CN113024586A - Cell membrane targeted BODIPY type organic photosensitizer and application thereof - Google Patents
Cell membrane targeted BODIPY type organic photosensitizer and application thereof Download PDFInfo
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- CN113024586A CN113024586A CN202110213557.3A CN202110213557A CN113024586A CN 113024586 A CN113024586 A CN 113024586A CN 202110213557 A CN202110213557 A CN 202110213557A CN 113024586 A CN113024586 A CN 113024586A
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- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/022—Boron compounds without C-boron linkages
-
- 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
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- General Chemical & Material Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention belongs to the field of tumor photodynamic therapy application, and particularly relates to a cell membrane targeted BODIPY type organic photosensitizer and application thereof. The invention provides the BODIPY type organic dye molecule which has the advantages of cell membrane targeting, AIE characteristics, high ROS generation efficiency, capability of realizing fluorescence imaging guided tumor photodynamic therapy and the like.
Description
Technical Field
The invention belongs to the field of tumor photodynamic therapy application, and particularly relates to a cell membrane targeted BODIPY type organic photosensitizer and application thereof.
Background
Cancer, a major disease that threatens human life and health worldwide, has attracted considerable attention due to its problems of difficulty in early detection, rapid malignant progression, and rapid metastasis at a late stage. In recent years, it has been found that photodynamic therapy (PDT) induces an apoptotic response in malignant cells by generating free radicals or Reactive Oxygen Species (ROS) by photosensitizers under light irradiation. PDT is highly reproducible, less costly, less invasive, and has fewer side effects than surgical, radiation, and chemotherapy. To date, photodynamic therapy has gained high acceptance in clinical practice and is a promising alternative treatment for various types of cancer.
The traditional photosensitizers such as porphyrin, methylene blue and the like have the defects of poor stability, low fluorescence quantum yield in water, weak active oxygen generation capacity and the like. Conventional photosensitizers fluoresce strongly in dilute solutions, but in the aggregated state they are quenched, a phenomenon commonly referred to as aggregate fluorescence quenching (ACQ). The ACQ phenomenon may hinder the practical application of photosensitizers, especially for fluorescence imaging guided photodynamic therapy. In this case, photosensitizers with aggregation-induced emission (AIE) characteristics have opened new advances in cancer photodynamic therapy. AIE photosensitizers can exhibit enhanced ROS generation efficiency in the aggregated state by enhancing intersystem crossing between singlet and triplet states. The BODIPY structure has the characteristics of high molar extinction coefficient, high fluorescence quantum yield, good light stability and the like, and is widely applied to photodynamic therapy as a photosensitizer.
The cell membrane, an important organelle, consists of a phospholipid bilayer, which is a protective layer between living cells and the surrounding environment. Cell membranes have been shown to be involved in various cellular processes and biological functions, such as cell signaling, cell adhesion, endocytosis, extracellular and permselective substances. Therefore, in order to develop a photosensitizer having a cell membrane targeting ability and an excellent photodynamic therapy effect, the present inventors designed and synthesized a class of cell membrane targeting organic photosensitizers based on the BODIPY structure, and applied them to photodynamic therapy of tumors.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a cell membrane targeted BODIPY type organic photosensitizer and application thereof in tumor photodynamic therapy.
In a first aspect of the present invention, a cell membrane-targeted BODIPY-type organic photosensitizer is provided, which has a structural general formula:
wherein: r is H, halogen, straight-chain alkoxy of C1-C6 or branched-chain alkoxy of C1-C6;
x is halogen anion and hexafluorophosphate anion.
Preferably, R ═ OCH3 and X ═ PF 6-.
In a second aspect of the present invention, there is provided an application of the cell membrane-targeted BODIPY-type organic photosensitizer in preparing a medicament for treating tumor, wherein the BODIPY-type organic photosensitizer can kill tumor cells by illumination.
Preferably, the tumor cells comprise cervical cancer cells and liver cancer cells.
In a third aspect of the present invention, there is provided a pharmaceutical composition for treating tumor, comprising the cell membrane-targeted BODIPY-type organic photosensitizer as described above, and a pharmaceutically acceptable carrier.
The invention has the following beneficial effects:
1. the BODIPY type organic photosensitizer provided by the invention has the advantages that tetraphenyl ethylene with an uneven surface structure can effectively increase the distance between molecules and inhibit the pi-pi accumulation effect between molecules, and benzene rings and pyridine groups of the tetraphenyl ethylene can freely rotate in a dispersed state, so that the molecules have AIE characteristics;
2. compared with the traditional BODIPY organic photosensitizer, the BODIPY organic photosensitizer provided by the invention has a wider absorption spectrum by introducing additional electron donor tetraphenylethylene and electron acceptor pyridinium derivatives. In addition, the photosensitizer shows bright red fluorescence, and is better helpful for fluorescence imaging of tissues and photodynamic therapy under the guidance of imaging;
3. the BODIPY type organic photosensitizer provided by the invention can enter cell targeting cell membranes and emit red fluorescence;
4. the BODIPY type organic photosensitizer provided by the invention has strong ROS generation efficiency, shows stronger ROS generation efficiency than commercial dye Rose Bengal, and can obviously detect the generation of ROS in cells;
5. the BODIPY type organic photosensitizer provided by the invention has lower cell dark toxicity, and shows strong phototoxicity under white light irradiation, which shows that the photosensitizer has high biological safety and excellent photodynamic therapy effect;
6. the BODIPY type organic photosensitizer has the advantages of easily available raw materials, simple synthesis and low cost. Similar photosensitizers are not reported to be used for photodynamic therapy of tumors, and have strong commercial application value.
In conclusion, the invention provides the BODIPY type organic photosensitizer which has the advantages of cell membrane targeting, AIE characteristics, high ROS generation efficiency, capability of realizing fluorescence imaging guided tumor photodynamic therapy and the like.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is within the scope of the present invention for those skilled in the art to obtain other drawings based on the drawings without inventive exercise.
FIG. 1 is a scheme showing the synthesis of the organic photosensitizer in example 1;
FIG. 2(a) shows the photosensitizing dye synthesized in example 1 in a methanol/glycerol system (concentration: 1X 10)-5M) fluorescence emission plots at different methanol/glycerol volume ratios, and FIG. 2(b) is a plot of the change in fluorescence intensity of the dye at different concentrations of bovine serum albumin;
FIG. 3(a) shows the dyes synthesized in example 1 in DMSO solvent (concentration: 1X 10)-5M) in DMSO solvent, and FIG. 3(b) is a graph showing the UV-visible absorption spectrum of the liquid in which the dye synthesized in example 1 was present (concentration: 1X 10)-5M) fluorescence emission spectrum;
FIG. 4 is a graph of co-localization fluorescence imaging of the dye synthesized in example 1 with the cell membrane commercial dye DiO in HeLa cells;
FIG. 5(a) is a graph showing the enhancement of fluorescence intensity of the ROS indicator DCFH-DA by the dye synthesized in example 1 under white light irradiation, and FIG. 5(b) is a graph showing the enhancement of fluorescence of DCFH-DA by the commercial dye Rose Bengal under the same conditions;
FIG. 6 is a graph of fluorescence imaging of the dye synthesized in example 1 enhanced by ROS indicator DCFH-DA when irradiated by a white light lamp in HeLa cells at different times;
FIG. 7 is a graph of experimental data on staining of live and dead cells in HeLa cells with the dye synthesized in example 1;
FIG. 8 is a bar graph of phototoxicity and dark toxicity data for the dye synthesized in example 1 in HeLa cells.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in further detail with reference to the accompanying drawings.
Example 1:
a BODIPY type organic photosensitizer-based TBVP has the chemical formula as follows:
wherein R is OCH3，X＝PF6 -。
The chemical route of the preparation is shown in figure 1, and the specific synthetic steps are as follows:
(1) synthesis of Compound 3
In a 50mL two-necked round-bottom flask under argon, 272mg (2.0mmol) of Compound 1 and 399mg (4.2mmol) of Compound 2 are added to 15mL of THF solvent, followed by 0.05mL of trifluoroacetic acid. The reaction mixture is stirred and reacted for 12 hours at normal temperature. After the reaction, 499mg (2.2mmol) of 2, 3-dichloro-5, 6-dicyan-p-benzoquinone was added to the reaction mixture and reacted at room temperature for 6 hours. Then, the product is processed5mL of triethylamine and 5mL of boron trifluoride were added, and the mixture was reacted at room temperature for 6 hours, after the reaction was completed, 20mL of deionized water was added to the reaction solution, and extracted with ethyl acetate several times. Drying the organic phases obtained by extraction and combination by using anhydrous magnesium sulfate, then removing the organic solvent by rotary evaporation, and separating and purifying the crude product by silica gel column chromatography, wherein the organic phase is obtained by using normal hexane: ethyl acetate (8:1) as the mobile phase gave compound 3 (432mg) as a dark green solid in 64% yield. Nuclear magnetism:1H NMR(400MHz,CDCl3)δ7.16(d,J＝8.8Hz,2H),7.01(d,J＝8.7Hz,2H),5.97(s,2H),3.87(s,3H),2.55(s,6H),1.43(s,6H).
(2) synthesis of Compound 4
In a 50mL two-necked round-bottomed flask, under argon, 5mL of DMF and 5mL of phosphorus oxychloride were added, and the mixture was stirred at 0 ℃ for 5 minutes, 354mg (1.0mmol) of Compound 3 was further added, and the reaction mixture was stirred at 50 ℃ for 4 hours. After cooling to room temperature, the reaction mixture was slowly dropped into 30mL of ice water, and extracted with ethyl acetate several times. Drying the organic phases obtained by extraction and combination by using anhydrous magnesium sulfate, then removing the organic solvent by rotary evaporation, and separating and purifying the crude product by silica gel column chromatography, wherein the organic phase is obtained by using normal hexane: ethyl acetate (3:1) as the mobile phase gave (0.34g) compound 4 as a yellow solid in 85% yield. Nuclear magnetism:1H NMR(400MHz,CDCl3)δ9.99(s,1H),7.15(d,J＝8.5Hz,2H),7.03(d,J＝8.6Hz,2H),6.13(s,1H),3.87(s,3H),2.80(s,3H),2.59(s,3H),1.70(s,3H),1.47(s,3H).
(3) synthesis of Compound 5
In a 50mL round-bottom flask, 382mg (1mmol) of Compound 4, 267mg (1.5mmol) of N-bromosuccinimide, and 20mL of tetrahydrofuran were added as a solvent. The reaction mixture was reacted at room temperature for 1 hour. After the reaction, 20mL of deionized water was added to the reaction mixture, and ethyl acetate was usedThe ester is extracted several times. Drying the organic phases obtained by extraction and combination by using anhydrous magnesium sulfate, then removing the organic solvent by rotary evaporation, and separating and purifying the crude product by silica gel column chromatography, wherein the organic phase is obtained by using normal hexane: ethyl acetate: dichloromethane (8: 1: 1) as the mobile phase gave (0.28g) compound 5 as an orange solid in 61% yield. Nuclear magnetism:1H NMR(400MHz,CDCl3)δ9.94(s,1H),7.09(d,J＝8.6Hz,2H),6.99(d,J＝8.6Hz,2H),3.83(s,3H),2.75(s,3H),2.58(s,3H),1.65(s,3H),1.40(s,3H).
(4) synthesis of Compound 6
In a 50mL two-necked round-bottomed flask, under protection of argon, 461mg (1.0mmol) of Compound 5, 458mg (1.0mmol) of 1- (4-phenylboronic acid pinacol ester) -1,2, 2-triphenylethylene, and 3mL of 2M K2CO3The aqueous solution was added to 20mL of THF solvent, followed by 60mg of Pd (PPh)3)4A catalyst. The reaction mixture is heated to 70 ℃ to react for 12 h. After cooling to room temperature, 30mL of deionized water was added to the reaction solution, and extracted several times with dichloromethane. Drying the organic phases obtained by extraction and combination by using anhydrous magnesium sulfate, then removing the organic solvent by rotary evaporation, and separating and purifying the crude product by silica gel column chromatography, wherein the organic phase is obtained by using normal hexane: acetone (15:1) as the mobile phase gave (0.51g) compound 6 as a red solid in 71% yield. Nuclear magnetism:1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),7.31(d,J＝8.1Hz,2H),7.16–7.06(m,11H),7.03–6.90(m,10H),3.82(s,3H),2.71(s,3H),2.41(s,3H),1.65(s,3H),1.29(s,3H).
(5) synthesis of Compound TBVP
In a 50mL two-necked round-bottomed flask, under protection of argon, 357mg (0.5mmol) of compound 6, 177mg (0.5mmol) of 1- (3-trimethylammonium propyl) -4-methylpyridine dibromide, 300mg (5mmol) of acetic acid, 386mg (5mmol) of acetic acidAmmonium was added to 20mL of toluene solvent. The reaction mixture is heated to 110 ℃ for reaction for 24 h. After the reaction is finished, cooling the reaction solution to normal temperature, carrying out vacuum filtration to obtain a dark red solid, and washing the solid with 10mL of glacial ethanol. A50 mL round bottom flask was then charged with the dark red solid obtained above and 15mL DMSO, followed by 5mL saturated KPF6An aqueous solution. Stirring the reaction solution at room temperature for 1h, filtering to remove the solvent after the reaction is finished, and separating and purifying the crude product by using a neutral alumina column chromatography, wherein the weight ratio of dichloromethane: methanol (10:1) was used as the mobile phase to give 217mg of the deep red photosensitizer TBVP. The yield was 37%. Nuclear magnetism:1H NMR(400MHz,DMSO-d6)δ9.04(d,J＝6.5Hz,2H),8.34(d,J＝6.5Hz,2H),7.90(d,J＝16.5Hz,1H),7.36(d,J＝8.4Hz,2H),7.20–7.09(m,12H),7.06–6.93(m,10H),4.62(m,2H),3.87(s,3H),3.51–3.42(m,2H),3.12(s,9H),2.76(s,3H),2.50–2.38(m,5H),1.61(s,3H),1.32(s,3H).
example 2:
the photosensitizer TBVP of example 1 was subjected to AIE performance testing as shown in figure 2. The BODIPY-based organic photosensitizer TBVP was tested for its AIE performance in a methanol/glycerol system as well as in bovine serum albumin. From FIG. 2a, it can be seen that the fluorescence intensity of the solution gradually increases with the increase of the volume of glycerol, and from FIG. 2b, it can also be seen that the fluorescence intensity of the solution continuously increases with the increase of the concentration of bovine serum albumin, which indicates that the photosensitizer has good AIE performance.
Example 3
Liquid uv and fluorescence tests were performed on the photosensitizer TBVP of example 1. As shown in fig. 3. The ultraviolet-visible absorption spectrum of the dye TBVP in DMSO is shown in FIG. 3a, the maximum absorption wavelength of the dye is 560nm, and the absorption spectrum covers most of the visible light region. FIG. 3b is a fluorescence emission spectrum of the dye with a peak at 600nm, showing that the dye has bright red fluorescence.
Example 4
Cell imaging and fluorescence co-localization experiments with cell membrane targeting dyes were performed on the photosensitizer TBVP of example 1, as shown in figure 4. HeLa cells were incubated with 2. mu.M TBVP for 20 min and co-localization with cell membrane commercial dye DiO confirmed the targeted location of the photosensitizer. From fig. 4B, it can be seen that the photosensitizer TBVP can well enter HeLa cells and emit red fluorescence. From FIG. 4D, it can be seen that the overlap of fluorescence of the photosensitizer TBVP and the cell membrane commercial dye is high, which indicates that the photosensitizer TBVP can target cell membranes well.
Example 5
An assay for the detection of ROS-producing ability was performed on the photosensitizer TBVP of example 1, as shown in FIG. 5. DCFH-DA is an indicator of ROS, and from FIG. 5a it can be seen that the dye TBVP rapidly enhances the fluorescence of the solution under light conditions. FIG. 5b is a photograph of the enhancement of DCFH-DA fluorescence by the commercial dye Rose Bengal under light conditions. Comparing the graphs of a and b, it is clear that the photosensitizer TBVP has higher ROS production efficiency than the commercial dye Rose Bengal, indicating that the photosensitizer TBVP shows excellent ROS production performance.
Example 6
An experiment for measuring ROS-producing ability in HeLa cells was performed on the photosensitizer TBVP of example 1, as shown in FIG. 6. DCFH-DA is an indicator of ROS, and can combine with ROS to generate green fluorescence. Fig. 6A and 6B show that no visible green fluorescence is produced in the absence of photosensitizer and in the presence of photosensitizer but in the absence of light, but that fig. 6C to 6E show an increasing green fluorescence with increasing light exposure time. This indicates that the photosensitizer TBVP also shows excellent ROS production performance in cells.
Example 7
Live and dead cell staining experiments of HeLa cells were performed on the photosensitizer TBVP of example 1, as shown in fig. 7. Calcein-AM stains live cells producing green fluorescence, while Propidium Iodide (PI) stains only dead cells producing red fluorescence. As can be seen from FIG. 7, as the illumination time is prolonged, the green fluorescence of the Calcein-AM channel is continuously reduced, and the red fluorescence of the PI channel is continuously enhanced. Under 30 minutes of irradiation, green fluorescence basically disappears, only red PI dead cell signals are displayed, and meanwhile, the cell morphology is obviously changed under a bright field. The experiment also shows that the photosensitizer TBVP has good tumor photodynamic treatment effect.
Example 8
Phototoxicity and dark toxicity studies of HeLa cells were performed on the photosensitizer TBVP of example 1, as shown in fig. 8. The 96-well plates were incubated with the photosensitizer at the concentrations shown in fig. 8 for 24 hours, respectively, with HeLa cells divided into three groups, one group with 10 minutes of white light irradiation, one group with 5 minutes of white light irradiation, and one group without light irradiation. From the figure, it can be seen that the photosensitizer TBVP has little cytotoxicity in the dark state, and shows high phototoxicity under the light condition. The experiment shows that the photosensitizer TBVP has good tumor photodynamic treatment effect.
The above disclosure is only for the purpose of illustrating the preferred embodiments of the present invention, and it is therefore to be understood that the invention is not limited by the scope of the appended claims.
Claims (5)
1. A cell membrane targeted BODIPY type organic photosensitizer is characterized in that the structural general formula is as follows:
wherein: r is H, halogen, C1～C6Linear alkoxy of (5) or C1～C6A branched alkoxy group of (4);
x is halogen anion and hexafluorophosphate anion.
2. The cell membrane-targeted BODIPY-type organic photosensitizer of claim 1, wherein: r ═ OCH3，X＝PF6 -。
3. Use of a cell membrane-targeted BODIPY-type organic photosensitizer of claim 1 or 2, capable of killing tumor cells by illumination, for the preparation of a medicament for the treatment of tumors.
4. The use of the cell membrane-targeted BODIPY-type organic photosensitizer according to claim 3 for preparing a medicament for treating tumors, wherein: the tumor cells comprise cervical cancer cells and liver cancer cells.
5. A pharmaceutical composition for treating a tumor, comprising: comprising the cell membrane-targeted BODIPY-type organic photosensitizer of claim 1 or 2, and a pharmaceutically acceptable carrier.
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