CN110818739A - Metal iridium complex with synergistic response to tumor microenvironment pH/hypoxic and application thereof - Google Patents
Metal iridium complex with synergistic response to tumor microenvironment pH/hypoxic and application thereof Download PDFInfo
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- CN110818739A CN110818739A CN201810911662.2A CN201810911662A CN110818739A CN 110818739 A CN110818739 A CN 110818739A CN 201810911662 A CN201810911662 A CN 201810911662A CN 110818739 A CN110818739 A CN 110818739A
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- 238000003325 tomography Methods 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention designs a phosphorescent ionic iridium complex capable of carrying out fluorescence imaging under the hypoxic condition, which has the following structure:
or
Description
Technical Field
The invention belongs to the field of metal complexes, and particularly relates to a phosphorescent metal iridium complex with synergistic response to tumor microenvironment pH/hypoxia and application thereof.
Background
The early diagnosis of the tumor has important significance in improving the tumor treatment effect and improving the survival rate of cancer patients, so that the survival quality of the patients can be improved, and the pain, the spirit and the economic burden of the patients can be relieved. At present, early diagnosis of cancer is mainly achieved by tumor marker detection, genetic screening, ultrasound imaging (US), Magnetic Resonance Imaging (MRI), thermal tomography imaging (TTM), positron emission tomography (PET-CT), and the like. Compared with the traditional medical methods, the fluorescence imaging method can realize the nondestructive detection of the tumor position information and simultaneously can detect a series of related biological processes of the tumor in situ in real time, thereby being beneficial to medical workers to deeply research the development stage of the tumor, formulate the optimal treatment scheme and realize the purpose of early discovery and early treatment.
Hypoxia and acidification are pathological features coexisting in various diseases such as tumors, cardiovascular and cerebrovascular diseases, inflammation, ischemia, shock, chronic lung diseases and the like. In the formation of tumors, this phenomenon is due to the growth rate of tumor cells, which is much greater than the rate of production of their internal blood vessels, and the aerobic glycolysis (warburg effect) characteristic of tumor cells. The identification and diagnosis of tumors by hypoxia or acidification has become a major focus of current research, and some reports for tumor detection based on the two tumor markers have appeared. However, the difference between tumor and normal tissue in vivo is often not apparent in these hallmarks. For example, the pH in solid tumors is about 6.5-6.9, and in normal tissues is about 7.4, with limited differences; on the other hand, the oxygen partial pressure in hypoxic tumor tissue is about 0-3%, while the oxygen partial pressure in a normal oxygen supply environment under physiological conditions is about 5-21%, and the difference between the two is very limited. Meanwhile, due to the limited response sensitivity of the probe, the signal-to-noise ratio obtained by using the probe with the stimulation response to detect the tumor microenvironment is low. Although probes with ultra-high sensitivity for tumor marker features can also achieve relatively high signal-to-noise ratio in tumor detection, such probes are very few, and the requirement of ultra-high response sensitivity is difficult to satisfy in the design of customized probes for a specific target.
In 2017, inspired by the principle of cascade amplifiers in electronics, such as professor of Jiangjing university Jiangtang Xi group, a concept and a method of two-stage amplification are provided to improve tumor microenvironment signals. That is, the probe is firstly converted into another form called reporter molecule under the first stimulation of the tumor microenvironment; then, the signal of the reporter molecule is in a new channel and responds to the second stimulation of the tumor microenvironment, thereby realizing the two-step amplification of the tumor microenvironment signal. Accordingly, the authors report that a probe that can exhibit a continuous response to the acidification and hypoxic properties induced by tumor metabolism can better achieve two-stage amplification of tumor microenvironment signals associated with tumor metabolism. The optical probe continuously responding to acidification and hypoxia and its signal amplification mechanism are shown in fig. 8.
Synergistic response to acidity and hypoxia may be another effective strategy to amplify tumor microenvironment signals. However, the current optical chemical probes capable of simultaneously responding to acidification and hypoxia are usually realized by adopting a way of sharing multiple indicating dyes, and the sharing of multiple dyes often causes overlapping in a common wavelength window (350-. Therefore, it may be more efficient to achieve amplification of tumor microenvironment signals using a luminescent probe molecule that can respond synergistically to hypoxia and acidification.
Disclosure of Invention
Compared with the traditional single-factor (hypoxic or acidification) response optical probe, the probe can obtain stronger signals, thereby improving the signal-to-noise ratio of tumor imaging and enhancing the capability of early diagnosis of tumors.
The specific technical scheme of the invention is as follows:
a phosphorescent metal iridium complex has the following structure:
The above complexes may further be combined with an anion selected from the group consisting of Cl-、Br-，I-，NO3 -Or PF6 -。
The invention discloses a specific phosphorescent metal iridium complex which comprises the following components in parts by weight:
the invention also aims to disclose the application of the phosphorescent metal iridium complex in preparing a cell oxygen or pH detection reagent. The phosphorescent metal iridium complex can perform reversible phosphorescence detection and identification on oxygen concentration.
In the application, the phosphorescent metal iridium complex is a chemical probe responding to acidity and/or hypoxic.
The invention also aims to disclose the application of the phosphorescent metal iridium complex chemical probe in cell imaging and biological labeling. Preferably, the cell is a tumor cell.
In the application, the phosphorescent metal iridium complex can be applied to in-vitro single-layer cell acidification and hypoxic cooperative cell imaging, and can also be applied to cell intrabulbar acidification and hypoxic cooperative imaging research.
The phosphorescent ionic iridium complex capable of carrying out fluorescence imaging under the hypoxic condition can be prepared by the following method. The preparation method comprises the following synthetic route:
compound 1- (benzob ] thiophen-2-yl) -isoquinoline (hiqbt) was synthesized according to standard Suzuki coupling methods: under argon atmosphere, dissolving 2-bromoisoquinoline and benzo [ b ] thiophen-2-yl boric acid in tetrahydrofuran, adding 1mol/L potassium carbonate solution, then adding tetrakis (triphenylphosphine) palladium, and reacting at 60 ℃ overnight. After the reaction is finished, separating an organic phase, washing the organic phase for three times by using saturated saline solution, and performing column chromatography separation to obtain Hiqbt. Hiqbt and anhydrous iridium trichloride are reacted in a mixed solvent of 2-ethoxyethanol and water (3:1 volume ratio) at 120 ℃ for 24 h. After cooling, the resulting brown suspension was filtered and the filter cake was washed with water, diethyl ether, n-hexane, respectively, to give the dimeric iridium compound Ir2(iqbt)4Cl 2. Synthesis of primary ligand L1 synthesis was performed according to the Sonogashira cross-coupling reaction procedure: 4-ethynylphenol, 5-bromophenanthroline, tetrakis (triphenylphosphine) palladium and n-propylamine are added into a Schlenk bottle, the mixture reacts for 2 days at the temperature of 80 ℃, and after column chromatography, the mixture is recrystallized in methanol to obtain off-white L1. Dissolving a ligand L1 and a dimer iridium compound Ir2(iqbt)4Cl2 in a dichloromethane-methanol mixed solvent with a volume ratio of 2:1, refluxing for 6h, replacing anions with excessive ammonium hexafluorophosphate, and performing column chromatography to obtain a probe Ir-NIR-pH-1. The synthesis method of the probe Ir-NIR-1 is similar to that of Ir-NIR-pH-1, and the ligand L2 is used for replacing L1, so that a dark red solid product is finally obtained.
Advantages of the invention
Aiming at the defects in the prior art, the invention provides a probe design idea for amplifying a tumor microenvironment signal by simultaneously responding to hypoxia and acidification, designs a ligand responding to pH based on phenolic hydroxyl, introduces a metal center, can reduce the pKa of the metal center to the pH range of the tumor microenvironment, and obtains a phosphorescent metal iridium (III) probe capable of cooperatively responding to acidity and hypoxia by utilizing the phosphorescence quenching effect of oxygen molecules on a phosphorescent metal iridium (III) complex. Under the condition of low pH or reduced oxygen concentration, the phosphorescence emission intensity or phosphorescence lifetime of the probe molecule can be enhanced to a certain degree, and under the condition of simultaneous existence of acidification and hypoxic, the emission intensity and lifetime of the probe can be synergistically changed, so that the probe molecule is greatly enhanced. The response mechanism is very suitable for realizing the imaging of high signal-to-noise ratio of the tumor under the conditions of acidification of the tumor microenvironment and hypoxia, and the sensitivity of tumor identification is improved. Meanwhile, the phenolic hydroxyl in the structure is removed through the modification of the ligand, so that the structure loses the capability of responding to pH, a reference compound only responding to hypoxic conditions can be obtained, and the capability of responding to the coordination of the tumor microenvironment provides a contrast. The probe is utilized to realize the synergistic response to acidification and hypoxia in vitro single-layer cells and three-dimensional tumor multicellular spheres, and compared with the traditional single-factor response probe, the probe can obtain larger signal change. The probe provides a new idea for designing a phosphorescent probe for early diagnosis, and has potential application value in the aspects of early diagnosis, observation and treatment and the like of cancers.
Drawings
FIG. 1 Probe Ir-NIR-pH-1 emission spectra at different pH and pKa of phosphorescent emission intensity at 685nm versus pH were fitted to a working curve.
FIG. 2 is a graph showing phosphorescence emission spectra of probes Ir-NIR-pH-1 and Ir-NIR-1 at different oxygen concentrations and the decay curves of the intensity of phosphorescence emission peaks with increasing oxygen concentration.
FIG. 3 shows the change of phosphorescence intensity and phosphorescence lifetime under different oxygen and pH conditions of a probe Ir-NIR-pH-1 and the probe Ir-NIR-1.
FIG. 4 shows the change of phosphorescence intensity of the probes Ir-NIR-pH-1 and Ir-NIR-1 at different pH and oxygen concentrations.
FIG. 5 in vitro dark toxicity and phototoxicity experiments of probe Ir-NIR-pH-1 on MCF-7.
FIG. 6-acidification and hypoxia co-imaging of probe Ir-NIR-pH-1 in MCF-7 and phosphorescence intensity curves for selected cells.
FIG. 7 shows the imaging conditions of probe Ir-NIR-pH-1 at different pH values of MCF-7 tumor three-dimensional multicellular spheres.
FIG. 8 is an optical probe with continuous response to acidification and hypoxia and its signal amplification mechanism.
Detailed Description
The invention is described in further detail below with reference to the accompanying drawings.
In order to better understand the contents of the present patent, the technical solutions of the present invention are further described below by specific examples. However, these examples do not limit the present invention.
EXAMPLE 1 preparation of Probe Ir-NIR-pH-1
Synthesis of Compound 1- (benzob thiophen-2-yl) -isoquinoline (Hiqbt)
1-Bromoisoquinoline (1g, 4.8mmol) and benzo [ b ] thiophen-2-ylboronic acid (856mg, 4.8mmol) were dissolved in tetrahydrofuran (24mL) under an argon atmosphere, followed by addition of potassium carbonate solution (1M, 24mL) and palladium tetratriphenylphosphine (227mg, 0.24mmol, 5% n/n), reaction at 60 ℃ overnight, and reaction progress was detected by TCL. After the reaction is finished, cooling to room temperature, recovering the organic phase, extracting the water phase twice by using dichloromethane, combining the organic phases, drying by using anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and performing column chromatography to obtain a light yellow Hiqbt solid (85.6%).
Synthesis of Compound 4-ethynylphenol
Trimethylsilylacetylene (1.9mL, 13.44mmol) was added dropwise to a solution of 4-iodophenol (2.04g, 9.28mmol), cuprous iodide (53.4mg, 0.28mmol), bis triphenylphosphine palladium dichloride (194.4mg, 0.28mmol) in triethylamine (30mL) and refluxed at 90 ℃ under argon for 3 h. After the reaction is finished, insoluble substances are filtered out, and the 4-trimethylsilyl ethynyl phenol is obtained by reduced pressure distillation and column chromatography. Dissolving the obtained 4-trimethylsilylethynyl phenol in 50mL of tetrahydrofuran, dropwise adding tetra-n-butylammonium fluoride (tetrahydrofuran solution, 1M, 1.5eq.) at 0 ℃, continuously stirring for 15min, and adding a saturated ammonium chloride solution for quenching. Separating organic phase, extracting water phase with ethyl acetate, mixing organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, evaporating solvent under reduced pressure, and performing column chromatography to obtain white 4-ethynylphenol (80.3%).
Synthesis of ligand L1
5-bromophenanthroline (300mg, 1.16mmol), 4-ethynylphenol (274mg, 2.32mmol), tetrakistriphenylphosphine palladium (134mg, 0.12mmol), n-propylamine (25mL) were added to a pressure reaction tube, heated to 80 ℃ for two days, reacted after completion of the reaction, the solvent was distilled off under reduced pressure, column chromatography (dichloromethane: methanol ═ 30:1) was performed, and recrystallization from methanol gave ligand L1 (pale yellow solid, 192mg, 56%).1H NMR(400MHz，DMSO-d6):δ10.07(s，1H)， 9.22(dd，J＝4.3，1.7Hz，1H)，9.11(dd，J＝4.3，1.7Hz，1H)，8.84(dd，J＝8.2，1.7 Hz，1H)，8.50(dd，J＝8.2，1.6Hz，1H)，8.31(s，1H)，7.91(dd，J＝8.2，4.3Hz，1H)， 7.80(dd，J＝8.1，4.3Hz，1H)，7.60(d，J＝8.6Hz，2H)，6.89(d，J＝8.7Hz，2H).13C NMR(101MHz，DMSO-d6):δ158.60，150.58，150.41，145.34，145.21，136.06，134.29， 133.43，130.21，127.96，127.58，123.86，123.77，119.22，115.88，111.87，96.01， 84.01。
Synthesis of ligand L2
5-bromophenanthroline (300mg, 1.16mmol), phenylacetylene (237mg, 2.32mmol), tetrakistriphenylphosphine palladium (134mg, 0.12mmol) and n-propylamine (25mL) are added into a pressure reaction tube, heated to 80 ℃ for reaction for two days, after the reaction is finished, the solvent is evaporated under reduced pressure to obtain a solid, the solid is washed by water, dichloromethane is used for extraction, liquid separation is carried out, the organic phase is respectively washed by water and saturated saline water, dried by anhydrous sodium sulfate, filtered, subjected to column chromatography (dichloromethane: methanol ═ 30:1) and recrystallized in ether to obtain a ligand L2.
Iridium complex chloro-bridged dimer Ir2(iqbt)4Cl2Synthesis of (2)
The synthesized ligand Hiqbt (364mg, 1.39mmol), anhydrous iridium trichloride (191mg, 0.64mmol), water (12mL) and 2-ethoxyethanol (4mL) were added to a reaction vessel, and the reaction was refluxed at 120 ℃ overnight under argon protection, cooled to room temperature, and the solution became dark reddish brown. Deionized water (20mL) was added, the filtrate was filtered off, and the resulting solid filter cake was washed sequentially with water, diethyl ether and n-hexane and dried in a vacuum oven to give the product as a dark reddish brown powder. The product was used directly in the next reaction without purification.
Synthesis of Probe Ir-NIR-pH-1
Taking the synthesized iridium complex chlorine bridge dimer Ir2(iqbt)4Cl2(154mg, 0.1mmol), L1(59mg, 0.2mmol) and a mixed solvent of dichloromethane and methanol (12mL, 2:1 by volume) were placed in a three-necked flask and heated under reflux for 6h under an argon atmosphere. After the reaction was completed, the reaction mixture was cooled to room temperature, and 1mm of ammonium hexafluorophosphate was added. The suspension was stirred for 15min and filtered to remove insoluble inorganic salts. The solvent was evaporated under reduced pressure and column chromatography gave a deep red Ir-NIR-pH-1 solid (175mg, 76%).1H NMR(400MHz，CD3CN-d3)δ9.08(d，J＝8.4，3H)，8.60(d， J＝8.4，1H)，8.40(s，1H)，8.35(dd，J＝5.1，1.4，1H)，8.27(dd，J＝5.1，1.4，1H)，7.91- 7.95(m，6H)，7.89-7.82(m，3H)，7.77(dd，J＝8.3，5.1，1H)，7.60(d，J＝8.7，2H)，7.50 (s，1H)，7.38(d，J＝6.6，1H)，7.34(d，J＝6.6，1H)，7.26–7.13(m，4H)，6.91(d， J＝8.8，2H)，6.73(t，J＝7.7，2H)，6.19(d，J＝8.3，2H).13C NMR(101MHz，CD3CN-d3)δ 166.14，159.58，155.75，155.55，153.25，152.93，147.59，146.99，145.41，144.46， 143.10，139.69，138.82，138.22，137.21，137.17，134.84，133.66，132.30，132.16， 131.77，130.30，128.72，128.66，127.77，127.43，126.74，125.89，125.54，123.57， 120.89，116.88，113.60，99.58，83.43。
Example 2 Synthesis of Probe Ir-NIR-1
Taking the synthesized iridium complex chlorine bridge dimer Ir2(iqbt)4Cl2(154mg, 0.1mmol), L2(56mg, 0.2mmol) and a mixed solvent of dichloromethane and methanol (12mL, 2:1 by volume) were placed in a three-necked flask and heated under reflux for 6h under an argon atmosphere. After the reaction was complete, the reaction mixture was cooled to room temperature and 1mmol ammonium hexafluorophosphate was added. The suspension was stirred for 15min and filtered to remove insoluble inorganic salts. The solvent was evaporated under reduced pressure and column chromatography afforded a deep red Ir-NIR-pH-1 solid (62%).1H NMR(400MHz，CD3CN-d3)δ9.07(d，J＝8.4Hz，3H)，8.57(dd， J＝8.3，1.4Hz，1H)，8.43(s，1H)，8.33(dd，J＝5.0，1.4Hz，1H)，8.27(dd，J＝5.1，1.4 Hz，1H)，7.96–7.87(m，6H)，7.87–7.79(m,3H)，7.78–7.64(m，3H)，7.49(d，J＝6.9 Hz，3H)，7.36(dd，J＝10.5，6.6Hz，2H)，7.22–7.10(m，4H)，6.70(t，J＝7.6Hz， 2H)，6.20(d，J＝8.2Hz，2H).13C NMR(101MHz，CD3CN-d3)δ166.17，155.73，155.55， 153.34，153.21，147.60，147.21，145.45，144.50，143.16，139.87，138.78，138.27， 137.24，133.71，132.98，132.62，132.30，132.07，130.97，130.35，129.94，128.81， 128.72，127.80，127.47，126.78，125.93，125.59，123.60，123.05，122.57，120.95， 98.79，84.74。
Example 3 determination of the probe Ir-NIR-pH-1 absorption spectrum and phosphorescence spectrum.
Accurately weighing probe Ir-NIR-pH-1 and probe Ir-NIR-1, respectively transferring into a 5mL volumetric flask, diluting to constant volume with DMSO, and preparing into a solution with a concentration of 1.0 × 10-3Transferring 25 mu L of the solution into a 5mL volumetric flask, and preparing the solution with DMSO and PBS buffer solution with pH of 7.4 to constant volume to obtain the solution with the concentration of 1.0 multiplied by 10-5The UV spectrum of the solution in mol/L was determined so that the volume fraction of DMSO contained in the buffer solution was 10%. The phosphorescence spectrum is measured by using the maximum absorption wavelength of the ultraviolet spectrum as the excitation wavelength of the phosphorescence spectrum. Accurately weighing the compound to be detected to prepare the compound with the concentration of 1.0 multiplied by 10-5The spectral properties of the samples were determined in mol/L PBS buffer containing 10% volume DMSO under acidic and alkaline conditions. The results are shown in FIG. 1. FIG. 1a shows the emission spectra of probe Ir-NIR-pH-1 at different pH values; FIG. 1b is a pKa fitted working curve of phosphorescence emission intensity versus pH at 685nm for probe Ir-NIR-pH-1.
To verify the response of the probe to pH, a phosphorescent titration of Ir-NIR-pH-1 was performed in phosphate buffered PBS (containing 10% DMSO by volume). As can be seen from FIG. 1(a), the maximum emission wavelength of the probe Ir-NIR-pH-1 in acidic or basic medium is in the near infrared range (685 nm). The intensity of phosphorescence emission from the emission peak at 685nm gradually increased with a factor of about 5 as the pH decreased from 10.0 to 3.5, but the maximum excitation and emission wavelengths did not shift during the intensity increase. The curve obtained by plotting the phosphorescence intensity at 685nm and the pH of the probe is shown in FIG. 1 (b). The pK of Ir-NIR-pH-1 can be obtained by fitting the curve obtained by using the Henderson-Hasselbach equationaIs 6.80, can be used for detecting the pH in the tumor microenvironment within the pH range (6.5-6.9) of the tumor microenvironment.
Henderson-Hasselbach equation:
where P represents the phosphorescent emission intensity at a certain fixed wavelength, and pmax and pmin represent the maximum and minimum phosphorescent emission intensities, respectively, at the corresponding wavelengths.
Example 4 Probe Ir-NIR-pH-1 and Ir-NIR-1 response to oxygen concentration Studies
The invention researches the phosphorescence response of a 10 mu M probe Ir-NIR-pH-1 and Ir-NIR-1 to oxygen concentration in toluene. The results of the experiment are shown in FIG. 2. FIGS. 2a and 2b are phosphorescence emission spectra of probes Ir-NIR-pH-1 and Ir-NIR-1 at different oxygen concentrations, respectively; FIG. 2c is a graph showing the decay of the intensity of the phosphorescence emission peak at 685nm with increasing oxygen concentration for probe Ir-NIR-pH-1; FIG. 2d is a graph showing the decay of the intensity of the phosphorescence emission peak at 680nm of probe Ir-NIR-1 with increasing oxygen concentration.
The near infrared phosphorescence emission peak intensity at 685nm of the probe Ir-NIR-pH-1 increases nonlinearly with the decrease of the oxygen concentration. In the solution without oxygen and saturated with oxygen, the intensity ratio of the maximum emission peak of the probe can reach 26.3. The probe is particularly sensitive to oxygen partial pressure at low oxygen concentrations, as shown by the decay curve of the maximum emission peak intensity with increasing oxygen concentration, and a slight decrease in oxygen concentration under low oxygen conditions can cause a sharp increase in the emission intensity of the probe, for example, a decrease in oxygen concentration from 2% to 0% can result in an increase in the maximum emission peak phosphorescence intensity of about 20%, which makes the probe particularly suitable for hypoxic imaging under physiological conditions.
For the probe Ir-NIR-1, the emission peak position of the probe does not change under the condition of different oxygen concentrations. However, as the oxygen concentration is increased, the emission intensity of Ir-NIR-1 is reduced in a significant nonlinear manner. The emission intensity of Ir-NIR-1 is 5.6% in the case of pure oxygen gas and pure argon gas. Under hypoxic conditions, the probe is also very sensitive to oxygen partial pressure, and small changes in oxygen concentration can cause large changes in the emission intensity of the probe. Meanwhile, the response capacities of the two probes to oxygen are compared, and the response capacity of the iridium (III) complex to oxygen is not changed by introducing phenolic hydroxyl in the complex.
Example 5 Probe Ir-NIR-pH-1 Studies on the synergistic response Properties to acidification and hypoxia
In order to confirm the synergistic response capability of the probe Ir-NIR-pH-1 to hypoxia and acidification, the present example investigated the changes in phosphorescence intensity and phosphorescence lifetime in the DMSO-PBS system (1:9, v/v versus Ir-NIR-pH-1 and probe Ir-NIR-1 in the presence of hypoxia and acidification simultaneously, in order to show small changes in pH and oxygen concentration in the microenvironment of solid tumors compared to normal tissues.
Accurately weighing probe Ir-NIR-pH-1 and probe Ir-NIR-1, and preparing to 1.0 × 10-5Adjusting pH of the prepared solution with hydrochloric acid or potassium hydroxide (the addition amount is less than 1% of the volume of the solution to be detected), and measuring the pH value of the prepared solution by using 488nm excitation under a HORIBA Jobin Yvon FluoroMax-4 fluorescence spectrometerEmission spectra at different pH values. Phosphorescence lifetimes were tested using time-dependent single photon counting Technology (TCSPC) under a HORIBA Jobin Yvon Fluorolog-3 modular fluorescence spectrometer.
Determination of influence of oxygen concentration on phosphorescence and phosphorescence lifetime of probe Ir-NIR-pH-1 and Ir-NIR-1, the synthesized probe Ir-NIR-pH-1 and probe Ir-NIR-1 are dissolved in spectrum-level toluene and respectively prepared into 1.0 x 10 in a quartz fluorescence four-way cuvette-5mol/L solution. Argon and oxygen were adjusted to different proportions using a flow meter (HORIBA, STEC, SEC-40js.60sccm), bubbled through the bottom of the probe Ir-NIR-pH-1 or probe Ir-NIR-1 solutions for 30 minutes, respectively, and the cuvettes were sealed. Emission spectra were measured at different oxygen concentrations using 488nm excitation under a HORIBA Jobin Yvon FluoroMax-4 fluorescence spectrometer. Phosphorescence lifetimes were tested using a time-dependent single photon counting Technique (TCSPC) under a HORIBA Jobin Yvon Fluorolog-3 modular fluorescence spectrometer.
For probe Ir-NIR-pH-1, as shown in FIGS. 3a and 3b, in the intensity and luminescence lifetime modes, respectively, lowering the system pH to 6.4 causes its maximum emission peak intensity to increase by 0.13 times and the phosphorescence lifetime to increase by 14ns, relative to its phosphorescence emission peak intensity and luminescence lifetime at 685nm at pH 7.4, 21% oxygen concentration. By lowering the oxygen concentration to 0% and maintaining the pH at 7.4, it was found that the maximum emission peak intensity became 2.3 times and the phosphorescence lifetime was extended by 53 ns. Under the condition of acidification and simultaneous existence of oxygen deficiency (pH is 6.4, [ O ]2]0%), the magnitude of these changes becomes maximum, the phosphorescence emission intensity is enhanced to 3.1 times under the conditions of pH 7.4, oxygen concentration 21%, and the phosphorescence lifetime is extended to 161ns, which is 1.9 times thereof.
For probe Ir-NIR-1, as shown in FIGS. 3c and 3d, the phosphorescence emission intensity and phosphorescence lifetime do not change significantly with only pH change, since probe Ir-NIR-1 lacks a phenolic hydroxyl group that can respond to pH, losing the ability to respond to pH. Under the influence of a simple change in oxygen concentration, both the phosphorescence intensity and the lifetime achieved a certain degree of enhanced change (about 2.5 times and 1.3 times for an oxygen concentration of 21%, respectively).
The research comparison shows that due to the introduction of phenolic hydroxyl in the ligand, the synergistic response to hypoxia and acidification is realized, and the probe Ir-NIR-pH-1 can obtain larger change compared with the traditional single-factor response probe. In the early detection of tumors, the method has great significance for realizing detection and diagnosis of the tumors through slight changes of two characteristic factors (acidification and hypoxia) in the tumor microenvironment. The synergistic response can greatly improve the obtained tumor signal intensity, thereby realizing high signal-to-noise ratio for tumor imaging.
Example 6 reversibility study of probes Ir-NIR-pH-1 and Ir-NIR-1
The hypoxia and acidification of the tumor are important characteristics of a malignant solid tumor microenvironment, and the real-time reversible detection of hypoxia and acidification floating in the tumor is an important index of poor prognosis of tumor deterioration, metastasis and the like. This example demonstrates the reversibility of phosphorescence on pH response for probe Ir-NIR-pH-1. In a PBS-DMSO buffer system (9: 1, v/v), 3mL of probe solution was cycled between pH 3.5 and 10.0 using HCl and KOH, respectively.
Oxygen-dependent phosphorescence quenching is a direct, reversible method of detecting oxygen concentration. Oxygen-dependent phosphorescence quenching is a photochemical process that quenches phosphorescence by collisions of oxygen molecules with excited dye molecules, which is a reversible process by which the oxygen concentration can be detected by measuring the degree of phosphorescence quenching. This example demonstrates the reversibility of the response of probe Ir-NIR-pH-1 to oxygen concentration. In a 10. mu.M toluene solution of probe Ir-NIR-pH-1 or probe Ir-NIR-1, respectively, argon and a mixed gas of argon and oxygen containing 21% by volume of oxygen were circulated and tested for their intensity at their maximum phosphorescence emission peak.
The results are shown in FIG. 4. FIG. 4a shows the change in phosphorescence intensity at probe Ir-NIR-pH-1685nm at two pH values of 3.50 and 10.0. The results show that the phosphorescence intensity does not substantially change within 5 cycles. Therefore, the probe Ir-NIR-pH-1 can be used as a phosphorescent contrast agent responding to pH in a biological system.
FIG. 4b shows the change in phosphorescence intensity at 685nm for probe Ir-NIR-pH-1 at both oxygen concentrations 0% and 21%. FIG. 4c shows the change in phosphorescence intensity at 680nm for probe Ir-NIR-1 (10. mu.M in toluene) at both concentrations of 0% and 21% oxygen. The excitation wavelength was 488 nm.
The result shows that in 5 cycles, the probe Ir-NIR-pH-1 or the probe Ir-NIR-1 can realize the cycle of 'reduction-enhancement-reduction-enhancement' of the probe for the oxygen concentration, and the result shows that the probe Ir-NIR-pH-1 and the probe Ir-NIR-1 can realize the reversible phosphorescence detection identification of the oxygen concentration.
Example 7 Probe Ir-NIR-pH-1 for adherent cytotoxicity (MTT).
Cell culture
Human breast cancer cells MCF-7 cells were cultured in RPMI-1640 medium containing 10% Fetal Bovine Serum (FBS) and 100U/mL penicillin and 50U/mL streptomycin were added. The environment in the cell culture box is 37 ℃ and 5% CO2And saturation humidity. Cell culture conditions with oxygen concentrations of 0% and 10% were constructed using anaerobic gas-generating bags and microaerophilic gas-generating bags (Mitsubishi gas chemical, Japan). To maintain the viability of the cells, all experimental cells were within two months of revival in liquid nitrogen.
At 37 ℃ with 5% CO2Culturing the cells in incubator to logarithmic growth phase, digesting the cells with trypsin (0.25%), suspending the cells in RPMI-1640 medium, and adjusting the concentration of the cell suspension to about 5X 104one/mL, 100. mu.L/well of each well was inoculated into a 96-well plate and placed at 37 ℃ in 5% CO2And culturing for 24h to adhere to the wall. Incubating MCF-7 cells with probes with different concentrations for 4h, setting 3 parallel samples for each concentration, adding culture medium with the same volume as the probes into a blank control group without the probes, dividing the blank control group into a non-irradiation group and an irradiation group, irradiating the irradiation group with a 450nm laser at an irradiation dose of 30J/cm2Irradiation time was 300s, then placed at 37 ℃ with 5% CO2The cultivation was continued in a saturated humidity incubator for 24 h. After the completion of the incubation, 30. mu.L of MTT (5 mg/mL) solution was added to each well, and the mixture was placed in an incubator to continue the incubation for 4 hours. The supernatant medium was carefully aspirated, 200. mu.L of DMSO was added to each well, shaken for 10min, and the absorbance (OD) of each well at 570nm was measured using a microplate reader (Thermo Scientific, Varioskan Flash). The cell growth survival rate of the control group without drug is set as 100 percentAnd the cell survival rate calculation formula is as follows: the survival rate of the cells is determined by adding the OD value of the medicine group/the OD value of the control group multiplied by 100 percent.
The results are shown in FIG. 5. The probe Ir-NIR-pH-1 has very low cytotoxicity in the concentration range of 20. mu.M. Firstly, after MCF-7 cells and a probe are incubated for 24 hours in a dark place, the cell survival rate is found to be more than 85% at the experimental concentration, which indicates that the probe has lower dark toxicity; next, probe-incubated MCF-7 cells were irradiated using a 450nm laser (30J/cm)2300s), the survival rate of the cells at the experimental concentration is also found to be above 85%. These results indicate that the probe has high biocompatibility and very low biotoxicity.
Example 8 in vitro monolayer intracellular acidification and hypoxia cooperative imaging with Probe Ir-NIR-pH-1
Taking MCF-7 cells in logarithmic growth phase in a confocal dish, placing the cells at 37 ℃ and 5% CO2And culturing for 4h to adhere to the wall. The cell groups were cultured under different conditions. Imaging experiments were performed on a Zeiss LSM-710 laser confocal microscope.
pH imaging experiment: high concentrations of K containing 10. mu.M Nigericin sodium at different pH values (5.4, 6.4, 7.4, 8.4) were formulated at normal oxygen concentrations (21%)+Buffer solution (137mM NaCl, 120mM KCl, 10.1mM Na)2HPO4，1.8mMKH2PO4). Cells were incubated for 4h with probe Ir-NIR-pH-1 or control probe Ir-NIR-1 (10. mu.M), respectively. Washing with pH 7.4 buffer solution for three times, and incubating with the above pH buffer solution for 5min for phosphorescence imaging.
Hypoxic response test: high concentration K containing 10. mu.M Nigericin sodium at pH 7.4+MCF-7 cells were incubated with probe Ir-NIR-pH-1 (10. mu.M) in buffer for 4h, followed by laser confocal imaging after incubation for 30min under hypoxic conditions (0%, 10%). Cell culture conditions with oxygen concentrations of 0% and 10% were constructed using anaerobic Gas-producing bags and microaerophilic Gas-producing bags (Mitsubishi Gas Chemical, Japan).
And (3) testing the cooperative response capability: MCF-7 cells were incubated with probe Ir-NIR-pH-1 (10. mu.M) for 4h, washed three times with PBS buffer at pH 7.4, replaced with pH 6.4 containing 10. mu.M NigeriaHigh concentration of rhzomorph sodium K+Buffer solution (137mM NaCl, 120mM KCl, 10.1mM Na)2HPO4，1.8mM KH2PO4) And continuously incubating for 30min under the condition of 0% oxygen concentration, and performing laser confocal imaging.
The results are shown in FIG. 6
In order to investigate the response capability of the probe Ir-NIR-pH-1 and the probe Ir-NIR-1 to pH in MCF-7 cells. Incubating probe Ir-NIR-pH-1 or probe Ir-NIR-1 with MCF-7 cells for 4h in a medium containing Nigericin sodium (K)+/H+Ionophore capable of balancing intracellular and extracellular pH values) in high potassium ion buffer solution (137mM NaCl, 120mM KCl, 10.1mM Na) with different pH values2HPO4，1.8mM KH2PO4pH 5.4, 6.4, 7.4, 8.4), respectively under a confocal laser fluorescence microscope. The excitation wavelength is 488nm, and the emission wavelength range is 650-720 nm. As can be seen from FIG. 6, for the probe IR-NIR-pH-1, the intracellular phosphorescence intensity increases significantly with decreasing pH, and gradually increases by a factor of about 2.5 as the pH changes from 8.4 to 5.4. In contrast, for probe Ir-NIR-1, the phosphorescence intensity in MCF-7 cells did not change significantly in buffer solutions of different pH values due to the absence of phenolic hydroxyl groups that could sense pH.
Example 9 in vitro three-dimensional tumor multicellular acidification with hypoxia for Probe Ir-NIR-pH-1 coordinated imaging.
Culture of three-dimensional tumor multicellular spheres
The three-dimensional tumor multicellular spheres are cultured by a Liquid overlap method: first, 0.75g of agarose was weighed and dissolved in 10mL of DMEM medium to prepare a 0.75% agarose solution, which was then autoclaved in a liquid mode. Immediately after the sterilization was completed, the agarose solution was removed, and the 96-well plate was treated with hot agarose solution: 50 μ L of the sterilized agarose solution was added to each well, placed horizontally in a clean bench, and allowed to stand until the agarose becomes cold and solidifies (the 96-well plate was treated with agarose at a higher speed, preventing the agarose from solidifying during the treatment, and preventing the formation of air bubbles). Taking MCF-7 cells in logarithmic growth phase, digesting with pancreatin, suspending the cells in DMEM medium containing 5% fetal calf serum, and adjustingCell density of 3X 104one/mL. The cell suspension adjusted for density was added to the treated 96-well plate at 200. mu.L per well, i.e., about 6000 cells per well. Place 96-well plate in incubator at 37 ℃ with 5% CO2After 72 hours of culture, a sphere-like 3D cell cluster of 400-500 μm diameter was formed in the center of the bottom of the well.
Culturing to form three-dimensional tumor multi-cell spheres (the diameter is about 500 mu M), and adding 10 mu M probe Ir-NIR-pH-1 for incubation for 6 h. Half of the volume of the medium was carefully aspirated, the same volume of PBS solution (pH 7.4) was added, and the cell pellet was washed 3 more times. Cell sphere imaging was performed using a Zeiss LSM 710 laser confocal microscope (10 × objective). The excitation wavelength is 488nm, and the collection wavelength range is 650-750 nm. The cell pellet was replaced with a high concentration K containing 10. mu.M of Nigericin sodium at pH 6.4+Buffer solution (137mM NaCl, 120mM KCl, 10.1mM Na)2HPO4，1.8mM KH2PO4) After incubation for 10min, synergy imaging of acidification and hypoxia was performed.
As a result, as shown in FIG. 7, it was revealed that the phosphorescence signal was substantially concentrated in the central portion of the three-dimensional multicellular spheroids, in a region of about 100 μm from the outer edge of the multicellular spheroids, which coincided with the oxygen concentration diffusion suppression gradient inside the multicellular spheroids. The Z-axis phosphorescence scan can more clearly illustrate the phosphorescence intensity distribution inside the three-dimensional multicellular spheroids, and the probe has better penetration depth due to the near infrared emission of the probe Ir-NIR-pH-1. To test the imaging of the probes in the presence of both acidification and hypoxia, three-dimensional multicellular spheroids were incubated in a high potassium pH 6.4 buffer solution (137mM NaCl, 120mM KCl, 10.1mM Na2HPO4, 1.8mM KH2PO4) containing nigericin sodium (K +/H + ionophore, which balances the intracellular and extracellular pH), and imaging was continued using confocal laser microscopy, which resulted in increased phosphorescence intensity in the central part of the tumor multicellular spheroids and the appearance of a phosphorescent bright part extending to about 50 μm at the edge. This demonstrates the ability of the probe Ir-NIR-pH-1 to respond synergistically also within the cell sphere in the presence of hypoxia and acidification. Since hypoxia and acidification are features that coexist in all solid tumor microenvironments, the use of a similar synergistic response probe helps achieve a more sensitive and accurate early diagnosis of tumors.
Claims (10)
1. A phosphorescent metal iridium complex has the following structure:
2. the phosphorescent metallic iridium complex of claim 1, wherein the complex may be further combined with an anion.
3. The phosphorescent metallic iridium complex of claim 2, wherein the anion is selected from the group consisting of Cl-、Br-，I-，NO3 -Or PF6 -。
4. Use of a phosphorescent metallic iridium complex as claimed in any one of claims 1 to 3 in the preparation of a reagent for the detection of cellular oxygen or pH.
5. The use according to claim 4, wherein the phosphorescent iridium metal complex is capable of performing reversible phosphorescence detection and identification on oxygen concentration.
6. The use according to claim 4, wherein the phosphorescent metallic iridium complex is a chemical probe responsive to acidity and/or hypoxia.
7. Use of the phosphorescent metallic iridium complex of any one of claims 1 to 3 as a chemical probe in cellular imaging and biomarkers.
8. The use according to claim 7, wherein said cell is a tumor cell.
9. The use according to claim 7, wherein the phosphorescent metallic iridium complex is used for in vitro monolayer cellular acidification and hypoxic collaborative cellular imaging.
10. The use according to claim 7, wherein the phosphorescent metallic iridium complex is used in intracellular acidification and hypoxia co-imaging studies.
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| GUORUI FU等: "Efficient near-infrared (NIR) polymer light-emitting diodes (PLEDs) based on heteroleptic iridium(III) complexes with post-modification effects of intramolecular hydrogen bonding or BF2-chelation", 《J. MATER. CHEM. C》 * |
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