CN114105967B - Targeted mitochondrial AIE fluorescent probe capable of inducing tumor cell apoptosis and preparation method and application thereof - Google Patents
Targeted mitochondrial AIE fluorescent probe capable of inducing tumor cell apoptosis and preparation method and application thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
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- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0032—Methine dyes, e.g. cyanine dyes
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- C09K2211/1018—Heterocyclic compounds
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Abstract
The invention discloses a mitochondrial targeting aggregation-induced emission (AIE) fluorescent probe, a preparation method and application thereof, and the compound is marked as TPA-2TIN and has the structure shown as follows. The AIE fluorescent probe can generate visible light fluorescence and near infrared two-region fluorescence under different excitation light irradiation, can be combined with mitochondria of tumor cells through electrostatic interaction to realize mitochondrial imaging, and can induce caspase-3 to activate and cut gasdermin E (GSDME) to further damage cell membranes by triggering mitochondrial ROS oxidative stress, thereby causing the scorching of the tumor cells, so that the AIE fluorescent probe can be used as a tumor imaging probe and a therapeutic drug. In addition, the AIE fluorescent probe has a photodynamic effect and a photothermal effect, and can be used as a phototherapy reagent for tumor treatment.
Description
Technical Field
The invention belongs to the field of tumor imaging and anti-tumor treatment, and particularly relates to a targeted mitochondrial AIE fluorescent probe capable of inducing tumor cell apoptosis, and a preparation method and application thereof.
Background
Cancer is the second leading cause of death in the world next to cardiovascular disease, and despite the long-term development of cancer diagnosis techniques and treatment methods, tumor patients continue to grow, and the prognosis of treatment is difficult to achieve the desired effect. Therefore, the development of new tumor imaging agents and therapeutic drugs is of great importance for early diagnosis and treatment of tumors. In recent years, the discovery and mechanism analysis of cell apoptosis provides a new scheme for anti-tumor treatment. Cell apoptosis is a programmed cell death mode, and is different from traditional apoptosis and necrosis, and the activation mode is that GSDM D/E/A3 protein is further cut by activating caspase-1/3/4/5/11, the cut fragments are combined with cell membranes and perforated, cell membrane potentials are destroyed, cell swelling and vacuolation are caused, and cells can be caused to secrete a large amount of lactate dehydrogenase and cytokines to generate inflammatory reaction and immune stimulation effect. Thus, tumor focal death can produce auxiliary enhancement effect on tumor immunotherapy.
On the other hand, the state of the tumor position can be visually analyzed by means of molecular imaging, so that tumor treatment can be better guided. The fluorescent imaging is an imaging means widely used for preclinical research, plays a certain role in clinical tumor fluorescent surgery navigation, combines fluorescent imaging and tumor treatment functions, and plays an important role in developing an integrated tumor diagnosis and treatment probe for accurate diagnosis and treatment of tumors. Conventional fluorescent probes tend to aggregate at higher concentrations, which can result in an aggregate fluorescence quenching (ACQ) effect, resulting in the disappearance of fluorescence. Thus, the use concentration of the fluorescent dye needs to be controlled in an extremely low concentration range, which can lead to easy photo-bleaching, and the fluorescence quantum efficiency is obviously reduced, so that the imaging time is greatly limited. Aggregation-induced emission (AIE) molecules are a new class of fluorescent materials that have received much attention in recent years, which produce an increase in fluorescence under aggregation conditions, are resistant to photobleaching, and thus allow for a greatly increased imaging time, allowing for a more stable and long-term follow-up of disease progression.
At present, no AIE probe which directly causes tumor cell apoptosis is reported, the invention discloses a mitochondrion targeting AIE fluorescent probe, a preparation method and application thereof, and particularly the application of the probe in tumor imaging and apoptosis treatment and the combination of the probe with anti-tumor immunotherapy have broad prospects.
Disclosure of Invention
The invention aims to provide a targeted mitochondrial AIE fluorescent probe capable of inducing tumor cell apoptosis, and a preparation method and application thereof.
The small molecule AIE fluorescent probe of the invention is marked as TPA-2TIN, and has the following structure:
wherein the counter anion R-is selected from singly or multiply charged anions, and can be Cl-, br-, I-, HCO 3 - 、PF 6 - 、CO 3 2- 、SO 4 2- 、PO 4 3- Etc.
The invention also discloses a synthesis method of the AIE fluorescent probe, which comprises the following steps:
1) Adding a compound 4-methoxyaniline with a structure shown in a formula 1 and 1-bromo-4-iodobenzene into toluene according to a molar ratio of 1:2.2-1:3, and reacting at a heating temperature of 115-125 ℃ by taking cuprous iodide, 1, 10-phenanthroline and potassium tert-butoxide as catalysts to obtain a compound 2;
2) Dissolving a compound 2 and the bisboronic acid pinacol ester in a molar ratio of 1:2.2-1:3 in 1, 4-dioxane, and reacting at a heating temperature of 105-120 ℃ by taking 1,1' -bis-diphenylphosphine ferrocene palladium dichloride and potassium acetate as catalysts to obtain a compound 3;
3) Adding a compound 3 and 5-bromothiophene-2-formaldehyde into a toluene/ethanol/water mixed solution according to a molar ratio of 1:2.2-1:3, and reacting at a heating temperature of 105-115 ℃ by taking tetraphenylphosphine palladium and potassium carbonate as catalysts to obtain a compound 4;
4) Dissolving a compound 4, 1, 2-trimethyl-1H-benzo [ e ] indole and potassium tert-butoxide in ethanol according to a molar ratio of 1:2.5:10-1:10:50, heating at 75-90 ℃, and reacting to obtain a compound 5:
5) Dissolving a compound 5 and methyl iodide in acetonitrile according to a molar ratio of 1:5-1:25, heating to 85-100 ℃, reacting to obtain an intermediate, removing a solvent, and adding NH 4 R (R is selected from single-charge or multi-charge anions) and methanol/water solution, and reacting to obtain a compound TPA-2TIN:
the AIE fluorescent probe is applied to the preparation of tumor cell imaging reagents.
The AIE fluorescent probe is applied to the preparation of tumor imaging reagents.
The application of the AIE fluorescent probe in preparing the medicine for triggering the tumor cell apoptosis comprises the following mechanisms: AIE causes oxidative stress of the mitochondria ROS of tumor cells, triggers caspase-3 activation and GSDME (gasdermin E) cleavage, and breaks cell membranes to finally lead to the scorch of the tumor cells.
The AIE fluorescent probe is applied to the preparation of tumor photodynamic or photothermal therapeutic agents.
The beneficial effects of the invention are as follows:
the invention provides an AIE fluorescent probe capable of directly leading to the scorching of tumor cells, which is combined with mitochondria of the tumor cells through electrostatic interaction, and the aggregation of a large amount of probes in the mitochondria causes the oxidative stress of the mitochondrial ROS, so that the mitochondrial function is damaged, the activation of intracellular case-3 is triggered and GSDME is cut, the cut fragments are combined with cell membranes and perforated, the cell membrane function is dysregulated, the cell swelling and rupture, the contents such as lactate dehydrogenase, cytokines and the like flow out, and finally the cell death is caused. In addition, the AIE fluorescent probe can generate blue fluorescence under short wave excitation, so that cell imaging and mitochondrial imaging can be realized; and near infrared two-region fluorescence can be generated under the excitation of long waves, so that living body fluorescence imaging can be realized. Therefore, the developed AIE fluorescent probe can be used as an imaging reagent and a tumor therapeutic drug for tumor imaging, chemotherapy and immunotherapy research. In addition, the AIE probe has photodynamic and photothermal effects at the same time, and has application value in photodynamic or photothermal treatment of tumors.
Drawings
In order that the contents of the present invention may be more clearly understood, the present invention will be further described in detail below with reference to specific embodiments thereof with reference to the accompanying drawings.
FIG. 1 is a synthetic route diagram of AIE fluorescent probe TPA-2 TIN;
FIG. 2 is a diagram of Compound 2 1 H NMR analysis chart;
FIG. 3 is a diagram of Compound 3 1 H NMR analysis chart;
FIG. 4 is a diagram of Compound 4 1 H NMR analysis chart;
FIG. 5 is a diagram of Compound 5 1 H NMR analysis chart;
FIG. 6 is a compound TPA-2TIN 1 H NMR analysis chart;
FIG. 7 is an absorption spectrum of AIE fluorescent probe;
FIG. 8 is a graph showing the emission spectrum of AIE fluorescent probe at 405nm excitation;
FIG. 9 is a graph showing the emission spectra of AIE fluorescent probes in DMSO/Toluene solvents in different ratios under 600nm excitation;
FIG. 10 is a graph of tumor cytotoxicity of AIE fluorescent probes;
FIG. 11 is a microscopic image of AIE fluorescent probe-induced tumor cell pyro-death (arrows indicate pyro-death cells);
FIG. 12 is a graph of an Annexin V/PI biscationic flow quantitative analysis after incubation of AIE fluorescent probes with tumor cells;
FIG. 13 is a diagram of immunoblot analysis after incubation of AIE fluorescent probes with tumor cells;
FIG. 14 is a confocal imaging of AIE fluorescent probes and mitochondrial commercial dye MTDR after incubation with tumor cells;
FIG. 15 shows 0.1W/cm of AIE fluorescent probe after mixing with ABDA 2 An ABDA absorption intensity change chart under laser illumination;
FIG. 16 is a graph showing the temperature change of AIE fluorescent probe solutions under laser light of different intensities.
Detailed Description
Materials and reagents
4-methoxyaniline, 1-bromo-4-iodobenzene, cuprous iodide, pinacol biborate, 1' -bis-diphenylphosphine ferrocene palladium dichloride, tetraphenylphosphine palladium, potassium t-butoxide, and the like were purchased from An Naiji reagent company. Methyl iodide, 1, 2-trimethyl-1H-benzo [ e ] indole, 1, 10-phenanthroline, 3, 5-bromothiophene-2-carbaldehyde and the like are purchased from Aba Ding Shiji company. Potassium hydroxide, potassium carbonate, potassium acetate, etc. are available from national pharmaceutical chemicals, inc.
Example 1
The synthetic route of the AIE fluorescent probe of the present invention is shown in fig. 1, and the present invention is further described below with reference to a specific example:
compound 2
Under the protection of nitrogen, 6.16g (50.0 mmol) of 4-methoxyaniline, 35.40g (125.0 mmol) of 1-bromo-4-iodobenzene, 2.20g (0.02 mmol) of 1, 10-phenanthroline, 22.40g (0.2 mmol) of potassium tert-butoxide, 1.90g (10.2 mmol) of cuprous iodide are added to 85mL of toluene, reflux reaction is carried out at 116 ℃ for 13h, cooling, removal of solvent in vacuo, addition of dichloromethane and water extraction, drying of the organic phase, filtration, removal of solvent in vacuo and column chromatography of the solid to give 5.4g (yield: 25.0%) of white solid product.
Compound 3
5.0g (11.5 mmol) of Compound 2,7.2g (28.2 mmol) of Diboric acid pinacol ester, 6.30g (64.7 mmol) of potassium acetate, 0.6g (0.8 mmol) of 1,1' -bis-diphenylphosphino ferrocene palladium dichloride were dissolved in 120mL of 1, 4-dioxane under nitrogen, reacted at 110℃under reflux for 8h, cooled, extracted with dichloromethane and water, and the organic phase was collected and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the oily liquid was subjected to column chromatography to give 5.4g (yield: 89.4%) of the product as an orange-yellow oily liquid.
Compound 4
3.0g (5.7 mmol) of the compound 3,2.6g (13.7 mmol) of 5-bromothiophene-2-carbaldehyde, 12.3g (90.0 mmol) of potassium carbonate and 0.35g (0.3 mmol) of palladium tetraphenylphosphine were added to a 90/45/22.5mL toluene/water/ethanol mixed solvent under nitrogen atmosphere, and the mixture was refluxed at 110℃for 6 hours. Cooled, extracted with water and ethyl acetate, and the organic phase was collected and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the solid was subjected to column chromatography to give 1.36g (yield: 48.3%) of a red solid product.
Compound 5
Under the protection of argon, 0.2g (0.4 mmol) of compound 4,0.5g (2.4 mmol) of 1, 2-trimethyl-1H-benzo [ e ] indole and 1.3g (12.0 mmol) of potassium tert-butoxide are dissolved in 6mL of ethanol and reacted at 80 ℃ under reflux for 12H. Cooling, removing the solvent in vacuo, subjecting the solid to column chromatography to give 0.1154g (yield: 32.8%) of a red solid product,
TPA-2TIN
0.04g (0.04 mmol) of Compound 5,0.11g (0.8 mmol) of iodomethane was dissolved in 3mL of acetonitrile and reacted at 90℃under reflux for 7h. Cooling, adding diethyl ether to give a black solid, filtering and washing with diethyl ether, drying, dissolving the solid in 15mL of methanol, adding 10mL of saturated NH 4 PF 6 The aqueous solution was stirred at room temperature for 24 hours, and a black solid was obtained by suction filtration, and 0.0382g (yield: 82.2%) of a black solid product was obtained after drying
Example 2
Detection of tumor cell killing effect of probe
Inoculating 4T1 cells into a 96-well plate, culturing for 24 hours, adding nano forms of TPA-2TIN molecules diluted by different volumes of culture media (TPA-2 TIN-NPs, a preparation method of the nano forms of the molecules comprises the steps of dissolving 1mg of TPA-2TIN molecules and 5mg of DSPE-PEG2k in 1mL of DMF, dropwise adding 9mL of water under the condition of ultrasound, and performing ultrasound for 2 minutes, dialyzing to remove DHF, thus obtaining the nano forms of TPA-2TIN molecules), incubating for 24 hours at 37 ℃ in a cell culture box, carefully washing twice with PBS, adding cck-8 reagent, incubating for 2 hours at 37 ℃ in the cell culture box, measuring absorbance of each hole by an enzyme-labeled instrument, and calculating the cell viability.
The killing effect of the probe on tumor cells is shown in fig. 10. With the increase of the probe concentration, the cell survival rate is obviously reduced, and the potential of the probe as an anti-tumor drug is reflected. The AIE fluorescent probe is positively charged, and the mitochondria of the tumor cells have negative membrane potential, and the potential difference of the AIE fluorescent probe is far greater than that of the mitochondria of normal cells, so that the AIE fluorescent probe is more prone to be gathered in the mitochondria of the tumor cells, thereby damaging the mitochondrial function and finally causing the apoptosis of the cells, thereby showing stronger tumor cytotoxicity and smaller toxicity to the normal cells.
Example 3
Detection of tumor cell apoptosis induction effect of probe
4T1 cells were inoculated into 96-well plates, cultured for 24h, nano-forms of TPA-2TIN molecules (TPA-2 TIN-NPs) diluted with different volumes of medium were added, incubated for 4h at 37℃in a cell incubator, and the plates were removed and photographed under a microscope.
The morphological analysis of the cells after incubation of the probe with tumor cells is shown in FIG. 11. With the increase of the probe concentration, the tumor cells which generate swelling and cavitation forms under the same size field of view are increased, namely the number of the scorched cells is continuously increased, and the drug effect of the probe on inducing the scorched cells of the tumor is reflected.
The results of flow-through quantitative analysis after incubation of the probe with tumor cells are shown in FIG. 12. As the probe concentration increases, the proportion of AM/PI biscationic cells (i.e. pyroapoptotic cells) increases and then decreases, reaching a maximum at 30uM concentration, probably because further increases in concentration result in an increase in the proportion of cells that die in other ways such as apoptosis or necrosis, while the proportion of pyroapoptotic cells decreases.
The immunoblot analysis results after incubation of the probe with tumor cells are shown in fig. 13. With increasing concentration, the content of caspase-3 enzyme gradually decreases, reaches the lowest value at 30uM concentration, and increases at 40uM, meanwhile, the content of GSDME protein gradually decreases, and the content does not change significantly in the concentration range of 20-40uM, wherein the content of GSDME cleavage fragment GSDME-N increases significantly at 30uM concentration, which indicates that the proportion of scorched cells at the concentration is higher and is consistent with the flow analysis result.
Example 4
4T1 cells were seeded into confocal dishes, cultured for 24h, added with a culture medium diluted 1uM TPA-2TIN molecular nano-form (TPA-2 TIN-NPs), incubated in a cell incubator at 37℃for 4h, medium was discarded, washed three times with PBS, stained with mitochondrial commercial dye MTDR, and after 4% formaldehyde fixation, photographed under microscopic observation.
The results of fluorescence imaging after incubation of the probe with the cells are shown in FIG. 14. The red channel is a mitochondrial commercial dye, the green channel is a probe TPA-2TIN, and fluorescent signals of the two dyes can be seen to be highly overlapped from a fusion image, so that the targeting of the probe to mitochondria of tumor cells is shown.
Example 5
ROS in vitro detection of probes
The probe prepared in example 1 (TPA-2 TIN) was dissolved in DMSO at a concentration according to DMSO: water = 1:99, the probe is added into the solvent according to the volume ratio, the ABDA is used for detecting the ROS, the intensities of three characteristic absorption peaks of the ABDA are detected under an ultraviolet spectrophotometer, when the red light is used for irradiation, the probe can generate the ROS, so that the ultraviolet absorption peak of the ABDA can be rapidly reduced, and the in-vitro detection of the ROS generation is carried out.
The in vitro assay results for ROS production are shown in FIG. 15. Using ABDA as an indicator, the peak of absorption gradually decreases with increasing light exposure, indicating that TPA-2TIN is capable of generating ROS in vitro.
Example 6
In vitro photothermal performance detection of probes
The probe prepared in example 1 was dissolved in DMSO at a concentration, the solution was irradiated with 638nm laser light at different powers, and the temperature change of the solution was monitored in real time with a thermal imager and recorded every 30 seconds.
The result of the photo-thermal effect detection of the probe is shown in FIG. 16. With the increase of irradiation time, the solution temperature gradually rises and becomes stable, and the laser irradiation power is increasedCan make the temperature difference of the solution continuously increase to 0.3W/cm 2 Can reach a temperature difference of 35 ℃, shows stronger photo-thermal performance, and has potential application value in tumor photo-thermal treatment.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that it will be apparent to those skilled in the art that numerous changes and modifications can be made without departing from the principles of the invention, which is also intended to be regarded as the scope of the invention.
Claims (6)
1. A small molecule AIE fluorescent probe, characterized in that its compound is denoted TPA-2TIN, having the structure shown below:
wherein the R is - Anions selected from single charge or multiple charge.
2. A method for preparing the small molecule AIE fluorescent probe of claim 1, comprising the steps of:
1) Adding 4-methoxyaniline and 1-bromo-4-iodobenzene with the structure shown in formula 1 into toluene, and reacting with cuprous iodide, 1, 10-phenanthroline and potassium tert-butoxide as catalysts to obtain a compound 2;
2) Dissolving a compound 2 and bisboronic acid pinacol ester in 1, 4-dioxane, and reacting with 1,1' -bis-diphenylphosphino ferrocene palladium dichloride and potassium acetate as catalysts to obtain a compound 3;
3) Adding the compound 3 and 5-bromothiophene-2-formaldehyde into a toluene/ethanol/water mixed solution, and reacting with triphenylphosphine palladium and potassium carbonate serving as catalysts to obtain a compound 4;
4) Dissolving the compound 4, 1, 2-trimethyl-1H-benzo [ e ] indole and potassium tert-butoxide in ethanol, and reacting to obtain a compound 5:
5) Dissolving compound 5 and methyl iodide in acetonitrile, reacting to obtain intermediate, removing solvent, adding NH 4 R and methanol/water solution, and reacting to obtain TPA-2TIN:
3. use of the AIE fluorescent probe according to claim 1 for the preparation of tumor cell imaging reagents.
4. Use of the AIE fluorescent probe according to claim 1 for the preparation of tumor imaging reagents.
5. Use of the AIE fluorescent probe according to claim 1 for the preparation of a medicament for triggering the scorch of tumor cells.
6. Use of an AIE fluorescent probe according to claim 1 for the preparation of a tumour photodynamic or photothermal therapeutic agent.
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