells with F−. Additionally, the average luminescence lifetime inside the cells was determined via PLIM. The lifetime value dropped from about 36 ns in the absence of F− to about 6.8 ns when 20 μM F− was added to the cell culture medium. 4.2.2.3. Transition-Metal Complexes for Reactive Oxygen Species Sensing. An aldoxime group readily reacted with ClO−, affording a carboxyl analogue. Luminescent probes equipped with an aldoxime group usually show emission enhancement upon reaction with ClO− due to elimination of the cis−trans isomerization of the aldoxime group.549,550 Compared to intensity-based sensors, ratiometric probes are more useful in intracellular detection since they are self-calibrating and have high accuracy and precision. Core−shell structured silica nanoparticles containing two Ir(III) complexes 15 and 157 (see Chart 12) were prepared as ratiometric phosphorescent probes for ClO−.551 The blue phosphorescence of complex 15 immobilized in the core of the nanoparticles was insensitive

reverse response and restoration of the original weak green phosphorescence, demonstrating the high reversibility of the ratiometric detection of Cr3+. Additionally, in the lifetime analysis, the Cr3+-free complex showed a biexponential decay with the lifetimes of 40 ns and 1.7 μs. The faster component was probably due to the emission quenching via the PET process, which was inhibited upon binding of Cr3+. As a result, the Cr3+bound complex only exhibited a monoexponential decay with the lifetime of 1.5 μs. Interestingly, the Cr3+-bound complex displayed a second stage ratiometric phosphorescence response. The emission color of the Cr3+-bound complex in airequilibrated acetonitrile solution changed from orange to green slowly but completely. However, the color conversion did not occur in a deaerated solution, indicating that the emission color change in the aerated solution was due to oxidative cleavage of the [Cr(BTTA)] moiety by oxygen (Scheme 7). 4.2.2.2. Transition-Metal Complexes for Anion Sensing. Halogen elements including fluorine, chlorine, bromine, and iodine play important roles in biological systems and are present in all organisms. F− is found in ivory, bones, teeth, blood, urine, and hair of organisms.528−531 It has been used as a potential therapy reagent for dental care and osteoporosis since F− can directly stimulate bone formation and increase bone mass.532 However, overexposure to F− causes health hazards such as bone disease and inhibition of the immune system. The design of probes for F− is mainly based on strategies involving F···H hydrogen-bonding formation531−538 and triarylboron−fluoride interactions.539−544 Probes readily forming F···H bonds usually show low selectivity since they may also produce positive signals in response to other bases such as H2PO4− and CH3COO−. Those containing triarylboron units display much more specific response to F− owing to the high Lewis acidity and electronaccepting ability of triarylborons.545 Particularly, sterically hindered dimesitylboryl and tridurylboryl moieties provide additional size-selectivity toward F−. For example, a cyclometalated Ir(III) complex 154 (see Chart 11) that contained two dimesitylboryl units bound F− (Scheme 8) with a binding Scheme 8. Sensing Mechanism of Complex 154

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enables the ratiometric detection of H2S. The nanohybrid had a long luminescence lifetime and displayed a significant change in luminescence lifetime in response to H2S. PLIM imaging indicated that the luminescence lifetime was decreased from 414 to 366 ns upon addition of NaHS. 4.2.2.4.2. Transition-Metal Complexes for Biothiol Sensing. Design of luminescent probes for thiols has relied on several strategies, one of which is based on the Michael addition reaction between a thiol group and an α,β-unsaturated carbonyl group. An Ir(III) complex 160 containing a maleimide unit underwent Michael addition with a thiol group, accompanied by a 60-fold emission enhancement.554 This complex was used as a probe for thiol-containing biomolecules including Cys, Hcy, and glutathione (GSH). Interestingly, Cys-containing lysozyme or BSA did not trigger similar luminescence response because the thiol groups participate in disulfide bonds. However, a 30-fold emission enhancement was observed when BSA was added to complex 160 at 60 °C, which induced more conformations of BSA. Despite the significant and specific luminescence response of complex 160 to thiols, the thiol detection in Dulbecco’s modified Eagle’s medium (DMEM) suffered from the strong autofluorescence. Owing to the long phosphorescence lifetime of thiol-modified complex 160 (about 99.2 ns), time-gated photoluminescence titration with a detection window of 60− 150 ns increased the sensitivity of the thiol detection by about 10fold since unwanted short-lived luminescence signals were not collected for analysis. An Ir(III) complex 161 containing two α,βunsaturated ketone groups exhibited selective phosphorescence response to Cys over Hcy, GSH, and other amino acids.555 The long phosphorescence lifetime allowed detection of Cys in the presence of highly fluorescent rhodamine B via TGL titration with a delay time of 100 ns. Additionally, complex 161 was twophoton excitable at 800 nm, which allows deeper penetration, weaker autofluorescence, less photobleaching, and lower phototoxicity than the UV and visible light excitation. The detection of intracellular Cys was performed via two-photon imaging, TGLM, and PLIM. Additionally, complex 161 was adsorbed into blueemissive FIrpic (30)-doped core−shell Si NPs, yielding a ratiometric probe for Cys. Two cationic Ir(III) complexes 162 and 163 containing two α,β-unsaturated carbonyl groups in the diimine ligand displayed luminescence turn-on in the orange-yellow in the presence of Cys.556,557 The use of complex 162 to image intracellular biothiols has been demonstrated via confocal luminescence imaging and lifetime imaging microscopy. By employing a blueemissive anionic Ir(III) complex, an ion-paired complex 164 was developed as a ratiometric sensor for thiols.556 Addition of Cys to the complex solution turned on the orange-yellow luminescence

Chart 12. Transition-Metal Complex 157 for Hypochlorous Acid Sensing

toward ClO−, and thus served as an internal standard in the detection. Complex 157 was weakly emissive in the absence of ClO− but emitted intense red phosphorescence in the presence of ClO−. Therefore, the nanoparticles displayed a sharp phosphorescence color change from blue to red upon exposure to ClO−. In the intracellular application, live RAW 264.7 cells incubated with the nanoparticles only exhibited blue emission, and the red emission was hardly observed until further incubation of the cells with ClO−. In contrast to the intensity of the red emission (Ired), which was also sensitive toward intracellular concentration of the nanoparticles and excitation laser power used for luminescence cell imaging, the intensity ratio (Ired/Iblue) was strongly resistant against these external influences. Additionally, the luminescence lifetime response of the nanoparticles toward intracellular ClO− was investigated via PLIM (Figure 30). RAW 264.7 cells treated with the nanoparticles showed an average luminescence lifetime of about 31 ns. Addition of ClO− to the incubation medium elongated this value to about 91 ns. When the cells were stimulated with LPS/PMA to generate endogenous ClO−, cells loaded with the nanoparticles displayed a longer lifetime of about 116 ns, indicative of a higher degree of reaction between the nanoparticles and endogenous ClO−. 4.2.2.4. Transition-Metal Complexes for Reactive Sulfur Species Sensing. 4.2.2.4.1. Transition-Metal Complexes for Hydrogen Sulfide Sensing. H2S can readily undergo the nucleophilic addition reaction with merocyanine derivatives, resulting in the absorption hypochromism and emission quenching due to disruption of the conjugated system.552 A nanohybrid based on mesoporous silica nanoparticles was designed for the detection of H2S.553 Fluorescent merocyanine derivative 158 (see Chart 13) and phosphorescent Ir(III) complex 159 were embedded into the nanohybrid. It exhibited a unique dual emission that was ascribed to complex 159 and fluorescent dye 158, respectively. Upon addition of NaHS, the emission from fluorescent dye 158 was quenched, while the emission from complex 159 was almost unchanged, which

Figure 30. PLIM images of RAW 264.7 cells treated with (a) SiO2-15@mSiO2-157, followed by stimulation with (b) HClO, and cells pretreated with LPS and PMA, and incubated with (c) SiO2-15@mSiO2-157 under excitation at 405 nm. Scale bar: 5 μm. Reprinted with permission from ref 551. Copyright 2015 Royal Society of Chemistry. AH


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Chart 13. Transition-Metal Complex (158−170) for Reactive Sulfur Species Sensing

of the cationic core but did not affect the blue luminescence of the anionic one. Living HeLa cells treated with the ion-paired complex 164 exhibited both blue and yellow luminescence because of the fast reaction of the complex with intracellular biothiols. When the cells were pretreated with N-ethylmaleimide, which is a thiol-consuming reagent, only blue luminescence was observed, because the cationic complex core was almost nonemissive before reacting with biothoils. In an alternative strategy, a luminophore was linked to a quencher via a sulfonyl group. The cleavage of sulfonyl linkage led to separation of the luminophore from the quencher, resulting in luminescence turn-on response. An Ir(III) complex 165 was modified with a DNBS unit, which is a strong electronacceptor and quenched the phosphorescence of complex 165 (Scheme 9).558 Reaction with Cys and Hcy cleaved the linkage between the complex core and the DNBS unit, generating the alcohol analog 165′ and switching on the long-lived phosphorescence. A less sensitive response of complex 165 to GSH was observed and ascribed to the bulkiness of the oligopeptide. Complex 165 was used to detect Cys in the presence of a strongly emissive BODIPY derivative via TGL measurement owing to the


much longer emission lifetime of complex 165′ (191.7 ns) compared to that of the BODIPY dye. A ruthenium(II) complex 166 containing DNBS units was also developed and modified with morpholine for visualization of biothiols in the lysosomes.559 This complex was almost nonemissive, but the luminescence was turned on upon addition of Cys, Hcy, or GSH. The TGL sensing maintained high sensitivity and selectivity even in the presence of highly fluorescent rhodamine B and human serum. HeLa cells incubated with complex 166 showed substantial lysosome staining owing to the affinity of morpholine to the organelle. The emission was hardly observable when the cells were pretreated with N-ethylmaleimide, indicating that the AI


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Chart 14. Transition-Metal Complex (171−179) for Biomolecules Sensing

intense luminescence of the 166-loaded cells resulted from the reaction products of 166 with intracellular biothiols. An arylic aldehyde group readily reacted with Cys and Hcy to form cyclic thiazolidine and thiazinane, respectively. Ir(III) complexes 167−169 containing two aldehyde groups displayed considerable phosphorescence changes upon reaction with Cys/ Hys due to the alteration in the excited state character.560 A water-soluble polymer 170 containing Ir(III) complex as the responsive unit and poly(N-isopropylacrylamide) (PNIPAM) as the backbone exhibited emission enhancement at 564 nm in the presence of Cys/Hcy.561 A hydrogel was prepared as a quasisolid sensor for Cys/Hcy using the cross-linked polymer 170. Exposure of the hydrogel to Cys/Hcy led to remarkable phosphorescence enhancement. Since the emission lifetime of polymer 170 was sufficiently long (366 ns), TGL measurements allowed the detection of Hcy without interference from shortlived background fluorescence even in the presence of fluorescein. The response of polymer 170 to intracellular thiols was studied using live KB cells. Upon internalization, polymer

170 accumulated in the cytoplasm of the cells and displayed intense phosphorescence, which became very dim when the cells were pretreated with N-ethylmaleimide. Additionally, when the cells were stimulated with L-buthionine sulfoximine and H2O2, which inhibited the production and accelerated the consumption of GSH, respectively, the intracellular phosphorescence was not affected. When N-acetylcysteine was used as an exogenous source of Cys, the phosphorescence became brighter. These results indicated that the phosphorescence should result from the reaction between polymer 170 and intracellular Cys. 4.2.2.5. Transition-Metal Complexes for Biomolecule Sensing. 4.2.2.5.1. Transition-Metal Complexes for Polysaccharide Sensing. Heparin is a highly sulfated linear acidic polysaccharide that is widely used as a natural anticoagulant in clinical applications. Its very high negative-charge density allows electrostatic attraction with polycations.562,563 Cationic conjugated polyelectrolytes 118 and 171 (see Chart 14) containing the polyfluorene and Ir(III) complex units were prepared for the detection of heparin.489,564 These polyelectrolytes showed AJ


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Figure 31. PLIM images of 172 in the presence of heparin with different concentrations under excitation at 405 nm. Reprinted with permission from ref 565. Copyright 2015 Wiley-VCH.

Figure 32. Sensing mechanism of binary probes 175 and Cy5. Binding to the same target DNA molecule induces spin-forbidden energy transfer from 175 to Cy5.

intense blue emission from polyfluorene units and weak red phosphorescence from the Ir(III) complex. Upon addition of heparin, the electrostatic interaction between heparin and these polyelectrolytes favored energy transfer from the polyfluorene units to the complex, resulting in ratiometric luminescence response. Owing to the long phosphorescence lifetime of the Ir(III) complex, the detection of heparin was demonstrated in the presence of rhodamine B via TGL technique. The heparin sensing studies were extended to a series of phosphorescent polyelectrolytes (172−174).565 The lifetime response of polyelectrolyte 172 to heparin was investigated via lifetime measurements and imaging. Results showed that the luminescence lifetime of 172 was increased from 1.7 to 2.7 μs upon addition of heparin (Figure 31). Additionally, cell imaging showed that 172 specifically stained the cell membrane. 4.2.2.5.2. Transition-Metal Complexes for DNA Sensing. DNA is the carrier of genetic information in all organisms and many viruses. In cells, most DNA is stored in the cell nucleus and dominates a variety of intracellular functions, such as RNA transcription and protein expression. Many DNA probes have been designed based on specific hybridization. For example, a DNA sensing system involving binary probes was constructed.566 Two oligonucleotides were labeled with a long-lived phosphorescent Ru(II) complex 175 (τ = 1.8 μs) and a short-lived fluorescent dye Cy5, respectively (Figure 32). In the absence of the target DNA strand, excitation of complex 175 resulted in intense emission only from complex 175, but when the probes hybridized to the target DNA strand, complex 175 and Cy5 were brought into close proximity, facilitating the energy transfer from complex 175 to Cy5, thus increasing the emission from Cy5. Although the emission of Cy5 was fluorescence in nature, the spin-forbidden energy transfer significantly extended the emission lifetime of Cy5. Therefore, the presence of the target DNA strand can be detected via TGL measurements to enhance the sensitivity especially in a complicated biological environment.

Molecular beacons (MBs) have been widely used in DNA sensing. A MB is an oligonucleotide strand with a sequence that is not only complementary to a target sequence of interest but also self-complementary at both ends. In a typical DNA sensing process, a MB is labeled with a luminescent dye and an energy acceptor (quencher) at different ends of the strand. In the absence of the target sequence, the strand was self-hybridized to form a hairpin structure, resulting in quenching of the dye emission due to close proximity to the quencher. Specific binding to the target sequence disrupts the hairpin structure, leading to a physical separation between the dye and the quencher, thus increasing the dye emission. Huang and Marti ́ performed detail investigation on the sensitivity of luminescent MBs in DNA sensing using time-resolved spectroscopy.567 Four MBs were prepared using phosphorescent Ir(III) and Ru(II) complexes (176 and 177) as the long-lived luminescent dyes and black hole quencher 2 (BHQ2) and Cy5 as the energy acceptors. Taking the Ir(III)-BHQ2MB as an example, prompt emission spectra showed that addition of the target sequence led to an emission enhancement of 8.2 fold. When the spectra were recorded in a time-gating from 60 to 140 ns, the emission enhancement factor was increased to 17.2, and the detection limit was reduced from 30 to 13.6 nM. Additionally, when the DNA detection was performed in a fluorescent environment containing rhodamine B, only a 1.35-fold increase of the Ir(III) emission was observed in the presence of target sequence. Time-gated spectra recorded in the optimum time window from 50 to 80 ns showed significantly improved sensitivity; the emission intensity was enhanced by 7.1 fold upon addition of the target sequence. 4.2.2.5.3. Transition-Metal Complexes for RNA Sensing. Similar to hybridization-based DNA sensing, the design of luminescent RNA sensors is usually based on the specific complementary hybridization of base pairs. Luminescent metal nanoshells which were composed of a silica core with encapsulated [Ru(bpy)3]2+ (122) and a silver shell were prepared.568 The surface of the nanoshells was covalently AK


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Chart 15. Transition-Metal Complex for Temperature Sensing (180−182), Polarity Sensing (183−193) and pH Values Sensing (194)

show substantial staining of nucleoli, which is a dense region of RNA in the cells. 4.2.2.5.4. Transition-Metal Complexes for Protein Sensing. Transition-metal complexes have been used to design protein probes because of their nonspecific hydrophobic−hydrophobic interaction with proteins and environmentally sensitive photophysical properties. A luminescent dipyridophenazine Ru(II) complex is nonemissive in aqueous solution but emits strongly in a hydrophobic environment.571 Marti ́ and co-workers used this complex to track the aggregation of amyloid-β (Aβ) peptides. In the presence of monomeric Aβ, complex 179 was nonemissive due to the poor interaction between the complex and the monomer. Upon protein aggregation, the emission of complex 179 increased by 50 fold due to the increase of rigidity of the surrounding environment of the complex. With rhodamine B present during the detection, the emission enhancement factor was increased from 1.4 to 12.0 by applying the data acquiring window at 350−700 ns. 4.2.2.6. Transition-Metal Complexes for Microenvironment Sensing. 4.2.2.6.1. Transition-Metal Complexes for Temperature Sensing. Transition-metal complexes usually display luminescence quenching upon increasing temperature because of thermally activated nonradiative process, but the sensitivity is lower compared to lanthanides due to their relatively short excited state lifetimes. Many organic polymers exhibit thermosensitive conformational change between swollen and shrunken states. Since the photophysical properties of transitionmetal complexes are highly sensitive to their microenvironment,

modified with single-stranded oligonucleotides to hybridize with target miRNA-486 molecules in the cells. PLIM cell imaging was performed using H460, H1944, MDA-MB-231, and A549 cells. Owing to the intense emission with long lifetime, the emission of the nanoshells was isolated distinctly from the cellular autofluorescence in the PLIM images. It was demonstrated that the long-lived emission spots in the images were closely related to the expression level of miRNA-486 in different cell lines. Additionally, in control experiments where the capsulated phosphorescent Ru(II) complex (122) was replaced by shortlived fluorescent Cy3, the signals from the nanoparticles were hardly distinguished from the autofluorescence. Ethidium bromide is commonly used to detect nucleic acids owing to its turn-on fluorescence upon intercalation into base pairs of DNA or self-complementary RNA.569 The fluorescence enhancement has been ascribed to the protection of the ethidium cation from interaction with solvent molecules by the nucleic acids strands. A Ru(II) complex-ethidium conjugate 178 was designed as a RNA probe, in which spin-forbidden resonance energy transfer from Ru(II) to the ethidium derivative quenched the Ru(II) phosphorescence and remarkably elongated the fluorescence lifetime of the acceptor in the presence of nucleic acids.570 The utilization of this conjugate to detect RNA was performed in cell growth medium. The RNA-induced enhancement of the ethidium emission was amplified using the timegated method with a delay time of 20 ns. Additionally, mammalian breast cancer cells incubated with this conjugate AL


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Figure 33. PLIM images of live, apoptotic, and dead HepG2 cells incubated with complex 186 under excitation at 405 nm. Annexin V-FITC and PI were used to identify apoptotic and dead cells, respectively. Reprinted with permission from ref 575. Copyright 2017 The Royal Society of Chemistry.

viscosity, the luminescence lifetime of complex-treated cells was correlated to the intracellular polarity. HepG2, HeLa, A549, and HL-7702 cells incubated with this complex showed substantial mitochondria staining. HepG2 cells exhibited the longest luminescence lifetime, indicative of a most nonpolar intracellular environment. Additionally, this complex was used as a polarity indicator during apoptotic cell death. The cells were treated with Annexin V-FITC and propidium iodide (PI) to identify apoptotic and dead cells, respectively. PLIM images indicated that live cells showed the shortest phosphorescence lifetime while the dead cells exhibited the longest phosphorescence lifetime (Figure 33). 4.2.2.6.3. Transition-Metal Complexes for pH Value Sensing. A luminescent ion pair (194), involving cationic and anionic luminescent Ir(III) complexes that were bonded together via electrostatic attraction, has been developed as a ratiometric pH sensor.576 Upon photoexcitation, the cationic and anionic complexes displayed red and blue luminescence, respectively. Protonation of the pendant pyridine moieties in the cationic complex significantly quenched the red luminescence, whereas blue luminescence of the anionic complex was independent of pH values. As a result, the ion pair exhibited significant luminescence color change in response to pH values. Additionally, as the luminescence lifetime of the cationic complex was much shorter than that of the anionic one, luminescence quenching of the cationic complex remarkably elongated the average luminescence lifetime of the ion pair. The ion pair has been used for quantitative measurements of intracellular pH values via ratiometric luminescence imaging and PLIM. A good colocalization of the red and blue luminescence in HepG2 cells suggested that the cationic and anionic complexes of the ion pair remained associated with each other after cellular internalization. The averaged intracellular pH value of living HepG2 cells was determined to be ca. 6.80. Treatment of the cells with H2O2 increased the pH value to ca. 7.20. 4.2.2.6.4. Transition-Metal Complexes for Hypoxia Sensing. Molecular oxygen (O2) plays a crucial role in many pathological and physiological processes in biological systems. Hypoxia, which refers to an inadequate supply of oxygen, is one of important features of many diseases such as solid tumors, inflammatory diseases, and cardiac ischemia.577−581 For example,

incorporation of these complexes into thermosensitive polymers provides a new design strategy for luminescent thermometers. Two Ir(III) complexes (180 and 181, see Chart 15) have been incorporated into poly N-n-propylacrylamide (PNNPAM), which undergoes a reversible phase transition in the physiological temperature range of humans and most animals.572 Upon increasing temperature from 16 to 36 °C, PNNPAM underwent conformational change from a swollen hydrated state to a shrunken dehydrated state, leading to an increase in the rigidity and a decrease in polarity of the Ir(III) surrounding, giving rise to luminescence enhancement and lifetime elongation. Interestingly, 180 exhibited a sensitivity ca. 3 times higher than 181, owing to their different excited state properties. Thus, incorporation of both complexes into the same PNNPAM polymer afforded a dual-emissive ratiometric phosphorescent thermometer 182. Upon gradually increasing the temperature from 10 to 40 °C, the luminescence ratio I470 nm/I590 nm increased by ca. 18.2 fold and the luminescence color changed from orange through white to cyan. 182 was employed for temperature sensing in living cells via ratiometric luminescence imaging. The luminescence ratio showed good correlation with intracellular temperature (15−35 °C). 4.2.2.6.2. Transition-Metal Complexes for Polarity Sensing. Polarity in biological environment is highly related to many physiological and pathological processes. A variation in cellular polarity may result from a variety of normal cellular events, such as adipogenic differentiation, molecular transport across cell layers, immune response activation, and cell migration and death,573 as well as biological disorders and diseases such as diabetes and liver cirrhosis.574 A series of phosphorescent Ir(III) complexes (183−193) functionalized with one or two icosahedral o-carborane moieties has been designed as polarity probes.575 All the complexes exhibited remarkable solvatochromism; the phosphorescence maximum was red-shifted by up to 42 nm accompanied by lifetime shortening when the solvent changed from less polar toluene to more polar DMSO. The reason has been ascribed to different singlet triplet (S0-T1) dipole moments in solvents of different polarity. The complex (186) exhibiting the most sensitive response toward polarity was selected for intracellular polarity sensing via PLIM. Given that the luminescence intensity and lifetime of the complex was hardly affected by pH values, common metal cations, ROS, or AM


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Chart 16. Transition-Metal Complexes (195−208) for Hypoxia Sensing

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Chart 16. continued

Figure 34. (a) Ratiometric luminescence (Ired/Iblue), (b) PLIM, and (e−j) TGLM images of HepG2 cells incubated with the 15, 195 loaded NP under 18% and 2.5% O2 conditions under excitation at 405 nm. Reprinted with permission from ref 583. Copyright 2015 Wiley-VCH.

the O2 content was reported to be about 4% in many solid tumors.581 Thus, early detection of intracellular hypoxia is important and helpful to disease diagnosis and therapy. Phosphorescent transition-metal complexes are commonly used as O2 sensors because their phosphorescence can be quenched by O2 via energy transfer between the long-lived triplet excited state of the transition-metal complexes and the triplet ground state of O2.582 Phosphorescent transition-metal complexes are capable of monitoring oxygen concentrations in real-

time nondestructively and reversibly. As luminescence intensity is also affected by probe concentration, most luminescence-based detection must rely on ratiometric approaches or measurement of the luminescence lifetime of the probe. Pt(II) and Pd(II) porphyrin complexes, as organic triplet state emitters are the most commonly used probes for detection of O2 due to their high sensitivity. To achieve intracellular O2 sensing, water-soluble porphyrin complexes are required. One method is to dope porphyrin complexes into silica nanoparticles. A AO


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TGLM. Additionally, the polyelectrolyte 197 was used for luminescence imaging of tumor hypoxia in nude mice. The luminescence intensity of the polyelectrolyte 197 rapidly increased after injection into the tumor. A higher SNR compared to normal nude mouse was obtained. Similarly, a class of copolymers (197 and 198) that consists of a substituted conjugated polymer [polyfluorene or poly(fluorene-alt-benzothiadiazole)] and a covalently bound Pt(II) porphyrin complex were designed and prepared.588 When the copolymers 197 form nanoparticles in aqueous solution, they showed brighter phosphorescence from Pt(II) complex units and increased the two-photon cross section compared to the reported MM2 probes. Additionally, the cell staining ability of these nanoparticles could be tuned with positively and negatively charged groups grafted to the backbone. The “zwitter-ionic” nanoparticles showed high staining efficiency of live cells and spheroid cell models and can be used for quantitative detection of O2 via PLIM. When the nanoparticles containing copolymers 198 were injected into the bloodstream of Balb/c mice, emission signals of the nanoparticles were detectable down to 70−100 μm depth and used for detection of tissue deoxygenation. Vinogradov and co-workers developed two Pd(II) porphyrin complexes, 199 and 200, for detection of O2.589 Both complexes were modified with PEG units dendritically and soluble in aqueous environments and stable under physiological conditions (pH 6.4−7.8, 22−38 °C). Complex 200 was used to image intravascular and interstitial oxygenation in murine tumors in vivo. PLIM imaging revealed that complex 200 was mainly localized in the blood plasma upon injection via the tail vein, and the partial O2 values (pO2) of the hypoxic tumor area reached 10 mmHg and lower. Interestingly, when complex 200 was injected locally into the nearby muscle of a tumor, the oxygen levels underwent marked alterations over time, with values well below normal. Such fluctuations were usually not observed in normal muscle but may be a response of muscle tissues near tumors to hypoxia. In another study, a Pt(II) porphyrin complex 201 with coumarin-343 fragments as two-photon excitation antenna was designed and synthesized for in vivo brain imaging.590 The pO2 inside the microvasculature of a mouse brain were determined based on two-photon lifetime imaging.591 Approximately 100 pO2 values were analyzed. From the pial arteriole to the capillary, the pO2 values varied from about 60 to 30 mmHg at a depth of 240 μm below the cortical surface. The utilization of complex 201 to investigate the hypoxia process was demonstrated. The complex was injected into the interstitial space, and the hypoxia was triggered by 30 s respiratory arrest. The temporal pO2 value at 100 μm depth was rapidly decreased in all measured locations, indicative of hypoxia. Additionally, complex 201 was used to characterize the pO2 in cortical arterioles before and after occlusion, which was induced by photothrombotic clotting of the entire lumen in the surface segment of the vessel.592 Upon occlusion, the pO2 showed a precipitous decrease in the surface segment of the descending arteriole. Recently, the same complex was applied for measurement of local O2 concentration in bone marrow in live mice via two-photon PLIM.593 The absolute pO2 of the bone marrow was determined to be below 32 mmHg despite very high vascular density. Phosphorescent Ir(III) complexes show long emission lifetime in the scale of hundreds of nanoseconds to microseconds. They are also capable of being transported across the cell membrane and used for intracellular O2 sensing. A water-soluble Ir(III) complex 202 emitting at 489 nm was prepared for intracellular O2 mapping.594 HepG2 cells treated with complex 202 showed

hybridized core−shell structured NP-based system containing an Ir(III) complex 15 and a Pt(II) complex 195 (see Chart 16) immobilized in the inner solid core and surface porous shell, respectively, was used for ratiometric sensing of O2.583 Ir(III) complex 15 exhibited blue phosphorescence and was protected by the solid core and outer shell from oxygen quenching, while the porous shell enlarged the contact area between the redemissive Pt(II) complex and O2, which ensured the high efficiency quenching. The intracellular O2 sensing was performed via wavelength-ratiometric imaging, PLIM, and TGLM (Figure 34). With increasing O2 content in the atmosphere for cell culture, the NP-loaded cells displayed reduced intensity and shortened lifetime of the red phosphorescence, but maintained similar character of the blue phosphorescence, and thus the intensity ratio of the red phosphorescence over the blue phosphorescence was reduced and the average lifetime was shortened. TGLM imaging showed that the emission intensity under 2.5% O2 condition was more intense than that under 18% O2 condition. An improvement of SNR was observed at the time range of 1000−2000 ns. Another method to develop water-soluble O2 probes is introduction of porphyrin complexes into hydrogel nanoparticles. Papkovsky and co-workers prepared a Pt(II) complex 196 and embedded the complex in cationic hydrogel nanoparticles giving the probe NanO2.584 When NanO2 was added to the media during the formation of neurospheres, it efficiently stained the neurosphere interior. Imaging of neurosphere oxygenation was performed via PLIM, and the results showed a longer emission lifetime in the core region, indicative of deoxygenation. According to the lifetime imaging, neurospheres with smaller sizes displayed higher average O2 levels in the core. When the neurospheres were treated with antimycin A, increased oxygenation was observed due to the reduced respiration activity of cells. Deoxygenation was observed when glutamate, which was excitotoxic for differentiated neurons, was used. In a more complicated design, poly(9,9-dioctylfluorene) (PFO) was also embedded in the cationic hydrogel nanoparticles containing the Pt(II) complex 196 to construct a FRET system MM2 where PFO acted as an energy donor and two-photon light harvesting antenna.585 Upon excitation at 400 nm, MM2 exhibited two emission bands at 410−450 nm and 600−750 nm which were respectively ascribed to PFO and the Pt(II) complex 196. Since only the Pt(II) phosphorescence was sensitive toward O2, MM2 was used to monitor intracellular O2 via confocal and multiphoton microscopy, PLIM, and ratiometric luminescence imaging. Additionally, the same group prepared a Pt(II)monosaccharide conjugate via click reaction between the Pt(II) porphyrin complex 196 and thiol-modified glucose.586 This conjugate displayed sensitive phosphorescence toward O2 and was applied in high-resolution PLIM imaging of O2 in multicellular spheroids of cancer cells, primary neural cells, and slices of brain tissue. Results showed that intracellular phosphorescence lifetimes changed from 20 μs under airsaturated condition to 57 μs under deoxygenated conditions. Porphyrin complexes can also be covalently linked to conjugated polymers, which are self-assembled into nanostructures in water for O2 detection. Cationic conjugated polyelectrolyte 197 composed of blue-fluorescent polyfluorene (O2 insensitive) and red-phosphorescent Pt(II) complex (O2sensitive) units was prepared.587 Reduction of O2 content gave rise to enhancement of the red phosphorescence with negligible effect on the blue fluorescence. The intracellular O2 sensing was also conducted via wavelength-ratiometric imaging, PLIM, and AP


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cytoplasmic staining. When the cells were cultured under a 4% O2 condition, brighter phosphorescence was observed. PLIM imaging demonstrated that the phosphorescence lifetimes of intracellular complex 202 were 260 and 380 ns when the cells were cultured under 21% and 4% O2, respectively. A dinuclear Ir(III) complex (203) localized in the cytoplasm upon internalization into living HeLa cells.595 PLIM imaging revealed that the phosphorescence lifetimes of the intracellular complex were 402 and 771 ns when the cells were cultured under 21% and 2.5% O2, respectively. An Ir(III)−Gadolinium(III) heterodinuclear complex 204 has been designed and synthesized for dual modal imaging.596 The rigid ligand facilitated high relaxivities for the Gd(III) complex in magnetic resonance imaging, while the triplet excited state of the Ir(III) complex allowed sensitive luminescence imaging of intracellular oxygen. HeLa cells treated with the complex showed diffuse cytoplasmic staining with punctate lysosomal staining. PLIM was demonstrated under twophoton excitation at 760 nm. The lifetime of the lysosomal luminescence was shorter than that of the cytoplasmic luminescence probably due to the different local environments. The average lifetime values were determined to be 435, 520, 586, and 644 ns with relative O2 concentrations of 100%, 50%, 21%, and 0%, respectively. An Ir(III) complex 205 was covalently immobilized on the shell layer of the core−shell structured UCNP NaYF4:Yb/[email protected] The Ir(III) luminescence at ca. 600 nm can be triggered by direct photoexcitation at 450 nm or sensitized by UCNP under excitation at 980 nm. Both the luminescence intensity and lifetime of the Ir(III) complex were very sensitive toward oxygen quenching. The nanoparticles were used to monitor intracellular oxygen levels via PLIM. HeLa cells cultured under ambient conditions exhibited an intracellular luminescence lifetime of ca. 620 ns upon loading of the nanoparticles. When the cells were cultured under 2.5 O2, the intracellular luminescence was elongated to 1350 ns. Additionally, the nanoparticles have been used to visualize the gradient oxygen distribution in living cells. Since most O2 in cells is consumed in mitochondria which are the centers of oxygen metabolism to produce ATP, the detection of intramitochondrial oxygen is of paramount importance and provides key insights into disease progression, cell death, and the influence of therapy on cellular metabolism. Keyes and coworkers prepared a binuclear Ru(II) complex 144 with a bridging mitochondrial directing peptide sequence.512 The luminescence intensity and lifetime of complex 144 were decreased with increasing concentrations of O2. The emission lifetime was determined to be 458 ± 7 and 948 ± 6 ns in aerated and deaerated PBS at 37 °C, respectively. Upon internalization into live HeLa, complex 144 specifically accumulated in the mitochondria. PLIM imaging revealed that the luminescence lifetime of complex 144 within the mitochondria was 525 ± 10 ns. According to the calibration plot at 37 °C, the intracellular concentration of O2 was about 183 μM. Additionally, complex 144 was used to monitor the dynamic change of mitochondrial function. Complex-treated cells were incubated with antimycin A, which can cause an increase in O2 concentration at the mitochondria by inhibition of the O2 consumption. PLIM images revealed that the luminescence lifetime was decreased from 525 to 423 ns after 10 min incubation of the cells with Antimycin A, indicative of increased O2 concentration in the mitochondria (Figure 35). In another study, two Ir(III) complexes (206 and 207) have been designed and synthesized to target the mitochondria and the lysosomes, respectively.598 Both complexes exhibited sensitive luminescence quenching toward

Figure 35. PLIM images under excitation at 405 nm (left) and luminescence lifetime distrution (right) of complex 144 loaded HeLa cells. (a) Complex 144 loaded HeLa cells, and followed incubation with antimycin A for (b) 10 min and (c) 100 min. Reprinted from ref 512. Copyright 2014 American Chemical Society.

oxygen, and thus sensitized intracellular single oxygen, which is the main reactive species that kills cancer cells during PDT. Further investigation revealed that the mitochondrion-targeting complex 206 exhibited a better PDT efficiency compared to the lysosome-targeting complex 207, especially under a hypoxia condition, because the former inhibited mitochondrial respiration, leading to a higher intramitochondrial oxygen content. A ruthenium(II) complex 208 has been used for oxygen monitoring in salivary duct cells via PLIM.599 In aqueous solution, the complex displayed a luminescence lifetime (τo) of ca. 2.08 μs in the absence of oxygen and a Stern−Volmer constant (Ksv) of ca. 7 × 10−4 μM−1 toward oxygen quenching. The cellular in situ calibration was established by perfusion of salivary duct cells with physiological solutions of defied [O2], giving in situ τo and Ksv to be ca. 2.44 μs and 3 × 10−4 μM−1, respectively. Salivary duct cells loaded with the complex displayed an intensity-weighted average luminescence lifetime of 2.24 μs. Addition of dopamine to the cell culture medium increased the lifetime to 2.36 μs due to a higher pericellular oxygen consumption resulted from dopamine-induced increased metabolic activity of salivary glands. Since luminescence signals with different decay rates can be simultaneously analyzed via PLIM, the endogenous autofluorescence of oxidized flavin adenine dinucleotide (FAD) was monitored via PLIM in the nanosecond scale. Addition of dopamine boosted protein binding of FAD and thus shortened the fluorescence lifetime of oxidized FAD. 4.2.2.6.5. Transition-Metal Complexes for Carbon Dioxide Sensing. Carbon dioxide (CO2) is involved in the carbon cycle in biology. It is an important reactant of photosynthesis of carbonhydrate and produced during respiration. An Ir(III) complex 209 with 2-phenylimidazo-[4,5-f ][1,10]phenanthroline was designed as a phosphorescent probe for CO2.600 This complex exhibited intense emission at about 596 nm, which was efficiently quenched in the presence of F− or AQ


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CH3COO− due to the formation of hydrogen bonding between the secondary amino group in imidazole and the inorganic anion (Scheme 10). Interestingly, the phosphorescence was recovered

and only the red phosphorescence exhibited quenching response toward oxygen, thus showing lifetime elongation in the hypoxia conditions. The probe was injected into zebrafish and the luminescence lifetimes were determined to be 133 and 127 ns at 520 ± 20 nm and 600 ± 20 nm, respectively. Interestingly, when the zebrafish was treated with 2,3-butanedione monoxime (BDM), which can trigger cerebral anoxia via abolishing cardiac contractility,602 the lifetime of the red phosphorescence was elongated to 331 ns. Nangaku and co-workers used an Ir(III) complex 210 (see Chart 17) to quantitate intracellular oxygen concentration in


Chart 17. Transition-Metal Complex (210) for TimeResolved Luminescence Imaging in Mice

upon bubbling CO2 gas into the solution probably because the weakly acidic CO2 broke the labile hydrogen-bonding interaction. The detection of CO2 in the presence of strongly fluorescent rhodamine B was also demonstrated via the TGL technique with a delay time of 100 ns. 4.2.3. Transition-Metal for Time-Resolved Photoluminescence Imaging of Tissues and Laboratory Animals. Imaging of tissues is difficult because the increased autofluorescence and scattering compromise the contrast. Time-resolved photoluminescence imaging can efficiently minimize these shortlived noise based on their different decay rates. The luminescent metal nanoshells were composed of a silica core with encapsulated [Ru(bpy)3]2+ (122) and a silver shell.568 The nanoshell-avidin conjugate displayed emission maximum at 608 nm with a lifetime of 40 ns. PLIM imaging demonstrated that the long-lived luminescence of the nanoshell-avidin conjugate was easily recognized from the background noise from the bone tissue specimens even though the tissue was simultaneously stained with other short-lived fluorescent dyes. The biothiol responsive ruthenium(II) complex 166 was used to detect biothiol in living Daphnia magna.558 Upon incubation with complex 166, the esophagus and gut of the Daphnia magna exhibited intense red luminescence. When the Daphnia magna were pretreated with the thiol-consuming reagent, N-ethylmaleimide, the phosphorescence signals were unobservable, indicating that the intense luminescence of 166-treated Daphnia magna resulted from the reaction product of complex 166 with endogenous biothiols. The luminescent polymeric thermometer 182 displayed good ratiometric response toward intracellular temperature.572 However, the ratiometric luminescence imaging failed in temperature mapping in zebrafish because of the interference from intense autofluorescence. By applying a time delay of 500 ns between the excitation and the detection, the TGL was remarkably enhancement upon increasing temperature from 22 to 28 °C. Additionally, the PLIM images showed that the phosphorescence lifetimes at 482 ± 35 nm increased from 321 to 448 ns in response to the same temperature increase. Gold nanoclusters (Au NCs) coated with phosphorescent Ir(III) complex 205 were designed and prepared as probes for hypoxia in zebrafish.601 The luminescence of the Au NCs and complex 205 occurred at about 510 and 590 nm, respectively,

mice.603 The phosphorescence lifetimes of the complex in HK-2 cells in various pO2 of incubating atmosphere were used to construct a calibration curve to convert in vivo phosphorescence lifetimes to oxygen concentration. The stereomicroscopic and luminescence images showed that the complex distributed in the tubular cells of the kidneys 30 min after intravenous administration. The phosphorescence lifetimes in mice kidneys were measured under three hypoxic conditions, acute ischemia, hypoemia, and anemia. Acute renal ischemia was induced by clamping the renal artery, and the phosphorescence lifetime of the complex immediately extended. Once the clamp was removed, the lifetime restituted. When the mice inhaled 15% O2 to induce hypoemia, the phosphorescence lifetime was reversibly elongated. Elongation of the phosphorescence lifetime was also observed in the anemic mice on which phlebotomy was performed. 4.3. Long-Lived Luminescent Organic Compounds for Cell Staining and Time-Resolved Photoluminescence Sensing

Commercially available dialkylcarbocyanine dyes including DiO, DiI, DiD, and DiR that contain two aliphatic carbon chains specifically bind to the phospholipids on the cell membrane. Although these dyes exhibit intense fluorescence upon incorporation into the cell membrane, their short fluorescence lifetimes make it difficult to differentiate from the autofluorescence in the time domain. Maliwal, Gryczynski, and co-workers designed a new membrane staining dye 211 (see Chart 18) by introducing a hexadecyl chain into a long-lived azaoxatriangulenium fluorophore.604 Compound 211 absorbed at 545 nm and emitted at 566 nm with biexponential decay (5.94 ns, 15%; 18.75 ns, 85%) in 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) lipid vesicles. Live breast cancer cell line (4T1) murine breast carcinoma cells incubated with compound 211 showed substantial cell staining in fluorescence intensity imaging. PLIM imaging revealed that the fluorescence lifetime on the cell membrane (15.6 ns) was much longer than that inside the cells (500 ns), the Au NCs were used for the detection of temperature in intracellular environments. In Figure 41, PLIM imaging showed that the luminescence lifetime was decreased with increasing temperature in HeLa cells. The intensity-weighted average lifetime dropped linearly from 970 ns at 14 °C to 670 ns at 43 °C with a resolution of about 0.3 to 0.5 °C. With the calibration curve, the utilization of the Au NCs to measure intracellular temperature distribution was also demonstrated. 4.4.3. Inorganic Nanomaterials for Time-Resolved Photoluminescence Imaging of Tissues, Organs, and Laboratory Animals. When inorganic nanomaterials are used for in vitro and in vivo bioapplications, important factors including particle size, shape, stability, toxicity, and surface functionalization should be considered.56−61 In general, nanoparticles smaller than 100 nm are more readily internalized into

CdSe/ZnS core/shell QDs capped MPA (252) were designed for pH monitoring.639 Upon basification, the deprotonation of MPA on the surface of the QDs resulted in luminescence blueshift with intensity enhancement and lifetime elongation. The response of the QDs to pH values of solutions mimicking the cellular cytoplasm was evaluated via PLIM. Data analysis revealed that the QDs exhibited multiexponential decay. The lifetime components that were associated with the surface states in recombination processes were remarkably elongated upon increasing the pH values. In the intracellular studies, MC3T3-E1 preosteoblast cells incubated with the QDs showed cytoplasmic staining. PLIM imaging showed that the average lifetimes of the QD-loaded cells were 9.04 and 18.30 ns when the cells were incubated at extracellular pH 4.87 and 8.14, respectively (Figure 39). Similar pH-dependent intracellular emission lifetime was

Figure 39. PLIM images of MPA-QDs (252) loaded MC3T3-E1 cells under excitation at 440 nm. Cells were incubated in buffers mimicking the extracellular medium at pH (a) 4.87 and (b) 8.14. The scale bar is 10 μm. Reprinted from ref 639. Copyright 2013 American Chemical Society.

also observed in CHO-K1 cells incubated with the QDs. Cai and co-workers reported ultrasmall Cu-doped gradient alloyed CdZnS QDs (253) with a Cd-rich core and a Zn-rich shell for in vivo luminescence lifetime-based pH sensing.640 QDs 253 exhibited NIR luminescence at about 720 nm in aqueous buffer

Figure 40. (a) PLIM images of microbeads equipped with QDs 253, dispersed in buffers with pH = 6.0 (left) and pH = 7.0 (right) under excitation at 485 nm, scale bar: 100 mm. (b) Photoluminescence lifetime histograms collected from the images. (c) In vivo PLIM experiments of the background of the nude mouse (left) and the 253 injected into adjacent locations with different pH values (green, pH = 6.0; red, pH = 7.0) on the back of the nude mouse (right), respectively (scale bar: 10 mm). Reprinted with permission from ref 640. Copyright 2015 The Royal Society of Chemistry. AX


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and left thoracic lymph node (TLN). PLIM study indicated that the red emission underwent biexponential decay with τ1 of 20− 23 ns and τ2 of 120−142 ns. Fluorescent nanodiamonds (257) containing negatively charged NV centers were prepared and exhibited NIR emission with luminescence lifetime longer than 15 ns.644 The low-energy emission allowed deeper tissue penetration, and the lifetime is substantially longer than that of the endogenous and exogenous fluorophores commonly used in cell biology. Lung stem cells (LSCs) incubated with the nanodiamonds displayed a 45-fold increase in the luminescence compared with the untreated cells. To track the LSCs in vivo, the nanodiamond-labeled LSCs were injected into the tail veins of adult mice. Flow cytometric analysis confirmed that the injected LSCs preferentially resided in the lungs over other organs. PLIM and TGLM imaging of lung tissue sections efficiently isolated the long-lived luminescence of the nanodiamonds from background noises. Additionally, the nanodimond-labeled LSCs were engrafted into mice with lung injury to monitor the regenerative capacity of the LSCs. PLIM and TGLM imaging revealed that the LSCs preferentially localized in the terminal bronchioles of the lung-injured mice. Since LSCs expressed club cell secretory protein (CCSP) that can repair the bronchiolar epithelium, the mice injected with the LSCs displayed a more significant restoration of the lung epithelium than the untreated mice. Luminescent porous silicon NPs (258) emitting at 600 to 900 nm with a long lifetime of 12 μs were coated with PEG.645 In the in vivo imaging of a nude mouse, the luminescence signals from the nanoparticles were readily distinguishable from that of the Cy3.5 dye, fluorescent protein mCherry, and autofluorescence via TGLM. The utilization of the nanoparticles for tumor imaging was demonstrated. In Figure 42, intravenous injection of the nanoparticles into a nude mouse bearing a human ovarian carcinoma SKOV3 xenograft tumor resulted in gradual accumulation of the nanoparticles in tumor tissues due to the enhanced permeability and retention effect. TGLM images showed a higher SNR compared to continuous wave (CW)

Figure 41. PLIM images of AuNCs (255) loaded HeLa cells at four different temperatures under excitation at 470 nm with an emission filter of 690 ± 70 nm. Scale bar: 20 μm. Reprinted with permission from ref 642. Copyright 2013 John Wiley & Sons.

living cells. Internalization of nanoparticles of larger sizes can also be achieved by modification with targeting moieties on the nanoparticle surface. The shapes of nanomaterials do not affect their bioapplications much. Different shapes of nanomaterials including nanosized particles, rods, clusters, and tubes have been used for bioimaging purposes. The biostability and biotoxicity of the nanomaterials can be improved by exclusion of toxic elements or surface modification with biocompatible groups such as amino acids, sugar molecules, or PEG. Cadmium-free QDs (256) were prepared to investigate the biodistribution in lymph node.643 As the toxic cadmium element was excluded, the biocompatibility of the QDs was significantly improved. Living rats were subcutaneously injected with the QDs at the left paw and sacrificed in 10 min. Luminescence imaging showed red emission signals from left axillary lymph node (ALN)

Figure 42. (a) Bright field image of a nude mouse bearing a tumor. (b−e) CW and TGLM images under excitation at 470 nm recorded after Si NPs injection. The time for detection is (b) 0, (c) 1, (d) 4, and (e) 24 h. The arrow indicates the tumor site. Reprinted with permission from ref 645. Copyright 2013 Nature Publishing Group. AY


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ligands to lanthanides and transition-metal complexes. Design of long-lived organic dyes and inorganic nanoparticles will provide more choices in the selection of material system for a certain purpose. (2) The focus of probe design will be put on the maximization of the luminescence lifetime response to the analyte to benefit from the time-resolved photoluminescence measurement and imaging. (3) Multiple probes with different luminescence lifetimes can be used simultaneously. They are distinguishable via time-resolved photoluminescence techniques, even if they emit with similar intensity at the same wavelength. (4) Combination of the time-resolved photoluminescence imaging techniques with upconversion dyes that are excitable at the NIR region is an efficient strategy to improve the quality of the images. The low-energy excitation reduces the population of the unwanted excited states and the time-resolved photoluminescence detection further filters off the short-lived noises. Additionally, NIR excitation allows deeper tissue penetration and is suitable for in vivo imaging using live animal models. (5) There are limited examples of long-lived emissive probes used for in vivo time-resolved photoluminescence imaging due to a lack of long-lived NIR emissive probes and imaging techniques. Thus, development of NIR emissive probes with long lifetime and timeresolved photoluminescence techniques that are suitable for live animal models will broaden the scope of time-resolved photoluminescence application in vivo. (6) PLIM using longlived probes requires longer imaging time. The imaging speed is unacceptable when lanthanides are used, and it needs to be improved. (7) The applications of persistent phosphors are of great usefulness in in vivo bioimaging, since photon acquisition can be performed when external excitation is turned off. The sensitivity is improved and phototoxicity is avoided. (8) Combination of time-resolved detection with modern imaging techniques, such as stimulated emission depletion microscopy, terahertz imaging, and fluorescence anisotropy imaging, will open up new directions in the development of imaging techniques. In summary, with the time-resolved photoluminescence techniques, long-lived luminescent probes show their advantages and excellent performance in many applications. We anticipate that the fast development of new probes and techniques for detection and imaging will lead to significant improvements of the precision and sensitivity of bioimaging and biosensing.

images. In another study, the same group demonstrated the utilization of the porous silicon NPs (259) for ex vivo imaging mouse organs.646 The NPs and Alexa Fluor 647 were directly injected in separate locations in the brain, liver, kidney, lung, and tumor of a mouse. While the luminescence signals of Alexa Fluor 647 were completely embedded in the autofluorescence, the signals of the NPs showed a contrast improvement of 50−100 fold in the TGL imaging relative to the CW mode. Additionally, the NPs were modified with tumor-targeting peptide iRGD and retro-orbitally injected into living mice bearing 4T1 breast tumors for tumor imaging. The SNR from the tumor of the animal was significantly improved in the TGL images compared to that in the CW images.

5. CONCLUSIONS AND OUTLOOK Rapid development of time-resolved photoluminescence techniques facilitates the utilization of long-lived luminescent probes for bioimaging and biosensing in a complicated autofluorescent environment. The TGL technique selectively records long-lived signals originated from the probe by applying a delay time between excitation and detection, thus enhancing the accuracy. The PLIM measures the luminescence lifetime of probes to distinguish it from short-lived autofluorescence and light scattering and maps its spatial distribution. For imaging of probes with extremely long emission lifetimes such as persistent phosphors, TGLM is more suitable and efficient because the signal-to-noise ratio can remain a high value even if a long gate time is applied but PLIM requires a very long photon acquiring duration. PLIM is better in time-domain resolution than TGLM, since the luminescence lifetimes of every individual pixel are distinguished. When these techniques are applied to biological sensing, PLIM is suitable for analysis of analytes that are able to induce a significant alteration in the luminescence lifetime, while TGLM is more suitable for long-lived probes that display significant intensity response to analyses. The sensitivity of both techniques is remarkably enhanced compared to the prompt luminescence imaging because of the minimized background noise. Till now, many long-lived luminescent probes have been developed for time-resolved bioimaging and biosensing. Among them, lanthanides and transition-metal complexes are the most widely used probes owing to their inherent long luminescence lifetimes. Lanthanides exhibts disdingishable narrow luminescence bands with extremely long lifetimes. The emission wavelengths and lifetimes of transition-metal complexes can be easily tuned by selecting different metal centers and coordinating ligands. They can also be used as energy donors in FRET systems to elongate the fluorescent lifetimes of acceptors. Effort has also been focused on the elongation of fluorescent lifetimes of pure organic dyes and inorganic nanoparticles. The luminescence wavelengths of organic dyes are easily tuned throughout the whole visible region and extending to the NIR region. Nanosized materials can be multiply functionalized by surface modification to meet different requirements. Despite the discussed applications of long-lived luminescent probes, the development of novel luminescent probes for bioimaging and biosensing with high precision and sensitivity is challenging. Current directions of the design of long-lived probes and the development of the timeresolved luminescence imaging techniques include but are not limited to the following: (1) lanthanides and transition-metal complexes contain heavy metal elements, which usually show certain toxicity to cells. Thus, it is necessary to develop novel probes with low toxicity through introduction of biocompatible

ASSOCIATED CONTENT S Supporting Information *

The photophysical properties and working conditions of longlived emissive probes reviewed. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.chemrev.7b00425. (PDF)

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Wei Huang: 0000-0001-7004-6408 Author Contributions ∥

AZ

K.Y.Z. and Q.Y. contributed equally. DOI: 10.1021/acs.chemrev.7b00425 Chem. Rev. XXXX, XXX, XXX−XXX

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Notes

ABBREVIATIONS

The authors declare no competing financial interest.

4-ABAH 5-FU Aβ A549 Acr+ AFt ALK ALN AOM APTES AS ATP Au NCs Au NPs BDM BHHTEGST

Biographies Kenneth Yin Zhang obtained his Ph.D. degree under the supervision of Prof. Kenneth Kam-Wing Lo from City University of Hong Kong in 2010. From 2010 to 2013, he worked as a Postdoctoral Research Fellow in the same group. He joined Institute of Advanced Materials, Nanjing University of Posts & Telecommunications in 2013. His research focuses on the applications of phosphorescent transition-metal complexes for bioimaging and biosensing. Qi Yu obtained her B. S. degree from Jiangxi Normal University in 2012, and now she is working as a Ph.D. candidate under the supervision of Professor Wei Huang and Professor Qiang Zhao in Institute of Advanced Materials, Nanjing University of Posts & Telecommunications. Her research interests focus on the development of long-lived luminescent probes for biosensing and bioimaging. Huanjie Wei obtained her bachelor degree from Qingdao University of Science and Technology in 2014, and now she is working as a postgraduate student under the supervision of Professor Qiang Zhao in Institute of Advanced Materials, Nanjing University of Posts & Telecommunications. Her research focuses on the utilization of phosphorescent transition-metal complexes for intracellular imaging and sensing via photoluminescence lifetime imaging microscopy.

BHQ2 BSA BTTA CBS CCD CCSP CHO c-PTIO

Shujuan Liu received her Ph.D. from Fudan University in 2006. Then she joined Institute of Advanced Materials, Nanjing University of Posts & Telecommunications. She was promoted as a full professor in 2013. Her research interests focus on the luminescent conjugated polymers for biological applications.

cRGD CSE CTCs CW CXCR4 Cys DHA DHLA DMEM DNBS DOPC DPA dppz eDHFR EGFR EMT ER ESI-MS FAD FBS FITC FRET GFP GSH GTP Hcy HDF HDF HEK293T HeLa HepG2 HSA IFN-γ IL

Qiang Zhao received his Ph.D. from Fudan University in 2007. He then became a postdoctoral fellow at Nagoya University of Japan. He joined the Institute of Advanced Materials, Nanjing University of Posts & Telecommunications in 2008. He was promoted as a full professor in 2010. His research interests focus on the organic photofunctional materials for bioimaging and optoelectronic devices. Wei Huang received his Ph.D. degree from Peking University in 1992. In 1993, he began his postdoctoral research at the National University of Singapore. In 2001, he was appointed as a chair professor with Fudan University, where he founded and chaired the Institute of Advanced Material. In 2006, he was appointed vice president of Nanjing University of Posts and Telecommunications. He was elected to Chinese Academy of Sciences in 2011. In 2012, he was appointed the president of Nanjing Tech University. Now he is the Deputy President and Provost of the Northwestern Polytechnical University. His research interests include organic/polymer semiconductors for optoelectronic devices and biological applications.

ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (61775104, 51473078, 21671108, and 21501098), National Program for Support of Top-Notch Young Professionals, Scientific and Technological Innovation Teams of Colleges and Universities in Jiangsu Province (TJ215006), Natural Science Foundation of Jiangsu Province of China (BK20150833), Synergetic Innovation Center for Organic Electronics and Information Displays, and Priority Academic Program Development of Jiangsu Higher Education Institutions (YX03001) for financial support. BA

4-aminobenzoic acid hydrazide 5-fluorouracil amyloid-β human lung adenocarcinoma 10-methylacridinium apoferritin anaplastic lymphoma kinase axillary lymph node acousto-optical modulator (3-aminopropyl) trimethoxysilane ascorbate sodium adenosine triphosphate gold nanoclusters gold nanoparticles 2,3-butanedione monoxime 4,4′-bis(1″,1″,1″,2″,2″,3″,3″-heptafluoro-4″,6″hexanedion-6″-yl)sulfo-o-terphenyl-tetraethylene glycol-N-hydroxysuccinimide black hole quencher 2 bovine serum albumin bis(2-(2-(methylthio)ethylthio)ethyl)amino cystathionine β-synthase charge-coupled device club cell secretory protein Chinese hamster ovary 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide cyclic arginine-glycine-aspartic acid peptide cystathionine γ-lyase circulating tumor cells continuous wave chemokine receptor 4 cysteine dehydroascorbic acid dihydrolipoic acid Dulbecco’s modified Eagle’s medium 2,4-dinitrobenzenesulfonyl 1,2-dioleoyl-sn-glycero-3-phosphocholine 2,2′-dipicolylamine dipyrido[3,2-a:2′,3′-c]phenazine Escherichia coli dihydrofolate reductase epidermal growth factor receptor epithelial to mesenchymal transition endoplasmic reticulum electrospray-ionization mass-spectrometry flavin adenine dinucleotide fetal bovine serum fluorescein isothiocyanate Förster resonance energy transfer green fluorescent protein glutathione guanosine triphosphate homocysteine human dermal fibroblast human dermal fibroblasts human embryonic kidney human cervical carcinoma human liver carcinoma human serum albumin interferon-γ intraligand DOI: 10.1021/acs.chemrev.7b00425 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews KB LA LED LLCT LMCT LMMCT LPS LSCs MBs MCF-7 MEF MLCT MLLCT MMLCT MPA MPO MRI MSA MTO NIR NOS NV Pdots PDT PET PFO PKs PLIM PLNPs PMA PNIPAM PNNPAM PSLIM PVK PVP QDs RNS ROS RSS Si NPs SIN-1 SMMC-7721 SNRs SPECT SPR STED Syk T TCSPC TEM TGL TLN TMPyP TPEN TSLIM UCNP UV VEGF165

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