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Research progress of near-infrared fluorescence probes based on indole heptamethine cyanine dyes in vivo and in vitro

Abstract

Near-infrared (NIR) fluorescence imaging is a noninvasive technique that provides numerous advantages for the real-time in vivo monitoring of biological information in living subjects without the use of ionizing radiation. Near-infrared fluorescent (NIRF) dyes are widely used as fluorescent imaging probes. These fluorescent dyes remarkably decrease the interference caused by the self-absorption of substances and autofluorescence, increase detection selectivity and sensitivity, and reduce damage to the human body. Thus, they are beneficial for bioassays. Indole heptamethine cyanine dyes are widely investigated in the field of near-infrared fluorescence imaging. They are mainly composed of indole heterocyclics, heptamethine chains, and N-substituent side chains. With indole heptamethine cyanine dyes as the parent, introducing reactive groups to the parent compounds or changing their structures can make fluorescent probes have different functions like labeling protein and tumor, detecting intracellular metal cations, which has become the hotspot in the field of fluorescence imaging of biological research. Therefore, this study reviewed the applications of indole heptamethine cyanine fluorescent probes to metal cation detection, pH, molecules, tumor imaging, and protein in vivo. The distribution, imaging results, and metabolism of the probes in vivo and in vitro were described. The biological application trends and existing problems of fluorescent probes were discussed.

Introduction

Indole heptamethine cyanine dyes are the widely used class of cyanine dyes, and the ability to generate strong fluorescence emission at the near-infrared (NIR) region of 650–900 nm [1, 2]. Indole heptamethine cyanine dyes are composed of indole heterocyclic rings, heptamethine chains, and N-substituted side chains (Fig. 1) [3]. In recent years, indole heptamethine cyanine dyes have been widely used in biology; active groups are introduced into indole heptamethine cyanine dyes, or their structural nuclei are altered. The newly generated fluorescent probes have been widely investigated in the field of fluorescence imaging because of their different biological functions. In the present work, the application of indole heptamethine cyanine dyes to the detection of pH changes in vivo and in vitro, trace metal ions, active small molecules, tumor cell-targeted imaging, and other aspects was reviewed to provide references for the development of NIR fluorescence probes in the fields of biological science and medical imaging.

Fig. 1
figure1

Structures of indole heptamethine cyanine dyes

Main text

Application of pH-sensitive NIR Fluorescence probes

Organisms have the ability to regulate the acid–base balance in vivo. However, such ability is weakened when organisms are affected by malignant diseases and leads to acid–base imbalance and causes the pH value of body fluids to exceed the normal range [4,5,6]. Some dyes exhibit different absorption or fluorescence properties with changes in pH values [7,8,9,10,11,12]. Fluorescence pH measurement showing different optical signals with pH changes can compensate for the deficiency of other methods for pH detection [13, 14]. In addition, the fluorescence method has the advantages of high detection sensitivity, simple operation and portability [15], which is suitable for fluorescence biomolecular studies and for detecting pH changes in cells in real time. The pH fluorescence probes can be divided into pH fluorescence probes for detecting neutral ranges and those for detecting acidic environments. Intracellular acidity is approximately 4.5–6.0, and the pH range of the cytoplasm is approximately 6.8–7.4. Many normal physiological processes in cells and organelles are associated with intracellular pH values [16, 17]. The changes in intracellular pH are associated with muscle spasm, cell proliferation, apoptosis, ion transport, homeostasis, multidrug resistance, malignancies, endocytosis, and Alzheimer’s disease [18]. Therefore, hydrogen ion change is the main research target in vivo, and pH sensitive NIR fluorescence probes provide a new method for effectively monitoring pH changes in vivo.

Xue et al. [19] reported a pH-responsive photothermal ablation probe 1 based on cyanine dyes (Fig. 2) for photothermal therapy (PTT), the absorption of which in the NIR was increased by probe 1 by accepting protons. Compared with normal cells, the nanoparticles were formed by bovine serum albumin and probe 1 preferentially accumulate and could be activated in the acidic environment of the Golgi of cancer cells. Moreover, PTT could be effectively conducted in vivo and in vitro.

Fig. 2
figure2

Structure of probe 1

Fang et al. [20] synthesized a fluorescent probe 2 (Fig. 3) using bond-penetrating energy transfer. Probe 2 was consisted of ether bonds formed by tetrastyrene donors and cyanide receptors and exhibited aggregation-induced emission. The probe has dual visible and NIR excitation and emission capabilities, and can detect intracellular pH fluctuations in HeLa cells.

Fig. 3
figure3

Structure of probe 2

Fang et al. [21] used IR-822 as a fluorescent group because of its excellent tumor preferential aggregation and other characteristics. IR-822 was conjugated to N1-(pyridine-4-methyl) ethane-1,2-diamine (PY), a pH sensing receptor, to form a fluorescent spacer receptor molecular probe 3 (Fig. 4) to enhance its specificity in tumor imaging. The imaging principle is to adjust the fluorescence emission intensity by a fast photoinduced electron to achieve the probe “turn on” under the acidic tumor microenvironment and enhance fluorescent imaging. Probe 3 has a strong absorption capability at 600–850 nm. The probe achieved high spatial resolution photoacoustic (PA) imaging in mice and photothermal ablation of tumors. The mice exhibited significant ablation and no recurrence of tumors following the application of the 808 nm laser irradiation and probe 3 photothermal treatment.

Fig. 4
figure4

Structure of probe 3

Zhang et al. [22] synthesized a NIR fluorescence probe 4 (Fig. 5) with dual inspection characteristics for pH sensing. The probe was formed by binding a NIR rhodamine donor to a cyanide receptor via a C-N bond with short ethylene suppository. Probe 4 containing the cyanine and rhodamine moieties, showed corresponding fluorescence increases with pH decreases to achieve the double-checked capability, and responded to change in fluorescence intensity under the excitation of the rhodamine body at 450 nm with pH changes.

Fig. 5
figure5

Structure of probe 4

Mu et al. [23] synthesized two pH-responsive NIR fluorescence probes 5 and 6 (Fig. 6), which could be encapsulated in self-assemblies consisting of anionic, cationic, and neutral amphiphiles in phosphate buffered saline. The self-assembled polyethylene glycol (PEG)-tocopherol conjugated of neutral surfactants effectively encapsulated the dyes and did not lose their pH responsiveness for hours. At the same time, the pH-responsive dyes in self-assembled packaging were sensitive to acidification, the absorption and emission of NIR immensely increased, and the high pH response of self-assembled dyes with non charged surfactants was demonstrated.

Fig. 6
figure6

Structures of probes 5 and 6

Koji Miki et al. [24] reported three NIR fluorescence probes 7, 8 and 9 (Fig. 7) that responded to acidity and basicity and were essentially an indocyanine green (ICG) derivative with nucleophilic subunits (amino, hydroxyl, and mercapto). These dyes showed the pH dependence balance between the fluorescent open-loop and nonfluorescent closed-loop structures in the pH ranges of 7–9, 5–7, and 3–6. In vitro culture experiments of HeLa cells showed that probes 8 and 9 exhibited strong pH-dependent fluorescence enhancement through endocytosis. Control incubation experiments at 4 °C showed that the probes positively reacted with the open-loop structure, and ICG combined with the cell membranes through electrostatic interaction. The pH-responsive probes 8 and 9 were found to be powerful probes, which could be used for the highly sensitive analysis of active cells and high-contrast optical imaging of acidic parts of tissues, such as tumors.

Fig. 7
figure7

Structures of probes 7, 8, and 9

Hou et al. designed and synthesized two novel NIR fluorescent probes 10 and 11 (Fig. 8). The two probes were highly sensitive to pH fluctuations (especially at the range of 5.50–4.00, with pKa values of 4.72 and 4.45) and could be reversibly turned off and on by alternating the pH values. The fluorescence imaging experiment on pH showed that the two probes can monitor the pH fluctuations of living cells because of their good membrane permeability. The two probes show special potential in detecting pH fluctuations in biological systems [25].

Fig. 8
figure8

Structures of probes 10 and 11

Six N-p-carboxybenzyl(or ethyl)-5,5′-bisulfonic heptamethine cyanines were developed to detect extreme pH values in biological systems, wastewater, and/or sol/gel formation. They exhibited different pH responses in water, ethanol, and/or methanol under extreme pH conditions. The structure of SCy-Os (Fig. 9. probe 12, pKa of 3.02–3.09) reversibly changed into a tautomorphic isomer (SCy-OHs) at pH 2.11–4.28. Its maximum absorption and emission wavelength changed from 504–639 nm to 709–762 nm, and the color of the solution changed from red to green. At the same time, the corresponding strength of the solution immensely was changed. SCy-Cls and SCy-Ns were tautomerized under strong alkaline conditions (pH 9.80–13.90, pKa of 10.41–11.93) because of the difference between the intermediate atoms (Cl, N, O) of the cyanine molecules and the conjugated system. The cyanine molecules in the aqueous solution interacted with CTAB to change the absorption, emission wavelength, and intensity of cyanide. The pH responses changed under strong acidic conditions, and the CMC of CTAB significantly reduced. The interaction of cyanine with SiO2 sol and titanium dioxide sol particles affected the pH responses. Therefore, the probe was applicable to the manufacturing of particular materials because of their special sensitive pH responses under extremely complex acidic and alkaline environments [26].

Fig. 9
figure9

Structures of probes 12, 13, and 14

Zhang et al. [27] developed four NIR fluorescence probes to show that pH in physiological environments could switch NIR fluorescence and photothermal efficiency. Probe 16 (Fig. 10, pKafluo 4.6) maximized its NIR fluorescence intensity in the acidic lysosome cavity and the photothermal effect in the alkaline mitochondrial matrix, specifically visualizing and removing various cancer cells, by fine-tuning the pKa values of these probes. This probe could facilitate image-guided tumor ablation by completely eradicating the tumors caused by organelle acidity and basicity disorder and improving prognosis.

Fig. 10
figure10

Structures of probes 15–18

He et al. [28] developed the NIR fluorescence probe 19 (Fig. 11) to prove that the internal fluorescence switch by spirocyclization in cyanines could be effectively used in the development of NIR pH detectors. They indicated that the probe 19 could be used to monitor the changes in pH values in biological systems in real time.

Fig. 11
figure11

Structure of probe 19

A new NIR fluorescence probe 20 (Fig. 12) was designed and synthesized by introducing 3-aminophenol into the parent nucleus of indole heptamethine cyanine dye. A light stability experiment showed that probe 20 had good light stability. Phagocytic experiments showed that the probe had good cell membrane penetration and strong intracellular pH sensitivity. The pH titrations indicated a more than tenfold increase in fluorescence intensity within the pH range of 4.0–6.5 with a pKa value of 5.14, which was valuable for studying acidic organelles in living cells, and a pKa value of 11.31 within the pH range of 10.5–11.8. The fluorescence imaging of HepG2 cells showed that the probe could monitor the changes in hydrogen ion concentrations in living cells [29].

Fig. 12
figure12

Structure of probe 20

Tang Bo’s experimental group [30] designed and synthesized a new pH-sensitive probe 21 (Fig. 13) to monitor slight fluctuations in pH values. The probe showed strong sensitivity with changing in hydrogen ion concentrations at the pH range of 6.70–7.90. The experimental results showed that the probe performed real-time in situ fluorescence imaging in living cells, effectively avoided the interference of biological tissues and spontaneous fluorescence, and exhibited important biological application value. In the same year, Kiyose et al. [31] introduced a NIR pH fluorescence probe on the basis of the FRET mechanism. The structure of probe 22 is shown in Fig. 13. The absorption and emission peaks of the probe red shifted when it was combined with H+.

Fig. 13
figure13

Structures of probes 21 and 22

Zhang et al. [32] synthesized three NIR fluorescence probes 23, 24, and 25 with pH-sensitive activities, as shown in Fig. 14. The removal of an N-substituted side chain in the ICG molecule by the three probes resulted in their pH sensitive characteristics in the NIR and related physiological range.

Fig. 14
figure14

Probes 23–25 with pH-sensitive activities

Mikhail et al. [33] developed three probes (Fig. 15) with pH-sensitive activities. The difference in the pH sensitivities of the three probes were mainly due to the electron coupling through the tertiary amine in their molecular structure and the dependence of the pKa sensitivity of the probes on the location of the amine. All three probes can be used to detect pH activity.

Fig. 15
figure15

Probes 26–28 with pH-sensitive activities

Application of metal ion selective NIR Fluorescence probes

The body contains a small amount of various metal ions with important physiological functions. Mg2+ is a metal ion with the most extensive life activities in the body [34] and is involved in various physiological functions, such as extensive material metabolism and energy metabolism. Zn2+ is widely involved in cell growth, neural transmission, enzyme catalysis, and other physiological functions [35, 36]. It can also maintain the normal metabolic function of Vitamin A and maintain the growth and development of the body. In addition, Zn2+ is a cofactor or activator of many enzymes. [37] Cu2+ is related to the regulation of melanin formation, hemoglobin production, and elastic tissue structure in vivo [38]. Studies have shown that the disorder of metal ions in the body will lead to the disorder of the physiological functions of the body and easily cause the formation of various diseases [39,40,41]. Therefore, a series of metal ion detection probes in vivo and in vitro should be developed.

Li et al. [42] reported the probe 29 (Fig. 16) that was used to detect Fe3+ and Cu2+ in MeOH/H2O and MeCN/H2O solvents, respectively. The detection limits of Fe3+ and Cu2+ detected by the probe were 0.737 μM and 1.019 μM, respectively. Compared with other common coexisting metal ion probes, probe 29 had stronger selectivity and higher sensitivity when detecting Fe3+ and Cu2+. The fluorescence imaging of Cu2+ in SH-SY5Y109 cells in vivo proved that the probe offered practical value in biological systems.

Fig. 16
figure16

Structure of probe 29

Three tricarbocyanine dyes (Fig. 17, IR-897, IR-877, and IR-925) with different thiourea substituents were used as dosimeter units through specific Hg2+-induced desulfurization. These dyes were evaluated using a fast indicator paper for Hg2+ and MeHg+ ions. Compared with existing Hg2+ selective chemical dosimeters, IR-897 and IR-877 had more convenient synthesis, longer wavelength, and higher molar extinction coefficient in the NIR, and less interference to Ag+ and Cu2+. The red shifts of the three dyes were apparent, resulting in a clear change in color from dark blue to bean-green, and the red shifts could be used as a useful indicator. Additionally, experiments with living SW1116 cells showed that these three tricarbocyanine dyes with low toxicity could exhibit special characteristics that were favorable for visualizing intracellular Hg2+ and MeHg+ ions in biological systems, including excellent membrane permeability, minimal interfering absorption and fluorescence from biological samples, low scattering, and deep penetration into tissues. [43].

Fig. 17
figure17

Structure of probes 30–32

Gao et al. [44] reported a novel type of NIR heptamethine cyanine ligand that selectively binds Hg2+ through the polymerization of monomers of NIR ligands. The sensor was simple and effective, and its detection limit in aqueous solution was 1.93 × 10−8 M. It had high sensitivity because of its unique sensing mechanism. Thus, the recognition of a small amount of Hg2+ led to the aggregation of probe 33 (Fig. 18), resulting in a change in the absorption spectrum. The results showed that probe 33 effectively detected Hg2+ and could thus serve as a good substitute for other sensors.

Fig. 18
figure18

Structure of probe 33

Wang et al. [45] designed and synthesized a NIR three-channel fluorescent probe HCy-SeH (Fig. 19, probe 34) to detect O·−2and Hg2+ in chronic mercury poisoning models in cells and mice. During detection, the proportional fluorescence signal provided by the three-channel response eliminated the interference caused by uneven load or uniform distribution. The probe showed good selectivity and sensitivity for the associated detection of O·−2 and Hg2+. The probe was evaluated through fluorescence imaging and flow cytometry analysis for the in situ detection of O·−2 and Hg2+ in the HEK 293 cell model. The accumulation of Hg2+ destroyed the antioxidant system of cells and caused the overproduction of O·−2. The results showed that the probe could be a powerful tool for the association detection of O·−2 and Hg2+ in vitro and vivo.

Fig. 19
figure19

Molecular structure and the proposed mechanism for O·−2 and Hg2+ associated detection

Debabrat Maity’s team [46] successfully developed a Cu+ selective water-soluble switch “NIR fluorescence-ready” probe (TPACy, Fig. 20, probe 35). The probe easily reacted with Cu+ by releasing the NIR-emitting cyanine dye under the physiologically relevant pH range. The fluorescence dye of the probe released during the catalytic reaction of metal ions could be used to effectively detect the submicromolar concentrations of Cu+. The probe can be used as a noninvasive tool for detecting NIR fluorescence and the in vivo imaging of Cu+ pools in biological fluids.

Fig. 20
figure20

Structure of probe 35

Long et al. [47] synthesized two NIR fluorescence probes, IR-DT and IR-DFT (Fig. 21, probes 36, and 37), which contains two thymines on the N-sides. These dyes could form a T-Hg-T complex through thymine and bind specifically to Hg2+. IR-DFT had a better response to Hg2+ compare with IR-DT. It also had relatively high sensitivity and low detection limits for Hg2+ because fluorine-substituted thymine could accelerate self-aggregation and fluorescence quenching. The experimental results showed that Hg2+ in the mitochondrial region of the cells was successfully detected by IR-DFT. He et al. [28] also reported a NIR fluorescence probe CyBS (Fig. 22, probe 38) to detect Hg2+ in living cells and animals.

Fig. 21
figure21

Structures of probes 36 and 37

Fig. 22
figure22

Possible sensing mechanism of 38 CyBS with Hg2+

Kiyose et al. [48, 49] designed and synthesized a novel NIR fluorescence probe (probe 39, Fig. 23), with a maximum molar extinction coefficient of 7.0 × 104 m−1 cm−1 and large Stokes shift to detect Zn2+. The electron cloud density around dipyridine methyl ethylenediamine decreased, and the fluorescence signal of the probe increased when the recognition group of methyl amine in the probe bound to Zn2+. The results showed that the probe was suitable for the detection of Zn2+. Tang Bo’s team [50] reported a new NIR fluorescence probe (probe 40) for the detection of Zn2+ (Fig. 23). The recognition group of the probe was 2, 2-dimethyl-1-pyridine, and the fluorophore was indole heptamethine cyanine dyes. Fluorescence quenching occurs when the fluorescent probe was combined with Zn2+, and photoinduced electron transfer (PET) of the probe was inhibited.

Fig. 23
figure23

Structures of probes 39, 40, and 41

Zhu et al. [51] reported a novel NIR fluorescence probe MCy-1 (Fig. 23, probe 41) to detect Hg2+ concentrations. The Hg2+ concentrations were obtained by introducing the recognition group of dioxane crown ether into the fluorescence group. The probe’s recognition group combined with Hg2+ affected the entire conjugate system of the macromolecule and changed the fluorescence signal. Thus, the presence of Hg2+ on the probe was observed by the naked eye. The results showed that the probe had good selectivity to Hg2+ and could thus easily detect the presence of Hg2+.

Cao et al. [52] presented an NIR fluorescence probe 42 (Fig. 24) with thioether ring as the recognition group and indole heptamethine cyanine dye as the fluorescent group to detect the presence of Cu+. Before the binding to Cu+, the recognition group provided electrons and weakened the fluorescence signal of the cyanine dyes. After the binding to Cu+, the fluorescence signal increased, and the absorption spectrum red shifted.

Fig. 24
figure24

Structures of probes 42, 43 and 44

Han et al. [53] synthesized as a fluorescent probe 44 (Fig. 24) for detection of Cu2+ with high selectivity. The probe 44 was composed of 2-(2-Amino-ethyl) pyridine and IR-780 iodide (Fig. 24, probe 43), and the response of the probe was based on the fluorescence quenching upon binding to Cu2+. The sensing performance of the proposed Cu2+-sensitive the probe was then investigated. The probe can be applied to the quantification detection of Cu2+ with a linear concentration range covering from 4.8 × 10−7 to 1.6 × 10−4 mol/L and a detection limit of 9.3 × 10−8 mol/L. The experimental results showed that the response of the probe to Cu2+ was independent of pH in medium condition, and exhibited excellent selectivity towards Cu2+ over other common metal cations.

Li et al. [54] synthesized a fluorescence probe 45 (Fig. 25) to detect Cu2+. The maximum absorption wavelength of the probe changed to blue when its recognition group bound to Cu2+. The increase in Cu2+ concentration boosted the fluorescence signal strength of the probe, thus increasing the fluorescence quantum yield to approximately six times. The experimental results showed that the probe had high affinity and selectivity for Cu2+ and recognized the presence of Cu2+.

Fig. 25
figure25

Structure of probe 45

Yang et al. [55] reported two NIR fluorescence probes 46 and 47 (Fig. 26) with good affinity and selectivity for Cd2+. Probe 47 has strong detection ability for Cd2+ and detected Cd2+ from a neutral solution and a solution mixed with other ions. Probe 48 (Fig. 27) consists of crown ether rings and indole heptamethine cyanine dye as the recognition and fluorescence groups, respectively. The experimental results showed that the probe could effectively identify and detect metallic lithium ions simultaneously [56].

Fig. 26
figure26

Structures of probes 46 and 47

Fig. 27
figure27

Structure of probe 48

Tang et al. [57] synthesized a probe 49 (BDP-Cy-Tpy) consisting of a fluorescent group of indole heptamethine cyanine dye and a recognition group of BODIPY to detect ferrous ions (Fig. 28). The probe emitted fluorescence signals when the ferrous ions combine with the recognition group of the probe. Fluorescence signals were observed at BODIPY, whereas no fluorescence signal was observed in the indole heptamethine cyanine dye with the combination of ferrous ions and the recognition group of the probe. Therefore, the probe is effective in detecting the presence of ferrous ions.

Fig. 28
figure28

Structure of probe 49

Application of small molecule-sensitive NIR fluorescence probes

Fluorescent probes to detect active sulfur

Sulfides play a unique role in biological systems, and the development of many sensitive probes is crucial for the fluorescence detection of S2−. An NIR fluorescence probe IR800-DPII (Fig. 29, probe 50) was synthesized by heptamethine cyanine and NBD as an “off–on” fluorescence sensor for detecting S2− using the matrix-induced cleavage mechanism. Its detection limit for S2− on neutral particles is 0.15 M, which indicates better selectiveness than other biologically related analytes. The probe is successfully applied to living cells, and the fluorescence imaging of S2− in living cells is achieved. The principle of group removal from the probe is the response induction of S2− by conducting a closed attack on the NBD group of the probe. The probe is suitable for measuring the accumulation of S2− for a time period because of the slow cleavage reaction [58].

Fig. 29
figure29

Structures of probes 50 and Cy-4

Cao et al. [59] synthesized an NIR fluorescence probe Cy-4 (Fig. 29) to detect the presence of sulfur ions. The probe exhibited fluorescence signals under normal conditions. However, the fluorescence signals were quenched when the nitrogen atom of the identification group bound to copper chloride. As the binding ability of sulfur ion to copper was stronger than that of nitrogen atom, the solution containing sulfur ion was added to the solution after fluorescence quenching. Moreover, the complexed copper ion combined with sulfur ion changed the molecular structure of the probe into its original state to generate fluorescence signals.

A novel NIR fluorescence probe Cy-1 (Fig. 30, probe 51) was presented to detect hydrosulfide. The reaction mechanism of the probe was a nucleophilic reaction in which HS replaces acryloyl moiety. Cy-1 exhibited a rapid fluorescence quenching (700 nm excitation) and a fast fluorescence enhancement (544 nm excitation) with the addition of NaHS. Its absorption spectra and colors were clearly observed by the naked eye in tens of seconds. Cy-1 had better selectivity to Cys compared with CyAc. The probe showed excellent selectivity and sensitivity to HS on various anions (0.33 μM detection limit). The probe was successfully used in the imaging of hydrogen sulfide (H2S) in fetal bovine serum samples and living cells [60].

Fig. 30
figure30

Structures of probes 51, HCy-Mito, and Hcy-Biot

Recent studies showed that hydrogen polysulfide (H2Sn) was a true intracellular signaling molecule that played an important role in the cardiovascular and nervous systems [61]. Fabiao Yu et al. [62] reasoned that the balance of O·−2 and H2S concentrations in vivo played a key role in human physiological and pathological processes, so they developed two NIR fluorescence probes, Hcy-Mito and Hcy-Biot (Fig. 30), for the detection of O·−2 and H2S in vivo. Studies showed that Hcy-Mito was highly sensitive and selective to endogenous O·−2 and H2Sn. Flow cytometry assays for apoptosis confirmed that H2Sn played an important role in the antioxidant system, and the assay results of RAW264.7 cells and HUVECs showed that H2Sn might be caused by mitochondrial oxidative stress. H2Sn could protect cells from mitochondrial oxidative stress by directly removing O·−2. In vivo near infrared fluorescence imaging experiments showed that the probe had a strong penetration depth and could detect O·−2 and H2Sn in vivo.

Fluorescent probes to detect reactive oxygen species (ROS)

Under the normal physiological metabolism of the body, hydrogen peroxide (H2O2), superoxide anion radical (O·−2), hydroxyl radical (HO·), peroxynitrite (ONOO), and other reactive oxygen radicals are produced and perform important functions in the body. The increase in the level of intracellular oxidation can cause abnormalities in biological molecules and the development of some diseases, such as cancer, tissue peroxidation, and inflammation. At present, the commonly used methods for the determination of ROS are electron paramagnetic resonance, chemiluminescence, and high-performance liquid chromatography. Few methods are available to detect free radicals in vivo because of the short half-life of ROS. NIR fluorescence imaging can detect ROS or tissue fluorescence in cells because of its unique fluorescence characteristics [63]. Therefore, fluorescent probes with high sensitivity, low cost, minimal errors, and strong specificity should be developed for the detection of ROS.

A NIR fluorescence probe 52 (Fig. 31) was presented by Oushiki et al. [64] The probe was formed through the covalent combination of two cyanine dyes, pentamethylcyanine and heptamethylcyanine. The reactivity of the two cyanine dyes was relatively different from that of reactive oxygen radicals. The probe could detect ROS free radicals and use for imaging in mice with peritonitis.

Fig. 31
figure31

Structures of probes 52 and 53

Yu et al. [65] designed and synthesized a new type of NIR fluorescence probe (Fig. 31, probe 53) to detect the presence of peroxynitrite ions. The probe did not react with ROS. The fluorescence quenching of the fluorescent probe was caused by the PET effect of selenium on the entire methionine chain. The PET function of the Cy-PSe probe was inhibited by oxidation with the addition of oxygen nitrite ions, resulting in the production of a fluorescence signal. The oxidized selenium reduced and returned to the molecular structure of the probe itself under the action of the enzymatic catalytic cycle. Hence, the probe is suitable for many biological applications.

Xu et al. [66] reported an indole heptamethine cyanine probe 54 with high sensitivity and selectivity to detect singlet oxygen in the mitochondria (Fig. 32). The probe resisted the interference of biological systems, displayed the singlet oxygen of cells, and had low cytotoxicity and strong stability. Experiments showed that the probe could be used to detect 1O2 in cells in vivo.

Fig. 32
figure32

Structure of probe 54

H2O2 and H2S are small molecule signal sensors in vivo that play an important role in the pathological and physiological processes of organisms. In 2012, Wang et al. [67] reported an NIR fluorescence probe to detect the reduction of H2S in cells using cyanine dyes as fluorescence agents and a nitro group as the functional group. Two fluorescence probes 55 and 56 were synthesized by Zhu et al. [68] to detect small molecules (Fig. 33) through the change of fluorescence ratio. The probes were found to be effective in detecting the presence of H2S and H2O2 in the body. During the experiment, no significant change was observed in the fluorescence intensity of probes 55 and 56 under the presence of other ROS or active nitrogen in the solution. Probe 55 showed a high degree of selectivity to H2O2 under the presence of H2O2 in the solution. The fluorescence intensity of probe 56 was significantly enhanced with the presence of H2S in the solution, indicating its high selectivity to H2S. The fluorescence stability experiment showed that the two probes had stable fluorescence characteristics in the range of the physiological pH. Confocal imaging experiments confirmed that the probes could be used to detect the presence of H2O2 and H2S molecules in vivo.

Fig. 33
figure33

Structures of probes 55, 56, 57, and 58

Yu et al. [69] synthesized an NIR fluorescence probe DA-Cy for the detection of H2O2 (Fig. 33, probe 57). The probe used catechol as the identification group and indole heptamethine cyanine dye as the fluorophore. Yu et al. [70] developed an NIR fluorescence probe Cy-N3 (Fig. 33, probe 58) for the detection of H2S in chemical substances. The probe molecule used azide as the identification group and cyanine dye as the fluorophore. The azide group became an electron group with the binding of oxygen sulfide to the amino group, resulting in the change of spectral energy before and after the reaction.

ONOO is a kind of oxidant in the human body, and its instability may lead to inflammation, neurodegenerative diseases, and other conditions. ONOO can greatly affect the content of GSH in body cells and thereby cause damage to the body. Therefore, the redox state between ONOO and GSH should be detected in vivo. Yu et al. [71] synthesized the probe 59 (Fig. 34) to detect the balance of ONOO/GSH in vivo. The fluorescence signal of the probe was enhanced and saturated in a short time period when it was combined with ONOO, and the probe had high selectivity to ONOO. The probe could be used to detect ONOO in cells with low cytotoxicity in cell experiments.

Fig. 34
figure34

Structures of probes 59 and 60

Xu et al. [72] designed and synthesized an indole heptamethine cyanine probe Trp-Cy (Fig. 34, probe 60) to detect ozone. The probe molecule is a tryptophan recognition group. Tryptophan had a distorted intramolecular charge transfer effect on the cyanine dyes, causing the blue shift of the maximum absorption peak. The structure of the indole ring was destroyed, and the twisted charge effect disappeared with the addition of ozone. This condition caused the reaction product molecule to undergo two wavelength red shifts. The probe could detect ozone in living cells.

Han et al. synthesized a rate-based NIR mitochondrial targeting fluorescent probe Mito-Cy-Tfs (Fig. 35, probe 61) to detect the changes in the level of O·−2 in cells and to assess the relationship of O·−2 concentration and apoptosis degree in I/R. The probe displayed deep tissue permeation for real-time imaging of O·−2 concentration in the liver of I/R mice. The experiment proved that the probe could be used to indicate and evaluate the correlation of O·−2 level and the degree of organ damage in I/R, IPC, and IPTC processes [73].

Fig. 35
figure35

Structure of probe 61

Sasaki et al. [74] synthesized two NIR fluorescence probes 62 and 63 for the determination of nitric oxide (NO), as shown in Fig. 36. The fluorescence penetration of the probe increased, and the background interference of spontaneous fluorescence was minimal with the small light absorption of the body. The fluorescent probes were suitable for the detection of NO in vivo. In the presence of NO, an enhanced fluorescence signal was observed in the probe molecule because of PET. In vivo imaging experiments confirmed that these probes could be used to detect the presence of NO in biological organs.

Fig. 36
figure36

Structure and photochemical mechanism of NO fluorescent probe

Fluorescent probes to detect glutathione and/or cysteine

Glutathione (GSH) is the most abundant non-protein biothiol in cells, which can protect and prevent cell apoptosis. Yu et al. [75] successfully synthesized a ratiometric fluorescent probe (CyO-Dise, Fig. 37) based on a selenium–sulfur exchange reaction to detect of GSH concentration fluctuations in vivo and in vitro. The probe had been successfully used to detect changes in GSH concentration in HepG2 and HL-7702 cells under low temperature and hyperthermia. CyO-Dise was composed of fluorescent cyanine, bis (2-hydroxyethyl) dienoamide and d-galactose, and the probe could detect the presence of GSH within 35 s in the selenium-sulfur exchange reaction. In addition, the probe could be used to image the GSH levels of HepG2 and HepG2/DDP xenografts in vivo.

Fig. 37
figure37

Structures of probes Cy-Dise and 54

Yin et al. [76] synthesized a NIR colorimetric fluorescence probe Cy-NB (Fig. 37, probe 54) to selectively detect GSH and cysteine (Cys) in the mitochondria for indicating oxidative stress. Indole heptamethine cyanine dye was used as the fluorescent group of Cy-NB, and p-nitrobenzoyl was used as the fluorescent regulator. The uncaged p-nitrobenzoyl rearranged the polymethine π-electron system of the fluorophore with the triggering of Cys, leading to remarkable spectrum shifts in absorption and emission profiles. A quantitative fluorescence signal of Cys with a detection limit of 0.2 μM within 5 min was obtained on the basis of the aforementioned spectral characteristics. The Cy-NB probe sensitively detected the changes of the mitochondrial Cys pool in the HepG2 cells under different oxidative stresses. Cy-NB was successfully used in the imaging of Cys level changes in live mice. Mitochondrial Cys could be used as a biomarker of toxic stress and utilized in clinical applications.

Liu et al. [77] reported a heptamethine cyanine probe DNIR (Fig. 38, probe 65) to detect GSH and its oxidative form (GSSG) in blood. The NIR excitation wavelength was 804 nm, and the NIR emission wavelength was 832 nm. The probe contained a fluorescent group of heptamethylene cyanine linked to the functional group of nitro azoaryl ether. It had rapid reaction (3 min) and good selectivity toward GSH. The selectivity of the probe to GSH was better than that to GSSG and other amino acids (AAs). The probe rapidly reacted to GSH, especially in the presence of GSH reductase and nicotinamide dinucleotide phosphate, and showed good performance for the indirect detection of GSH without requiring separation prior to fluorescence measurement.

Fig. 38
figure38

Structure of probe 65

Fluorescent probes to detect selenocysteine

Selenocysteine (Sec) is a highly reactive and unstable active selenium in cells. Although it has antioxidant activity in various liver diseases, Sec in living cells is difficult to determine in vivo. Han et al. reported a proportional NIR fluorescence probe Cy-SS (Fig. 39, probe 66) consisting of a heptamethylcyanine fluorescent group, reaction unit bis (2-hydroxyethyl) disulfide, and liver targeting d-galactose to quantitatively and qualitatively measure Sec in living cells in vivo. On the basis of the detection mechanism of the selenium-sulfur exchange reaction, the Sec concentrations in HepG2, HL-7702 cells, and primary mouse hepatocytes were 3.08 ± 0.11 × 10−6, 4.03 ± 0.16 × 10−6, and 4.34 ± 0.30 × 10−6 m, respectively. The experiment showed that the probe had high selectivity in the liver. The specific fluorescence signal of the probe could be used to quantitatively analyze the changes of Sec concentrations in cells and acute hepatitis mice models [78].

Fig. 39
figure39

Structure of probe 66

Fluorescent probes to detect cyanide anion

Liu et al. reported a NIR fluorescence probe T-Cy (Fig. 40, probe 67) to detect CN. The ultraviolet–visible (UV–vis) absorption and fluorescence spectra of the probe significantly changed with the addition of CN, and the color changes were visible to the naked eye. The change in the spectral signal was linearly proportional to the CN concentration. The detection limits of the probe were 14 nM and 0.23 μM in CH3CN and CH3CN/H2O (9/1, v/v), respectively. The probe showed high selectivity and anti-interference to CN under the presence of other common anions (F, AcO, Br, NO2, Cl, SO42−, I, HCO3, CO32−, SCN) and biothiol (Cys/HCy/GSH). The test strip of the probe was suitable for detecting CN, and fluorescence imaging showed the potential biological value of the probe [79].

Fig. 40
figure40

Structure of probe 67

Chen et al. [80] synthesized a detection of cyanide ion of NIR fluorescence probe Cy-I (Fig. 24, probe 44), and probe the Cy-I identify groups with copper ions, since light induced effects of electron transfer fluorescence signal disappears, when after the above add cyanide ion in the solution, as a result of the combination of cyanide ion and copper ion ability was stronger, from cyanide ion probe Cy-I, PET effect change, fluorescence and recovery.

figure1

Fluorescent probes to detect inorganic phosphate anions

The absorbance of phosphate anion was determined using a NIR reagent. The method was tested with two reagents, namely, anionic heptamethine cyanine (Fig. 41, probe HMC) and Tb3+. At the specified concentration, the addition of Tb3+ reduced the maximum absorbance of heptamethine cyanine to 778 nm, but the absorbance returned to the original value with the addition of phosphate anion. Under optimal conditions, the reciprocal degree of absorbance was proportional to the concentration of phosphate anion. Other ions had small interference because phosphate anion had a special affinity to Tb3+. This method is successfully applied to determine inorganic phosphate anions in human saliva samples [81].

Fig. 41
figure41

Structure of probe HMC

Application of NIR fluorescence probes to labeled tumor cell types

Cancer is a general term for a large class of malignant tumors, and it poses a serious threat to human life and health. Millions of people die from cancer every year. Cancer has constantly been a top priority in life science and medical research [82]. Therefore, a low-cost, low-harm, real-time, and in situ method should be developed to detect the location, size, and status of tumors. The development of NIR fluorescence probes has turned this idea into a reality. [83].

Tumor and normal cells have different energy metabolism pathways. The glycolysis rate of malignant tumor cells is higher than that of normal cells, and normal cells mainly consume most glucose through the glycolysis pathway. The specific molecular mechanism of high glycolysis energy in tumor cells remains unclear. The high glycolysis activity of tumor cells may be related to the low expression of enzymes and transporters, high sensitivity of DNA to oxidative stress, and overexpression of glycolytic enzymes and glucose transporters.

Shen et al. [84] reported a novel NIR probe Q3STCy (Fig. 42, probe 68) to detect and visualize the NAD (P) H quinone reductase activity of endogenous cells in 2D and 3D cancer cell cultures and established preclinical in vivo models of diffused peritoneal ovarian cancer. hNQO1(quinone oxidoreductase isozyme I) specific reductive activation of the carefully crafted, electron-transfer quenched probe leaded to autonomous release of its corresponding tricarbocyanine reporter. The Q3STCy probe had an energy-specific NIR fluorescence emission that was stronger than that of inactive probes by several orders of magnitude. The probe/reporting system could detect and differentiate human cancer cells with different hNQO1 activity levels, including cells experiencing different microenvironments because of their location in multicellular tumor mimics. The probe dilution could be locally used in mouse xenotransplantation models to identify human ovarian cancer tumors smaller than 0.5 mm in size. Quinone reductase-activated probes had high specificity and sensitivity for the detection of microtumors and were thus suitable for the evaluation of drug action and efficacy in clinical-related tumor models and preclinical animal studies.

Fig. 42
figure42

Structure of probe 68

Self-assembled nanoparticles (CF7Ns) of chemically synthesized folate (FA) and heptamethine cyanine-modified chitosan (CF7, Fig. 43, probe 69) were developed for tumor-specific imaging and photodynamic therapy. The spectrum showed that CF7 had a good binding effect between FA and Cy7. The diameter of CF7Ns measured by DLS was approximately 291.6 nm, and the morphology observed by AFM was a filamentous cluster. The targeting effect of CF7Ns on FA receptor-positive HeLa cells was higher than that of non-FA-modified nanoparticles. The cytotoxicity and apoptotic analysis showed that the NIR irradiation of CF7Ns could induce HeLa cell apoptosis and improve the therapeutic effect. The photodynamic mechanism of CF7Ns was confirmed on the basis of the determination of ROS and cytokines related to cell apoptosis. The experiments proved that CF7Ns was a tumor targeting carrier for fluorescence imaging and photodynamic therapy [85].

Fig. 43
figure43

Structure of probe 69

The development of functional drugs with tumor-targeting anticancer activity for tumors detected in imaging determines the future of personalized cancer treatment. However, these functional preparations have not been widely used in clinical practice because of the low efficiency of drug delivery, poor imaging specificity of tumors, development of drug resistance, and safety considerations for potential toxicity. Therefore, the combination of therapeutic drugs and appropriate fluorescent probes is the commonly used strategy for the research and development of these functional drugs. Ning et al. designed and synthesized a mitochondrial-targeted visualization anticancer agent Cy-TPP with absorption and emission curves in the NIR (Fig. 44, probe 70). Subcellular localization and cell viability analysis showed that the probe had mitochondrial-targeted NIR imaging and effective antiproliferation capabilities (IC50 = 3.04 μM). Therefore, Cy-TPP can be used as a new anticancer drug with mitochondrial-targeting ability [86].

Fig. 44
figure44

Structure of probe 70

Sanpeng Li’s team synthesized a novel tumor-targeting and GSH-activated conjugate-based theranostic prodrug Cy-SS-methylate (MTX) (Fig. 45, probe 71). The prodrug was constructed by binding disulfide Cy (IR 780) to MTX. The Cy dye as the targeting molecule carried the prodrug into human cancer cells and was activated by high concentrations of GSH in the tumor. The results showed the prodrug’s good capability for targeting tumors. At the same time, the prodrug significantly improved the antitumor ability and immensely reduced the toxicity of free MTX to normal cells. The structure of prodrug Cy exhibited an absorption peak at 654 nm in the UV–vis spectrum. A new UV–vis absorption peak appeared at 802 nm in the cyanide structure of the prodrug when GSH destroyed its disulfide bond. Meanwhile, the fluorescence emission peak of 750 nm (640 nm excitation) changed to 808 nm (745 nm excitation). The PA signals excited at 680 and 808 nm changed. The drug was successfully used in NIR laser excitation and cancer-targeting therapy for fluorescence and PA imaging to track MTX activation in real time. These studies promoted the tumor-targeted heptamethine cyanine dye-based prodrug as a reporting group for targeted therapy and the real-time tracking of drug activation [87].

Fig. 45
figure45

Structure of probe 71

Meng et al. reported a small molecule probe RhoSSCy with sensing, targeting, multimode imaging, and therapeutic functions (Fig. 46, probe 72). The RhoSSCy probe was synthesized from Rho and IR765 (Cy) by combining a disulfide bond and an amino group with adjustable acidity and basicity. The probe quantitatively detected free mercaptan and directly detected the changes of intracellular acidity and alkalinity and mercaptan concentration. At the same time, RhoSSCy molecules easily entered and accumulated in the tumor cells, indicating its NIRF/PA dual-mode imaging and the anticancer effect of high-efficiency photodynamic therapy in vivo and in vitro. Overcoming the shortcomings of NIRF dyes combined with exotic thermal analysis technology, this well-defined small-molecule probe laser was deemed suitable for multimode imaging and could offer important application value for targeted molecular diagnosis and imaging treatment of cancer [88].

Fig. 46
figure46

Structure of probe 72

Luo et al. [89] investigated various response mechanisms of tumor cells and observed that that differences in the energy metabolism of tumor cells could be used as therapeutic targets for hyperglycolysis. Guo et al. [90] used tumor cells to consume more glucose in the body than normal cells to synthesize two fluorescent probes Cypate-2DG and ICG-Der-02-2DG (Fig. 47, probes 73 and 74). The tumor targets of the two NIR fluorescence probes were compared through NIR fluorescence imaging, and the results showed that ICG-Der-02-2DG was more soluble in water than Cypate-2DG and was easily removed by the kidneys. In cancer cells, a correlation was found between the targeting ability of the probe and the level of glucose transporter protein expression. Cypate-2DG and ICG-Der-02-2DG were found to have a tumor-targeting ability, but Cypate-2DG showed a stronger tumor-targeting ability and was proportional to the glucose transporter. The two probes can be widely used in the optical imaging of tumors and glucose-related diseases.

Fig. 47
figure47

Structures of probes 73 and 74

Vendrell et al. reported an NIR fluorescence glucose derivative (probe 75) (Fig. 48). The absorption rate of the probe in cancer cells was significantly higher than that in normal cells. At the same time, the probe had a stronger labeling ability for cancer cells than the NIRF dye IRDye-800CW2-DG (Fig. 48, probe 76) [91].

Fig. 48
figure48

Structures of probes 75, 76 and IRDye800CW-SAHA

Histone deacetylases (HDACs) were found to be highly expressed in tumor samples from patients with Hepatocellular carcinoma (HCC), and suberoylanilide hydroxamic acid (SAHA) was clinically demonstrated to be a potent tumor suppressor for HCC. Accordingly, in this study, researchers synthesized HDAC-targeted NIR fluorescence probes for fluorescent imaging of HCC by using SAHA, which had a high affinity to HDAC, as a targeting group. In vitro experiments, SAHA was labelled with fluorescein isothiocyanate (FITC) to test its targeting, and the results showed that FITC-SAHA was specifically absorbed by HCC Bel-7402 cells. In vivo experiments, near infrared fluorescence dye IRDye800CW-SAHA on subcutaneous and in situ HCC tumor model in mice showed a strong targeted fluorescence imaging. IRDye800CW-SAHA could successfully guide surgical resection of hepatocellular carcinoma in situ and non-toxic to healthy tissue and cells. The results showed that the IRDye800CW-SAHA was a fluorescent probe for liver cancer diagnosis and surgery navigation. [92].

Cholesterol is the main component of the cell membrane, and cancer cells require more cholesterol to proliferate than normal cells. Thus, cancer patients frequently exhibit symptoms such as low cholesterol. Low-density lipoprotein (LDL), which mainly stores cholesterol in human plasma, enters the cells mostly through receptor mediation. Therefore, the relationship of LDL receptors and tumors has been widely investigated in cancer cell research [93]. Deng et al. [94] used NIR fluorescence probes 77 and ICG-Der-02 (Fig. 49, probes 77 and 78) as structural cores and designed and synthesized the NIR organic fluorescent probes FA-PEG-ICG-Der-01 and LDL-ICG-Der-02. The fluorescence signal intensity and light stability of the synthesized FA-PEG-ICG-Der-01 and LDL-ICG-Der-02 probes were higher than those of the corresponding dye monomers. The results of in vivo targeting imaging in mice showed that the two probes could identify the biological activity of folic acid and LDL. The two probes accurately targeted relevant tumor tissues, with clear fluorescence imaging and metabolization. The probes can be used for the early diagnosis and localization of tumors.

Fig. 49
figure49

Structures of probes 77 and 78

The FA receptor (FR) is an important means for cells to acquire FA. The expression level of FR in many malignant tumors is higher than that in normal cells. Therefore, FA (the corresponding ligand of folic acid receptor) has become an important target in the treatment of malignant tumors [95]. Liu et al. [96] synthesized a fluorescent probe FPI-01 (probe 79) by linking FA with benzoindole heptamethyocyanine dye 77 (Fig. 49) and PEG (Fig. 50). The results showed that the probe has high affinity to the FA receptor without obvious cytotoxicity and metabolic excretion in vitro. The probe has great potential in the diagnosis of FA receptor-positive tumors.

Fig. 50
figure50

Structure of probe 79

Anaerobic characteristics are a prominent feature of malignant tumors. Tumor cells at different anaerobic levels have different effects on the response of tumor cells to normal chemotherapy, radiotherapy, and other nonsurgical treatments. Thus, a noninvasive imaging technology utilizing the anaerobic characteristics of malignant tumors should be developed. Youssif et al. [97] designed and synthesized a corporate probe (probe 80) for the fluorescence imaging of malignant tumors (Fig. 51). In the experiment, the fluorescence signal intensity of hypoxic cells was significantly higher than that of normal cells with the introduction of probe 80 to pancreatic cancer cells. The results showed that the fluorescence intensity of the probe in cancer cells was closely related to the anaerobic activity of cancer cells. After 6 h of injection, the fluorescence signal of the probe in the tumor significantly decreased and gradually disappeared, indicating that some structural changes and instability occurred in the anaerobic tumor cells. Thus, the probe was wrapped with nanoparticles to improve its instability to anaerobic tumors. This process prolonged the interaction of drugs and blood and significantly reduced the nonspecific accumulation of drugs in the biological system. Thus, the probe plays a role in the detection of long-term treatment.

Fig. 51
figure51

Structure of probe 80

Duan et al. developed a probe IR-783 (Fig. 52) as a rapid imaging agent to detect human cervical cancer. They investigated the uptake, accumulation, and subcellular localization of IR-783 dyes in cervical cancer cells. Mouse whole-body imaging was conducted to detect the specific staining absorption and retention of human cervical cancer xenografts and freshly collected clinical cervical cancer specimens. Frozen tissue sections were used to determine the accumulation of dyes at the tissue and cell levels. Circulating tumor cells containing cervical cancer cells in peripheral blood were detected. The results showed that IR-783 can be specifically uptaken by cultured cervical cancer cells, human cervical cancer xenotransplantation, human cervical cancer cells, and human cervical cancer tissues but not by normal cell tissues. This study demonstrated the ability of IR-783 to detect cervical cancer cells in clinical specimens and circulating blood. The probe can be used in clinical practice as a modal agent for deep tissue imaging of cervical cancer. [98].

Fig. 52
figure52

Structures of probes IR-783, CyI, and ND-PG-Cy7

Cao et al. [99] reported a novel NIR probe CyI using heavy atom iodine and ICG derivative Cy7 (Fig. 52). The probe had the ability to increase the production and heat production of ROS in vivo, and its fluorescence properties were stable, which could be used for non-invasive fluorescence imaging in vivo. In vitro and in vivo experiments showed that CyI could rapidly and simultaneously produce enhanced ROS and heat under NIR irradiation, inducing apoptosis of HepG2 tumor cells. The results indicated that the probe was an ideal deep tumor therapy agent for the rapid cooperative photodynamic therapy (PDT)/photothermal therapy (PTT) treatment of deep tumor tissue.

Nanoparticles have been reported to achieve preferential accumulation in tumors by combined effects of active and passive targeting. Herein, the researchers synthesized a polyglycerol-functionalized nanodiamonds (ND-PG), which was then combined with a cyanine dye (Cy7) to form ND-PG-Cy7. It was found that ND-PG-Cy7 could accumulate in the tumor first, and the fluorescence images in vivo and in vitro showed clear fluorescence. One possible reason was that ND-PG-Cy7 had a longer in vivo blood circulation time (half-life: 58 h determined by the pharmacokinetic analysis) [100].

Application of NIR Fluorescence probes to other fields

Indocyanine dyes can be used to detect nucleic acids, proteins, and antibodies. The convenient labeling of proteins is important to observe their functions under physiological conditions. In tissues, the value of heptadecylamine cyanide dyes (Cy-7) is obvious because they are absorbed in the NIR with large light penetration.

Lin et al. [101] observed that Cy-7 dyes contain meso-Cl and can covalently bind to free Cys residues under physiological conditions (water environment, near-neutral pH, and 37 °C). The results showed that the meso-Cl of the dye was replaced by free thiols in the protein. Moreover, the nucleophilic side chains in amino acids, such as Tyr, Lys, and Ser, did not react. This condition showed the feasibility of using NIR fluorescence probes for the convenient and selective labeling of proteins. The probe MHI-148 (Fig. 53, Probe 81) was used to label free Cys residues, such as vimentin and serum albumin [102]. Other Cy-7 dyes containing meso-Cl (Fig. 53, probes 82, 83, and 84) were used to label vimentin. This process could be applied to the combination of NIR dyes containing meso-Cl with antibodies, monomers, and nanoparticles to form selective reagents for in vivo optical imaging. This method avoided dye modification to include the functions of maleimide or succinimide compared with traditional conjugation techniques [103, 104].

Fig. 53
figure53

Structures of probes 81–84

Coline Canovas’ team proved that probe IR-783 (Fig. 53, probe 83) containing a chloro-cyclohexyl moiety within its polymethine chain can react selectively at neutral pH, with Cys residues in proteins providing stable, site-specifically labeled conjugates that are emitted in the NIR spectral window. An example of this reaction was the labeling of polypeptides and two protein models, namely, albumin and Fab’ antibody fragments. As shown in the mouse model, the obtained fluorescent protein was stable and suitable for NIR fluorescence imaging in vivo. This simple step did not require the prior derivatization of the fluorophore with a biological conjugated handle and might promote the production and use of near-infrared-labeled proteins in life sciences [105].

Hong et al. [106] reported the determination of nucleic acid using a new indoxymethachene NIR fluorescence cyanine dye at the range of 0.08–1.2 g/mL. James et al. [107] synthesized an NIRF cyanine dye using succinimide ester and isocyanate as the recognition group and cyanine dye as the fluorophore. The experimental results showed that the dye has good physiological activity. Pham et al. [108] synthesized probe NIR820 (Fig. 54, probe 85) with good stability and fluorescence, and involved a simple operation, entailed low costs, and enabled the easy purification.

Fig. 54
figure54

Structure of probe 85

A novel NIR fluorescence probe NIR820-Tf was generated by combining TfR with NIR820 (Fig. 55). Fluorescence signals were observed in the tumor cells with the introduction of the probe in the gliosarcoma cell culture for 1 h. This result indicated that the NIR fluorescence-labeled Tf was absorbed by the cells and that NIR820-Tf did not hinder the absorption of Tf by gliosarcoma cells. Experiments showed that the dye NIR820, which was not bound to Tf, did not penetrate the cell membrane of gliosarcoma and must be metabolized and excreted from the body. The integrin ανβ3 receptor is not expressed in normal tissues but is overexpressed in many tumor cells. Thus, the integrin ανβ3 receptor can be used as a target for the diagnosis of tumor cells. Houston et al. [109] synthesized a new NIR fluorescence probe NIR820-Tf and labeled it with the radioactive isotope IIIIn and IRDye800 integrin ανβ3 for the detection of melanoma.

Fig. 55
figure55

Structure of probe NIR820-Tf

MMPs are a group of proteases that degrade the extracellular matrix and other extracellular proteins. Inactive MMPs are metabolized to the cell membrane or extracellular proteins. The active sites can be observed in the catalytic region through the hydrolysis and removal of the prepeptide region, thus activating the MMPs. Studies have shown that MMPs, including MMP-2 and MMP-9, are highly expressed in various tumor cells. Akers et al. [110] synthesized an NIR fluorescence probe LS276-THP based on trihelicopeptide to detect cancer-related MMPs in vivo. The fluorescence signal of the probe was enhanced, and the fluorescence quantum yield of the probe increased by approximately four times when trihelicopeptide was hydrolyzed, catalyzed, and activated and then released six labeled peptide chains by MMPs. After the self-assembly of the three-helix structure, the fluorophores were relatively close to one another because of the intertwined peptide chains, resulting in fluorescence quenching and reduction of the corresponding fluorescence intensity. LS276-THP was injected into tumor-inoculated mice, and the detection showed that the fluorescence signal in the tumor tissue was stronger than that in normal muscle tissue. Subsequently, Ilomastat, an MMP inhibitor, was injected into the above experimental mice, and the fluorescence signal intensity was found to be weakened. The results showed that LS276-THP was suitable for the detection of tumor-related MMP-2 and MMP-9 in vivo.

Monoamine oxidase (MAOs) is a novel biomarkers, including MAO-A and MAO-B isoforms. It plays an important role in maintaining the homeostasis of biogenic amines via catalyzing the oxidation of biogenic amines to generate the corresponding aldehydes and ROS. MAO-A is thought to be associated with neuropsychiatric and depressive disorders, while MAO-B is thought to be associated with several neurodegenerative. Therefore, in order to investigate their different roles in different diseases, it is essential to selectively detect changes in MAOs. Two novel NIR fluorescence probes, MitoCy-NH2 and MitoHCy-NH2 (Fig. 56), were synthesized to provide synergistic imaging of MAO-B and its contribution to oxidative stress in cells and in mice aging models. These probes were composed of heptamethine cyanine, propanamide and triphenylphosphonium cation. In the replicative senescence model, MitoHCy-NH2 had the ability to synergistically detect MAO-B and its response to oxidative stress. And the probe MitoCy-NH2 could offer ratiometric NIR fluorescence for the selective detection of MAO-B in the H2O2-induced cell aging model and in mice aging models. The excellent detection performance of these probes maked them useful chemical tools for selective analysis of MAO-B and its contribution to oxidative stress in biological systems [111].

Fig. 56
figure56

Structures of probes MitoCy-NH2 and MitoHCy-NH2

Conclusions

With the rapid development of optical detection and imaging technology, researchers have widely investigated the use of NIRF dyes as fluorescent probes and indicators. In this study, the research progress of indole heptamethylene cyanine dyes was reviewed in terms of the structure, properties, and biological applications of NIR fluorescence probes to provide reference for the future development and research of novel indole heptamethylene cyanine dyes.

Two important advantages of indole heptamethylene cyanine dyes are their small self-fluorescence and the background absorption of the tissue itself. However, the application of indole heptamethylene cyanine dyes is hindered because of the lack of fluorophores with high light stability and high fluorescence efficiency. Few indole heptamethylene cyanine dyes that are applicable to biology have been widely used in commercial applications. Many new indole heptamethylene cyanine dyes with good fluorescence performance have been developed to meet the biological detection requirements of fluorescent probes. Different groups should be introduced in the dye structure, and the stability and fluorescence efficiency of dyes can be improved by changing their molecular structure with different biological detection functions. Indole heptamethylene cyanine dyes with low background, strong light stability, high fluorescence quantum yield, and easy purification should be developed.

Availability of data and materials

Data supporting our findings is contained within the manuscript; any additional data will be shared upon request to the corresponding author.

Abbreviations

NIR:

Near-infrared

NIRF:

Near-infrared fluorescent

PTT:

Photothermal therapy

PY:

N1-(pyridine-4-methyl) ethane-1,2-diamine

PA:

Photoacoustic

PEG:

Polyethylene glycol

ICG:

Indocyanine green

SCy-OHs:

Tautomorphic isomer

DIPCY:

Dipicolylcyanine

DPEN:

Dipicolylethylenediamine

H2Sn :

Hydrogen polysulfide

ROS:

Reactive oxygen species

H2O2 :

Hydrogen peroxide

O·−2 :

Superoxide anion radical

HO·:

Hydroxyl radical

ONOO :

Peroxynitrite

NO:

Nitric oxide

GSH:

Glutathione

AAs:

Amino acids

Sec:

Selenocysteine

UV-vis:

Ultraviolet-visible

hNQO1:

Quinone oxidoreductase isozyme I

FA:

Folate

MTX:

Cy-SS-methylate

HDACs:

Histone deacetylases

HCC:

Hepatocellular carcinoma

SAHA:

Suberoylanilide hydroxamic acid

FITC:

Fluorescein isothiocyanate

LDL:

Low-density lipoprotein

FR:

Folate receptor

PDT:

Photodynamic therapy

PTT:

Photothermal therapy

ND-PG:

Polyglycerol-functionalized nanodiamonds

MAOs:

Monoamine oxidase

References

  1. 1.

    Mohammad I, Stanford C, Morton MD et al (2013) Structurally modified indocyanine green dyes. Modification of the polyene linker. Dyes Pigm 99:275–283

    CAS  Article  Google Scholar 

  2. 2.

    Lin YH, Weissleder R et al (2002) Novel near-infrared cyanine fluorochromes: synthsis, properties and bioconjugation. Bioconjug Chem 13:605–610

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Alaa SA, Elizabeth AS et al (2015) Design and spectroscopic characterization of novel series of near infrared indocyanine dyes. J Mol Struct 5:228–235

    Google Scholar 

  4. 4.

    Guilbault GG (1973) Practical Fluorescence Theory, Methods and Techniques. Marcel Dekker 598, New York

    Google Scholar 

  5. 5.

    Udenfriend S (1962) Fluorescence assay in biology and medicine. Academic Press 470, New York

    Google Scholar 

  6. 6.

    Wu A, Duan L (2011) A near-infrared fluorescent sensor for H+ in aqueous solution and living cells. Turk J Chem 35:475–479

    CAS  Google Scholar 

  7. 7.

    Michael EC, Susan G, Elaine A et al (2002) pH-sensitive cyanine dyes for biological applications. J Fluor 12:425–429

    Article  Google Scholar 

  8. 8.

    Watrob HM, Pan CP, Barkley MD (2003) Two-step FRET as a structural tool. J Am Chem Soc 125:7336–7343

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Mi L, Wu K et al (2008) Study on determination of bovine serum albumin by fluorescence resonance energy transfer. Chem Res Appl 20(2):181–183

    CAS  Google Scholar 

  10. 10.

    Wei Y, Li Y et al (1998) Application of fluorescence resonance energy transfer technique in bioanalysis. Chin J Anal Chem 26(4):477–484

    CAS  Google Scholar 

  11. 11.

    Xie X, Xia N (2001) Progress of the studies and applications of fluorescence resonance energy transfer in the field of biology. Lett Biotechnol 12(3):831–837

    Google Scholar 

  12. 12.

    Posch HE, Leiner MJ, Wolfbeis OS (1989) Towards a gastric pH-sensor: an optrode for the pH 0–7 range. Fresenius’ Z Anal Chem 334(2):162–165

    CAS  Article  Google Scholar 

  13. 13.

    Jiang L, Ding L, Fang Y, Hu D (2004) Progress in the application studies of fluorescence resonance energy transfer in biological science and supra-molecular science. Chin J Nat 26(6):333–338

    Google Scholar 

  14. 14.

    Liu C, Hang H (2006) A progress in detection of interactions between macromolecules: linked FRET using three color fluorophore. Progr Biochem Biophys 33(3):292–296

    CAS  Google Scholar 

  15. 15.

    Anderson S, Anderson HL, Bashall A et al (1995) Assembly and crystal structure of a photoactive array of five porphyrins. Angew Chem Int Ed Engl 34:1096–1099

    CAS  Article  Google Scholar 

  16. 16.

    Fuh MRS, Burgess LW, Hirschfeld T et al (1987) Single fibre optic fluorescence pH probe. Analyst 112:1159–1163

    CAS  Article  Google Scholar 

  17. 17.

    Khramtsov VV, Grigor EIA et al (2000) Biological applications of spin pH probes. Cell Mol Biol 46(8):1361–1374

    CAS  PubMed  Google Scholar 

  18. 18.

    Russell DA, Pottier RH et al (1994) Continuous noninvasive measurement of in vivo pH in conscious mice. Photochem Photobiol 59(3):309–313

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Xue F, Wen Y, Wei P et al (2017) A smart drug: a pH-responsive photothermal ablation agent for golgi apparatus activated cancer therapy. Chem Commun 53:6424–6427

    CAS  Article  Google Scholar 

  20. 20.

    Fang M, Xia S, Bi J et al (2018) A cyanine-based fluorescent cassette with aggregation-induced emission for sensitive detection of pH changes in live cells. Chem Commun 54:1133–1136

    CAS  Article  Google Scholar 

  21. 21.

    Meng X, Li W, Sun Z, Zhang J et al (2017) Tumor-targeted small molecule for dual-modal imaging-guided photo therapy upon near-infrared excitation. J Mater Chem B 5:9405–9411

    CAS  Article  Google Scholar 

  22. 22.

    Zhang Y, Bi J, Xia S, Mazi W, Wan S, Mikesell L et al (2018) A near-infrared fluorescent probe based on a FRET rhodamine donor linked to a cyanine acceptor for sensitive detection of intracellular pH alternations. Molecules 23:2679

    PubMed Central  Article  CAS  Google Scholar 

  23. 23.

    Mu H, Miki K, Takahashi Y, Teshima N, Oe M, Kojima K et al (2018) pH responsiveness of near-infrared fluorescent cyanine dyes encapsulated in self-assemblies composed of various amphiphiles. Chem Lett 47(9):180402

    Article  CAS  Google Scholar 

  24. 24.

    Miki K, Kojima K, Oride K, Harada H, Morinibu A, Oh K (2017) pH-Responsive near-infrared fluorescent cyanine dyes for molecular imaging based on pH sensing. Chem Commun 53:7792–7795

    CAS  Article  Google Scholar 

  25. 25.

    Hou J, Jin D, Chen B, Si L, Jin Y, Chen L et al (2017) Two near-infrared highly sensitive cyanine fluorescent probes for pH monitoring. Chin Chem Lett 28:1681–1687

    CAS  Article  Google Scholar 

  26. 26.

    Zheng L, Wang L, Liu Y, Guo C, Hou Y, Liu X et al (2018) The pH response of near infrared 5,5′-bisulfonic heptamethine indocyanines in water, CTAB solution and metal oxide-based sol under extremely acidic and basic conditions. Colloids Surf A 546:83–90

    CAS  Article  Google Scholar 

  27. 27.

    Zhang J, Liu Z, Lian P, Qian J, Li X, Wang L et al (2016) Selective imaging and cancer cell death via pH switchable near-infrared fluorescence and photothermal effects. Chem Sci 7:5995–6005

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    He L, Lin W, Xu Q, Ren M, Wei H, Wang JY (2015) A simple and effective “capping” approach to readily tune the fluorescence of near-infrared cyanines. Chem Sci 6:4530–4536

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Tang B, Liu X, Xu K et al (2007) A dual near-infrared pH fluorescent probe and its application in imaging of HepG2 cells. Chem Commun 36:3726–3728

    Article  CAS  Google Scholar 

  30. 30.

    Tang B, Yu F, Li P (2009) A near-infrared neutral pH fluorescent probe for monitoring minor pH changes: imaging in living HepG2 and HL-7702 Cells. J Am Chem Soc 131:3016–3023

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Kiyose K, Aizawa S, Sasaki E et al (2009) Molecular design strategies for near-infrared ratiometric fluorescent probes based on the unique spectral properties of aminocyanines. Chem Eur J 15(36):9191–9200

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Zhang Z, Shen D, Liang K et al (2005) Design, synthesis and evaluation of near infrared fluorescent ph indicators at physiological range. Chem Commun 21(47):5887–5889

    Article  CAS  Google Scholar 

  33. 33.

    Mikhail YB, Kevin G, Walter A et al (2011) Near-infrared fluorescence lifetime ph-sensitive probes. Biophys J 100:2063–2072

    Article  CAS  Google Scholar 

  34. 34.

    Liu J (2001) physiological and biochemical function of magnesium ion on human body. J Jiangxi Inst Educ (Nat Sci) 22(6):44–46

    Google Scholar 

  35. 35.

    Boening DW (2000) Ecological effects, transport, and fate of mercury: a general review. Chemosphere 40(12):1335–1351

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Silva JJ (2001) Williams R J. The Inorganic Chemistry of Life. Oxford University Press, New York, The Biological Chemistry of the Elements

    Google Scholar 

  37. 37.

    Tang Y, Luo C et al (2007) A novel near-infrared fluorescent probe for Zn2+. Acta Chim Sinica 65:1229–1233

    CAS  Google Scholar 

  38. 38.

    Li P, Duan X, Chen Z et al (2011) A near-infrared fluorescent probe for detecting copper (II) with high selectivity and sensitivity and its biological imaging applications. Chem Commun 47:7755–7757

    CAS  Article  Google Scholar 

  39. 39.

    Sun H, Chen R (2002) Metals in biology and medicine. Prog Chem 14(4):257–262

    CAS  Google Scholar 

  40. 40.

    Sun W, Hu D, Wu Z et al (2011) Research progress of fluorescent molecular probes for heavy and transition metallic cations based on rhodamine fluorophore. Chin J Org Chem 31(7):997–1010

    CAS  Google Scholar 

  41. 41.

    Tang B, Cui L, Xu K et al (2008) A sensitive and selective near-infrared fluorescent probe for mercuric ions and its biological imaging applications. Chem BioChem 9(7):1159–1164

    CAS  Google Scholar 

  42. 42.

    Li S, Zhang D, Xie X, Ma S, Liu Y, Xu Z et al (2016) A novel solvent-dependently bifunctional NIR absorptive and fluorescent ratiometric probe for detecting Fe3+/Cu2+ and its application in bioimaging. Sens Actuators B 224:661–667

    CAS  Article  Google Scholar 

  43. 43.

    Guo Z, Zhu W, Zhu M, Wu X, Tian H (2010) Near-infrared cell-permeable Hg2+-selective ratiometric fluorescent chemodosimeters and fast indicator paper for MeHg+ based on tricarbocyanines. Chem Eur J 16:14424–14432

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Gao X, Wu W, Xi J, Zheng H (2017) Manipulation of monomer-aggregate transformation of a heptamethine cyanine ligand: near infrared chromogenic recognition of Hg2+. RSC Adv 7:32732–32736

    CAS  Article  Google Scholar 

  45. 45.

    Wang Y, Gao M, Chen Q, Yu F, Jiang G, Chen L (2018) Associated detection of superoxide anion, mercury(II) under chronic mercury exposure in cells and mice models via a three-channel fluorescent probe. Anal Chem 90(16):9769–9778

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Maity D, Raj A et al (2015) A switch-on near-infrared fluorescence-ready probe for Cu(I): live cell imaging. Supramol Chem 27(9):589–594

    CAS  Article  Google Scholar 

  47. 47.

    Long L, Tan X, Luo S, Shi C (2017) Fluorinated near-infrared fluorescent probes for specific detection of Hg2+ in an aqueous medium and mitochondria of living cells. New J Chem 41:8899–8904

    CAS  Article  Google Scholar 

  48. 48.

    Kiyose K, Kojima H, Urano Y et al (2006) Development of a ratiometric fluorescent zinc ion probe in near-infrared region, based on tricarbocyanine chromophore. J Am Chem Soc 128(20):6548–6549

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Kiyose K, Kojima H, Nagano T (2008) Functional near-infrared fluorescent probes. Chem Asian J 3(3):506–515

    CAS  Article  Google Scholar 

  50. 50.

    Tang B, Huang H, Xu K et al (2006) Highly sensitive and selective near-infrared fluorescent probe for zinc and its application to macrophage cells. Chem Commun 34:3609–3611

    Article  CAS  Google Scholar 

  51. 51.

    Zhu M, Yuan M, Liu X et al (2008) Visible near-infrared chemosensor for mercury ion. Org Lett 10:1481–1484

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Cao XW, Lin W, Wan W (2012) Development of a near-infrared fluorescent probe for imaging of endogenous Cu+ in live cells. Chem Commun 48(50):6247–6249

    CAS  Article  Google Scholar 

  53. 53.

    Han Z, Yang Q, Liang L, Zhang X (2013) A new heptamethine cyanine-based near-infrared fluorescent probe for divalent copper ions with high selectivity. Adv Mater Phys Chem 3:314–319

    Article  CAS  Google Scholar 

  54. 54.

    Li P, Duan X, Chen Z et al (2011) A near-infrared fluorescent probe for detecting copper (II) with high selectivity and sensitivity and its biological imaging applications. Chem Commun 47(27):7755–7757

    CAS  Article  Google Scholar 

  55. 55.

    Yang Y, Cheng T, Zhu W et al (2011) Highly selective and sensitive near-infrared fluorescent sensors for cadmium in aqueous solution. Org Lett 13:264–267

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Tarazi L, Choi H, Christian MJ et al (2002) Characterization of a novel crown ether-bearing near-infrared heptamethine cyanine dye. Microchem J 72:55–62

    CAS  Article  Google Scholar 

  57. 57.

    Li P, Fang LB, Zhou H et al (2011) A new radiometric fluorescent probe for detection of Fe2+ with high sensitivity and its intracellular imaging applications. Chem Eur J 17(38):10519–10522

    Google Scholar 

  58. 58.

    Yang X, Zhang C, Shen L, Bao H, Xu J, Fang X et al (2017) A near-infrared fluorescent probe for sulfide detection. Sens Actuators B 242:332–337

    CAS  Article  Google Scholar 

  59. 59.

    Cao X, Lin W, He L (2011) A near-infrared fluorescence turn-on sensor for sulfide anions. Org Lett 13(17):4716–4719

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Jiang Y, Jin D, Li Y, Yan X, Chen L (2017) A near-infrared fluorescent probe for rapid and selective detection of hydrosulfide and imaging in live cells. Res Chem Intermed 5(43):2945–2957

    Article  CAS  Google Scholar 

  61. 61.

    Hang P, Han X, Yu F, Chen L (2016) Small-molecular fluorescent probes for the detection of hydrogen polysulfide ides and nitroxyl. Imaging Sci Photochem 34(5):402–425

    Google Scholar 

  62. 62.

    Huang Y, Yu F, Wang J, Chen L (2016) Near-infrared fluorescence probe for in situ detection of superoxide anion and hydrogen polysulfides in mitochondrial oxidative stress. Anal Chem 88(7):4122–4129

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Liu X (2008) Development and application of a novel fluorescent probe for the study of cell physiological characteristics: [Master Thesis]. Shandong Normal University, Jinan

    Google Scholar 

  64. 64.

    Oushiki D, Kojima H, Tera T et al (2010) Development and application of a near-infrared fluorescence probe for oxidative stress based on differential reactivity of linked cyanine dyes. J Am Chem Soc 132:2795–2801

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  65. 65.

    Yu F, Li I, Li G et al (2011) A near-IR reversible fluorescont probe modulated by selenium for monitoring peroxynitrite and imaging in living cells. J Am Chem Soc 133(29):11030–11033

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Xu K, Wang L, Qiang M et al (2011) A selective near-infrared fluoresent probe for singlet oxygen in living cells. Chem Commun 47:7386–7388

    CAS  Article  Google Scholar 

  67. 67.

    Wang R, Yu F, Chen L et al (2012) A highly selective turn-on near-infrared fluorescent probe for hydrogen sulfide detection and imaging in living cells. Chem Commun 48:11757–11759

    CAS  Article  Google Scholar 

  68. 68.

    Zhu D, Li G, Xue L et al (2013) Development of ratiometric near-infrared fluorescent probes using analyte-specific cleavage of carbamate. Org Biomol Chem 11(28):4577–4580

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  69. 69.

    Yu F, Li P, Song P et al (2012) Facilitative functionalization of cyanine dye by an on-off-on fluorescent switch for imaging of H2O2 oxidative stress and thiols reducing repair in cells and tissues. Chem Commun 48(41):4980–4982

    CAS  Article  Google Scholar 

  70. 70.

    Yu F, Li P, Song P et al (2012) An ICT-based strategy to a colorimelric and ratiometric fluorcscenco probe for hydrogen sulfide in living cells. Chem Commun 48(23):2852–2854

    CAS  Article  Google Scholar 

  71. 71.

    Yu F, Li P, Wang B et al (2013) Reversible near-infrared fluorescent probe introducing tellurium to mimetic glutathione peroxidase for monitoring the redox cycles between peroxynitrite and glutathione in vivo. J Am Chem Soc 135(20):7674–7680

    CAS  PubMed  Article  Google Scholar 

  72. 72.

    Xu K, Sun S, Li J et al (2012) A near-infrared fluorescent probe for monitoring ozone and imaging in living cells. Chem Commun 48(5):684–686

    CAS  Article  Google Scholar 

  73. 73.

    Han X, Wang R, Song X, Yu F, Lv C, Chen L (2018) A mitochondrial-targeting near-infrared fluorescent probe for bioimaging and evaluating endogenous superoxide anion changes during ischemia/reperfusion injury. Biomaterials 156:146

    Article  CAS  Google Scholar 

  74. 74.

    Sasaki E, Kojima H, Nishimatsu H et al (2005) Highly sensitive near-infrared fluorescent probes for nitric oxide and their application to isolated organs. J Am Chem Soc 127:3684–3685

    CAS  PubMed  Article  Google Scholar 

  75. 75.

    Han X, Song X, Yu F, Chen L (2017) A ratiometric fluorescent probe for imaging and quantifying anti-apoptotic effects of GSH under temperature stress. Chem Sci 8:6991–7002

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76.

    Yin K, Yu F, Zhang W, Chen L (2015) A near-infrared ratiometric fluorescent probe for cysteine detection over glutathione indicating mitochondrial oxidatives tress in vivo. Biosens Bioelectron 74:156–164

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  77. 77.

    Liu C, Qi F, Wen F, Long L, Yang R (2018) Fluorescence detection of glutathione (gsh) and oxidized glutathione (GSSG) in blood with a NIR-Excitable cyanine probe. Methods Appl Fluor 6(2):024001

    Article  CAS  Google Scholar 

  78. 78.

    Han X, Song X, Yu F, Chen L (2017) A ratiometric near-infrared fluorescent probe for quantification and evaluation of selenocysteine-protective effects in acute inflammation. Adv Funct Mater 27:1700769

    Article  CAS  Google Scholar 

  79. 79.

    Liu Y, Qiu D, Pan H, Li M, Chen H, Lia H (2018) A highly selective fluorescent probe for colorimetric recognition of cyanide anion based on heptamethine cyanine-triphenylamine conjugate. J Photochem Photobiol A 364:151–158

    CAS  Article  Google Scholar 

  80. 80.

    Chen X, Nam S, Kim G et al (2010) A near-infrared fluorescent sensor for detection of cyanide in aqueous solution and its application for bioimaging. Chem Commun 46(47):8953–8955

    CAS  Article  Google Scholar 

  81. 81.

    Gao X, Xu J, Ye B, Wu W, Zheng H (2019) Determination of phosphate anions with a nearinfrared heptamethine cyanine dye in a neutral aqueous solution. Anal Methods 11:2677–2682

    CAS  Article  Google Scholar 

  82. 82.

    Mahounga DM, Shan L, Cao J et al (2012) Synthesis of a novel l-Methyl-Methodize-ICGDer-02 fluorescent probe for in vivo near infrared imaging of tumors. World Mol Imaging Soc 14(6):669–707

    Google Scholar 

  83. 83.

    Gao M, Yu F, Lv C, Choo J, Chen L (2017) Fluorescent chemical probes for accurate tumor diagnosis and targeting therapy. Chem Soc Rev 46(8):2237–2271

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Shen Z, Prasai B, Nakamura Y, Kobayashi H et al (2017) A near-infrared, wavelength-shiftable, turn-on fluorescent probe for the detection and imaging of cancer tumor cells. ACS Chem Biol 124:1121–1132

    Article  CAS  Google Scholar 

  85. 85.

    Zhang Y, Lv T, Zhang H, Xie X, Li Z, Chen H, Gao Y (2017) Folate and heptamethine cyanine modified chitosan-based nanotheranostics for tumor targeted near-infrared fluorescence imaging and photodynamic therapy. Biomacromolecules 18(7):2146–2160

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Ning J, Huang B, Wei Z, Li W, Zheng H, Ma L et al (2017) Mitochondria targeting and near-infrared fluorescence imaging of a novel heptamethine cyanine anticancer agent. Mol Med Rep 15:3761–3766

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    Li S, Sun Z, Meng X, Deng G, Zhang J, Zhou K et al (2018) Targeted methotrexate prodrug conjugated with heptamethine cyanine dye improving chemotherapy and monitoring itself activating by dual-modal imaging. Front Mater 5:35

    Article  Google Scholar 

  88. 88.

    Meng X, Yang Y, Zhou L, Zhang I, Lv Y, Li S et al (2017) Dual-responsive molecular probe for tumor targeted imaging and photodynamic therapy. Theranostics 7(7):1781–1794

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    Luo X, Cao Y (2011) Research progress on bioenergy metabolic mechanism of cancer. Prog Biochem Biophy 38(7):585–592

    CAS  Article  Google Scholar 

  90. 90.

    Guo J, Du C, Shan L et al (2012) Comparison of near-infrared fluorescent deoxyglucose probes with different dyes for tumor diagnosis in vivo. Contrast Media Mol Imaging 7(3):289–301

    CAS  PubMed  Article  Google Scholar 

  91. 91.

    Vendrell M, Samanta A, Yun S et al (2011) Synthesis and characterization of a cell-permeable near-infrared fluorescent deoxyglucose analogue for cancer cell imaging. Org Biomol Chem 9:4760–4762

    CAS  PubMed  Article  Google Scholar 

  92. 92.

    Tang C, Du Y, Liang Q, Cheng Z, Tian J (2019) Development of a novel histone deacetylase-targeted near-infrared probe for hepatocellular carcinoma imaging and fluorescence image-guided surgery. Mol Imag Biol. https://doi.org/10.1007/s11307-019-01389-4

    Article  Google Scholar 

  93. 93.

    Xu S (1992) Low density lipoprotein receptor and its relationship with tumor. Chin Acad J Electron Publ House 19(1):29–32

    Google Scholar 

  94. 94.

    Deng D, Liu F et al (2010) Synthesis and tumor targeting research of two near-infrared fluorescence probes. Chin J Lasers 37(11):2735–2742

    CAS  Article  Google Scholar 

  95. 95.

    Hang Y (2012) The role of folate receptors in the targeted diagnosis and treatment of carcinoma. J Fudan Univ 39(1):74

    Google Scholar 

  96. 96.

    Yan X, Liu N, Wu G (2011) Application of in vivo near infrared imaging technology in tumor research. J Southeast Univ (Med Sci Edi) 30(2):380–383

    Google Scholar 

  97. 97.

    Youssif BG, Okuda K, Kadonosono T et al (2012) Development of a hypoxia-selective near-infrared fluorescent probe for non-invasive tumor imaging. Chem Pharm Bull 60(3):402–407

    CAS  PubMed  Article  Google Scholar 

  98. 98.

    Duan L, Wang L, Zhang C, Yu L, Guo F, Sun Z, Xu Y, Yan F (2019) Role of near-infrared heptamethine cyanine dye IR-783 in diagnosis of cervical cancer and its mechanism. Int J Clin Exp Pathol 12(6):2353–2362

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Cao J, Chi J, Xia J, Zhang Y, Han S, Sun Y (2019) Iodinated cyanine dyes for fast near-infrared-guided deep tissue synergistic phototherapy. ACS Appl Mater Interfaces 11:25720–25729

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Yoshino F, Amano T, Zou Y et al (2019) Preferential tumor accumulation of polyglycerol functionalized nanodiamond conjugated with cyanine dye leading to near-infrared fluorescence in vivo tumor imaging. Small 15:1901930

    CAS  Article  Google Scholar 

  101. 101.

    Lin C, Usama SM, Burgess K (2018) Site-specific labeling of proteins with near-ir heptamethine cyanine dyes. Molecules 23:2900

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  102. 102.

    Usama SM, Lin C, Burgess K (2018) On the mechanisms of update of tumor-seeking cyanine dyes. Bioconjugate Chem 29(11):3886–3895

    CAS  Article  Google Scholar 

  103. 103.

    Sato K, Gorka AP, Nagaya T, Michie MS, Nakamura Y, Nani RR, Coble VL, Vasalatiy OV, Swenson RE, Choyke PL et al (2016) Effect of charge localization on the in vivo optical imaging properties of near-infrared cyanine dye/monoclonal antibody conjugates. Mol BioSyst 12:3046–3056

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Nani RR, Gorka AP, Nagaya T, Kobayashi H, Schnermann MJ (2015) Near-IR light-mediated cleavage of antibody-drug conjugates using cyanine photocages. Angew Chem Int Ed 54:13635–13638

    CAS  Article  Google Scholar 

  105. 105.

    Canovas C, Bellaye PS, Moreau M, Romieu A, Denat F, Goncalves V (2018) Site-specific near-infrared fluorescent labelling of proteins on cysteine residues with meso-chlorosubstituted heptamethine cyanine dyes. Org Biomol Chem 16:8831

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  106. 106.

    Zhang H, Li D et al (1999) Synthesis of a novel near-IR fluorescent reagent and study on its in situ Dimer’s interaction with DNA. Chem J Chin Univ Ersities 27:122–123

    Google Scholar 

  107. 107.

    Flanagan JH, Khan SH, Menchen S (1997) Functionalized tricarbocyanine dyes as near-infrared fluorescent probes for biomolecules. Bioconjugate Chem 8:751–756

    CAS  Article  Google Scholar 

  108. 108.

    Pham W, Lai WF, Weissleder R et al (2003) High efficiency synthesis of a bioconjugatable near-infrared fluorochrome. Bioconjugate Chem 14(5):1048–1051

    CAS  Article  Google Scholar 

  109. 109.

    Houston JP, Ke S, Wang W et al (2005) Quality analysis of in vivo near-infrared fluorescence and conventional gamma images acquired using a dual-labeled tumor-targeting probe. J Biomes Opt 10(5):54010

    Article  CAS  Google Scholar 

  110. 110.

    Akers WJ, Xu BG, Lee H et al (2012) Detection of MMP-2 and MMP-9 activity in vivo with a triple-helical peptide optical probe. Bioconjugate Chem 23(3):656–663

    CAS  Article  Google Scholar 

  111. 111.

    Wang R, Han X, You J, Yu F, Chen L (2018) Ratiometric near-infrared fluorescent probe for synergistic detection of monoamine oxidase B and its contribution to oxidative stress in cell and mice aging models. Anal Chem 90:4054–4061

    CAS  PubMed  Article  Google Scholar 

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Acknowledgements

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Funding

This work was supported by Natural Science Foundation of Shandong Province [ZR2019MH054, ZR2018PC010, ZR2019PH097], China; Doctor Foundation of Binzhou University [2016Y17, 2016Y02], China.

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CS is the first author. CS and WD are the co-corresponding authors in this work. BD, BW1 and BW2 analysed the data to this work. All authors read and approved the final manuscript.

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Correspondence to Chunlong Sun or Wen Du.

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Sun, C., Du, W., Wang, B. et al. Research progress of near-infrared fluorescence probes based on indole heptamethine cyanine dyes in vivo and in vitro. BMC Chemistry 14, 21 (2020). https://doi.org/10.1186/s13065-020-00677-3

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Keywords

  • Near-infrared fluorescence probes
  • Indole heptamethine cyanine dyes
  • Biological application
  • Research progress