Preparation method and application of compound for near-infrared fluorescence imaging and photothermal-photodynamic synergistic treatment

Abstract

The invention belongs to the technical field of antitumor drugs, and particularly discloses a preparation method and application of a compound for near-infrared fluorescence imaging and photothermal-photodynamic synergistic treatment. The compound for near-infrared fluorescence imaging and photothermal-photodynamic synergistic treatment is shown in the following structural formula: # imgabs0, the molecular skeleton of the compound contains a triphenylamine unit and an N, N-dimethylaniline fragment, intramolecular rotation limitation and intramolecular vibration limitation can be generated, and obvious aggregation-induced emission (AIE) performance is shown. The function-integrated phototherapy agent has high active oxygen generation efficiency, photothermal conversion efficiency and near-infrared fluorescence quantum yield, and is beneficial to obtaining ideal photothermal-photodynamic therapy effect for deep tumors. The phototherapy agent is novel in structure, the preparation method is easy in raw material obtaining, the synthesis condition is mild, the preparation method is simple, purification is convenient and fast, implementation is easy, and the phototherapy agent has great application prospects.

Description

Technical Field

[0001] The present invention belongs to the technical field of anti-tumor drugs, and particularly relates to a preparation method and application of a compound for near-infrared fluorescence imaging and photothermal-photodynamic synergistic therapy. Background Art

[0002] Compared with visible light (400 - 750 nm) and the first near-infrared window (750 - 900 nm), the absorption and scattering of biological living tissues to the second near-infrared fluorescence (1000 - 1700 nm) are significantly reduced. The obvious increase in light absorption intensity significantly inhibits the scattering background in two-dimensional array imaging, thus improving the imaging effect. Therefore, the second near-infrared fluorescence has advantages such as higher tissue penetration depth and spatial resolution in in vivo imaging applications, and is regarded as one of the most potential optical in vivo imaging means with large depth and high resolution.

[0003] The current cancer treatment methods mainly rely on traditional surgical resection, supplemented by chemotherapy and radiotherapy. However, traditional treatment methods often cause serious side effects such as tumor recurrence, multi-drug resistance, and immune system damage. The booming development of nanotechnology has brought new hope for cancer diagnosis and treatment. At present, phototherapy combines real-time diagnosis and in-situ treatment, and has developed into a feasible treatment plan due to its non-invasive and low toxic side effects. As a light-controllable, non-invasive, and effective treatment means, phototherapy includes photodynamic therapy (PDT) and photothermal therapy (PTT), which usually use visible light or near-infrared light to excite nanomaterials to generate toxic reactive oxygen species or high temperature to kill tumor cells. The thermal signal generated during the PTT process can also be captured by a photothermal imaging system, thus providing the possibility of good temperature sensitivity and real-time monitoring. However, due to the hypoxia of the PDT tumor microenvironment and the heat shock effect of PTT, the efficiency of using PDT or PTT alone is usually not satisfactory. Therefore, in clinical applications, certain treatment effects are mainly achieved in the treatment of superficial tumors. However, most tumors (such as lung cancer, gastric cancer, ovarian cancer, and pancreatic cancer, etc.) often grow deep in tissues. Due to the strong absorption or scattering of human tissues before the light source reaches the tumor and the limited penetration depth, it is difficult to completely eradicate solid tumors by using photodynamic therapy or photothermal therapy alone (especially after a course of treatment). Therefore, it is necessary to design a phototherapeutic agent with strong absorption in the second near-infrared region for combined photothermal and photodynamic therapy, so that the two treatment methods complement each other, improve the diagnosis and treatment effect, reduce the toxic side effects, shorten the treatment cycle, and achieve an effect of 1 + 1 > 2.

[0004] Most of the reported phototherapeutic agents are inorganic materials, such as titanium dioxide, etc. However, inorganic nanomaterials have deficiencies such as long metabolic time and limited ability to generate reactive oxygen species. In contrast, organic phototherapeutic agents have advantages such as diverse structures and good biocompatibility. However, organic small molecules such as porphyrin precursors (5-aminolevulinic acid) and porphyrins usually exhibit chemical instability, photobleaching, and high cytotoxicity; or the absorption response range is in the first near-infrared region, making it impossible to treat deep tumors (such as glioblastoma). Therefore, developing phototherapeutic agents for NIR II region fluorescence imaging and photothermal-photodynamic synergistic therapy can utilize the advantages and disadvantages of various diagnostic and treatment methods, compensate for the shortcoming, and improve the treatment effect of deep tumors. Summary of the Invention

[0005] In order to overcome the above-mentioned disadvantages and deficiencies in the existing technology, the primary object of the present invention is to provide a compound for near-infrared fluorescence imaging and photothermal-photodynamic synergistic therapy.

[0006] Another object of the present invention is to provide a preparation method of the above-mentioned compound for near-infrared fluorescence imaging and photothermal-photodynamic synergistic therapy.

[0007] Another object of the present invention is to provide a phototherapeutic agent, including the above-mentioned compound or the compound prepared by the above-mentioned method.

[0008] Another object of the present invention is to provide the application of the above-mentioned compound in the preparation of a phototherapeutic agent for NIR-II region fluorescence imaging and / or tumor photothermal-photodynamic therapy.

[0009] The object of the present invention is achieved by the following technical solutions:

[0010] A compound for near-infrared fluorescence imaging and photothermal-photodynamic synergistic therapy, named XQ, and its chemical structure is shown in formula (Ⅰ):

[0011]

[0012] Among them, R2 is hydrogen or a straight-chain or branched-chain alkyl group with 1-30 carbon atoms; R1 is a straight-chain or branched-chain alkyl group with 1-30 carbon atoms.

[0013] Further, R2 is hydrogen or a straight-chain or branched-chain alkyl group with 1-10 carbon atoms;

[0014] Further, R2 is H or a straight-chain or branched-chain alkyl group with 1-6 carbon atoms;

[0015] Preferably, R2 is a straight-chain or branched-chain alkyl group with 4 carbon atoms, such as isobutyl.

[0016] Further, R1 is a straight-chain or branched-chain alkyl group with 4-22 carbon atoms.

[0017] Further, R1 is a straight-chain or branched-chain alkyl group with 8 to 16 carbon atoms.

[0018] Preferably, R1 is a straight-chain or branched-chain alkyl group with 8 carbon atoms, such as 2-ethylhexyl.

[0019] The preparation method of the above compound XQ for near-infrared fluorescence imaging and photothermal-photodynamic synergistic therapy includes the following steps:

[0020] (1) 4,7-dibromo-2,1,3-benzothiadiazole reacts at 140 °C for 24 hours under the action of iron powder and glacial acetic acid to undergo a ring-opening reaction, obtaining compound M1;

[0021] (2) Compound M1 reacts at 25 °C for 12 hours under the action of glacial acetic acid and sodium nitrite to undergo a ring-closure reaction, obtaining compound M2;

[0022] (3) Compound M2 is dissolved in N,N-dimethylformamide and undergoes an alkylation reaction with alkyl bromide R1-Br under the action of potassium carbonate, reacting at 110 °C for 12 hours to obtain compound M3;

[0023] (4) Compound M3 undergoes a nitration reaction in a concentrated nitric acid and concentrated sulfuric acid system, reacting at 100 °C for 12 hours to obtain compound M4;

[0024] (5) Compound M4 undergoes a reduction reaction under the action of iron powder and glacial acetic acid, reacting at 140 °C for 20 hours to obtain compound M5;

[0025] (6) 2,7-dibromobenzo[2,1-b:3,4-b']dithiophene-4,5-dione and 4',4'-diR2-yl-4-boronic acid pinacol ester triphenylamine are dissolved in tetrahydrofuran and undergo a Suzuki coupling reaction under the action of potassium carbonate and tetrakis(triphenylphosphine)palladium, reacting at 80 °C for 12 hours to obtain compound M6;

[0026] (7) Compound M5 undergoes a condensation reaction with compound M6 under the action of glacial acetic acid, reacting at 110 °C for 24 hours to obtain compound M7;

[0027] (8) Compound M7 and 4-dimethylaminostyrene are dissolved in toluene and undergo a Mizoroki-Heck coupling reaction under the action of potassium carbonate and tetrakis(triphenylphosphine)palladium, reacting at 125 °C for 24 hours to obtain compound XQ.

[0028] Further, steps (1)-(8) are all carried out under an inert gas atmosphere, such as an argon atmosphere.

[0029] Further, in step (1), the molar ratio of 4,7-dibromo-2,1,3-benzothiadiazole to iron powder is 1:0.02 - 0.1, preferably 1:0.05. The molar amount (mmol) of 4,7-dibromo-2,1,3-benzothiadiazole to the volume (mL) of glacial acetic acid is 1:5 - 10, preferably 1:8.

[0030] Further, in step (2), the molar ratio of compound M1 to sodium nitrite is 1:2 - 6, preferably 1:4. The molar amount (mmol) of compound M1 to the volume (mL) of glacial acetic acid is 1:4 - 10, preferably 1:5.

[0031] Further, in step (3), in alkyl bromide (R1-Br), R1 is a straight-chain or branched-chain alkyl group with 1 - 30 carbon atoms; preferably, R1 is a straight-chain or branched-chain alkyl group with 4 - 22 carbon atoms; more preferably, R1 is a straight-chain or branched-chain alkyl group with 8 - 16 carbon atoms; more preferably, R1 is a straight-chain or branched-chain alkyl group with 8 carbon atoms.

[0032] Further, in step (3), the molar ratio of compound M2, alkyl bromide (R1-Br), to potassium carbonate is 1:1 - 1.5:4 - 10, preferably 1:1.1:6; the molar amount (mmol) of compound M2 to the volume (mL) of N,N-dimethylformamide is 1:5 - 15, preferably 1:10.

[0033] Further, in step (4), the molar amount (mmol) of compound M3 to the volume (mL) of concentrated nitric acid is 1:5 - 10, preferably 1:8. The volume ratio of concentrated nitric acid to concentrated sulfuric acid is 1:0.5 - 5, preferably 1:1.

[0034] Further, in step (5), the molar ratio of compound M4 to iron powder is 1:0.05 - 0.15, preferably 1:0.1. The molar amount (mmol) of compound M4 to the volume (mL) of glacial acetic acid is 1:10 - 20, preferably 1:16.

[0035] Further, in step (6), in 4',4'-di-R2-4-boronic acid pinacol ester triphenylamine, R2 is hydrogen or a straight-chain or branched-chain alkyl group with 1 - 30 carbon atoms; R2 is a straight-chain or branched-chain alkyl group with 1 - 10 carbon atoms; more preferably, R2 is a straight-chain or branched-chain alkyl group with 1 - 6 carbon atoms; more preferably, R2 is a straight-chain or branched-chain alkyl group with 4 carbon atoms.

[0036] Further, in step (6), the molar ratio of 2,7-dibromobenzo[2,1-b:3,4-b']dithiophene-4,5-dione, 4',4'-bis(R2)-4-boronic acid pinacol ester triphenylamine, tetrakis(triphenylphosphine)palladium, and potassium carbonate is 1:2-4:0.01-0.1:5-10, preferably 1:2.5:0.05:8. The molar amount (mmol) of 2,7-dibromobenzo[2,1-b:3,4-b']dithiophene-4,5-dione to the volume (mL) of tetrahydrofuran is 1:10-30, preferably 1:20.

[0037] Further, in step (7), the molar ratio of compound M5 to compound M6 is 1:1-1.5, preferably 1:1.1. The molar amount (mmol) of compound M5 to the volume (mL) of glacial acetic acid is 1:10-15, preferably 1:12.

[0038] Further, in step (8), the molar ratio of compound M7, 4-dimethylaminostyrene, tetrakis(triphenylphosphine)palladium, and potassium carbonate is 1:2-4:0.01-0.1:5-10, preferably 1:3:0.05:8; the molar amount of compound M7 to the volume of toluene is 1 mmol:(10-30) mL, preferably 1 mmol:20 mL.

[0039] The preparation route of the above compound XQ for near-infrared fluorescence imaging and photothermal-photodynamic synergistic therapy is as follows:

[0040]

[0041] Wherein: Toluene means toluene.

[0042] A phototherapeutic agent, comprising the above compound or compound XQ prepared by the above method.

[0043] The application of the above compound XQ or compound XQ prepared by the above method in the preparation of a phototherapeutic agent for NIR-II region fluorescence imaging and / or tumor photothermal-photodynamic therapy.

[0044] In specific applications, the compound XQ and the amphiphilic polymer are dissolved in an organic solvent, and then ultrapure water is added to the system, and ultrasonic treatment is performed to make the system uniformly dispersed, and then the organic solvent is removed to obtain water-soluble photosensitizer nanoparticles, and the apparent concentration of the water-soluble photosensitizer nanoparticles is ≥200 μg / mL.

[0045] Further, the organic solvent is selected from one of tetrahydrofuran, chloroform, acetone, N,N-dimethylformamide, and dimethyl sulfoxide.

[0046] Furthermore, the amphiphilic polymer is an amphoteric triblock polymer formed by ethoxy-propoxy, distearoyl phosphatidylethanolamine-polyethylene glycol 2000, or distearoyl phosphatidylethanolamine-polyethylene glycol 5000.

[0047] Furthermore, the tumor is a deep tumor, such as glioblastoma.

[0048] The compound XQ skeleton of the present invention contains a triphenylamine unit and an N,N-dimethylaniline fragment, which can undergo intramolecular rotation restriction and intramolecular vibration restriction, showing obvious aggregation-induced emission (AIE) properties. The function-integrated phototherapeutic agent has high reactive oxygen generation efficiency, photothermal conversion efficiency, and near-infrared fluorescence quantum yield, which is beneficial to obtaining ideal near-infrared fluorescence imaging and photothermal-photodynamic combined treatment effects for deep tumors (such as glioblastoma). The phototherapeutic agent involved in the present invention has a novel structure, the raw materials of the preparation method are easily available, the synthesis conditions are mild, the preparation method is simple, the purification is convenient, it is easy to implement, and it has great application prospects.

[0049] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0050] 1. The phototherapeutic agent (XQ) contains a helical triphenylamine and an N,N-dimethylaniline fragment It can undergo intramolecular rotation restriction and intramolecular vibration restriction, and has typical aggregation-induced emission (AIE) properties.

[0051] 2. The phototherapeutic agent (XQ) has a strong absorption response in the second near-infrared region (in the range of 1000-1200 nm), can emit second near-infrared fluorescence through radiative transition for fluorescence imaging; can convert the absorbed light energy into heat through non-radiative transition for photothermal therapy; can also generate superoxide anions through type I photodynamic electron transfer process for photodynamic therapy.

[0052] 3. The small molecule phototherapeutic agent (XQ) of the present invention is a phototherapeutic agent that can be used for near-infrared fluorescence imaging and photothermal-photodynamic therapy of tumors. It is non-toxic to cancer cells in a normal cultivation environment and has good biocompatibility; under the irradiation of a single 1064 nm laser (5 min, 1.0 W / cm 2 ) it has the characteristic of high damage effect on cancer cells and is expected to achieve the therapeutic purpose of inhibiting tumor growth in a living model; the cells are cancer cells, especially breast cancer cells.

[0053] 4. The small molecule phototherapeutic agent (XQ) of the present invention has a novel structure, the raw materials of the preparation method are easily available, the synthesis conditions are mild, the preparation method is simple, and the purification is convenient.

[0054] 5. Monomer M6 has photothermal / photodynamic activity under the action of 660 nm laser light irradiation. Through structural optimization, the small molecule phototherapeutic agent (XQ) of the present invention has an increased conjugation degree, and its spectrum redshifts to the second near-infrared region, enabling it to simultaneously exert photothermal / photosensitization effects under the action of a single 1064 nm laser. Description of the Drawings

[0055] Figure 1 : High-resolution mass spectrum of compound XQ1.

[0056] Figure 2 : High-resolution mass spectrum of compound XQ2.

[0057] Figure 3 : UV-visible absorption spectrum of XQ1 nanoparticles with a concentration of 50 μg mL -1 .

[0058] Figure 4 : UV-visible absorption spectrum of XQ2 nanoparticles with a concentration of 50 μg mL -1 .

[0059] Figure 5 : Fluorescence intensity change diagram of XQ1 and XQ2 in a tetrahydrofuran / water system with different water contents.

[0060] Figure 6 : Fluorescence spectrum of XQ1 in a tetrahydrofuran / water system with different water contents (0%, 60%, 99%).

[0061] Figure 7 : Fluorescence spectrum of XQ2 in a tetrahydrofuran / water system with different water contents (0%, 60%, 99%).

[0062] Figure 8 : Fluorescence intensity change diagram of DHR123 under the action of 1064 nm laser light irradiation on XQ1 and XQ2 nanoparticles.

[0063] Figure 9 : Photothermal curves of XQ1 and XQ2 nanoparticles under the action of 1064 nm laser light irradiation.

[0064] Figure 10 : Test result diagram of the photothermal-photodynamic synergistic therapy of phototherapeutic agent XQ2 nanoparticles on GL261 cells.

[0065] Figure 11 : Live / dead double-stained cell fluorescence imaging diagram of phototherapeutic agent XQ2 nanoparticles on GL261 cells. Detailed Description of the Embodiments

[0066] The present invention will be further described in detail below with reference to the embodiments and the drawings, but the embodiments of the present invention are not limited thereto.

[0067] Example 1: Preparation of Compound XQ1

[0068] The reaction formula for the preparation process is as follows:

[0069]

[0070] (1) Preparation of 3,6-dibromo-1,2-benzenediamine (M1)

[0071] Under an argon atmosphere, 4,7-dibromo-2,1,3-benzothiadiazole (2.94 g, 10 mmol), iron powder (28 mg, 0.5 mmol), and glacial acetic acid (80 mL) were added to a 100 mL two-necked flask, and the reaction was carried out at 140 °C for 24 hours. The reaction was stopped, quenched with water, extracted with dichloromethane, and dried with anhydrous magnesium sulfate. After concentration of the solution, recrystallization was carried out with tetrahydrofuran and ethanol to obtain compound M1 with a yield of 89%. The results of MS and elemental analysis showed that the obtained compound was the target product.

[0072] (2) Preparation of 4,7-dibromo-1H-benzotriazole (M2)

[0073] Under an argon atmosphere, compound M1 (5.32 g, 20 mmol) and sodium nitrite (5.52 g, 80 mmol) were added to 100 mL of glacial acetic acid, and the reaction was carried out at 25 °C for 12 hours. After the reaction was stopped, it was quenched with water, extracted with dichloromethane, and dried with anhydrous magnesium sulfate. After concentration of the solution, recrystallization was carried out with tetrahydrofuran and ethanol to obtain compound M2 with a yield of 82%. The results of MS and elemental analysis showed that the obtained compound was the target product.

[0074] (3) Preparation of 4,7-dibromo-2-(2-ethylhexyl)-2H-benzo[d][1,2,3]triazole (M3)

[0075] Under an argon atmosphere, compound M2 (1.38 g, 5 mmol), 1-bromo-2-ethylhexane (1.06 g, 5.5 mmol), potassium carbonate (4.14 g, 30 mmol), and 50 mL of N,N-dimethylformamide (DMF) were added to a 250 mL two-necked flask, and the reaction was carried out at 110 °C for 12 hours. After the reaction was stopped, it was quenched with water, then extracted with dichloromethane, and dried with anhydrous magnesium sulfate. After concentration of the solution, it was purified by silica gel column chromatography, and a mixed solvent of petroleum ether and dichloromethane (volume ratio of petroleum ether to dichloromethane was 4:1) was used as the eluent, and then dried to obtain compound M3 with a yield of 89%. The results of MS and elemental analysis showed that the obtained compound was the target product.

[0076] (4) Preparation of 4,7-dibromo-2-(2-ethylhexyl)-5,6-dinitro-2H-benzo[d][1,2,3]triazole (M4)

[0077] Under an argon atmosphere, compound M3 (1.94 g, 5 mmol) was added to a mixed system of 80 mL of 98 wt% concentrated sulfuric acid and 68 wt% concentrated nitric acid (volume ratio 1:1), and the reaction was carried out at 100 °C for 12 hours. After the reaction was stopped, the reaction system was poured into ice water, extracted with dichloromethane and dried with anhydrous magnesium sulfate. After the solution was concentrated, it was purified by silica gel column chromatography using dichloromethane as the eluent, and dried to obtain compound M4 with a yield of 70%. The results of MS and elemental analysis indicated that the obtained compound was the target product.

[0078] (5) Preparation of 4,7-dibromo-2-(2-ethylhexyl)-2H-benzo[d][1,2,3]triazole-5,6-diamine (M5)

[0079] Under an argon atmosphere, compound M4 (2.40 g, 5 mmol) and iron powder (28 mg, 0.5 mmol) were added to 80 mL of glacial acetic acid, and the reaction was carried out at 140 °C for 20 hours. After the reaction was stopped, the reaction was quenched with water, extracted with dichloromethane and dried with anhydrous magnesium sulfate. After the solution was concentrated, it was recrystallized with tetrahydrofuran and ethanol to obtain compound M5 with a yield of 84%. The results of MS and elemental analysis indicated that the obtained compound was the target product.

[0080] (6) Preparation of 2,7-bis(4-(diphenylamino)phenyl)benzo[2,1-b:3,4-b']dithiophene-4,5-dione (M6) Under an argon atmosphere, 2,7-dibromobenzo[2,1-b:3,4-b']dithiophene-4,5-dione (1.13 g, 3 mmol), N,N-diphenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.78 g, 7.5 mmol), tetrakis(triphenylphosphine)palladium (0.17 g, 0.15 mmol), 50 wt% aqueous potassium carbonate solution (3.31 g, 24 mmol / 3.31 mL deionized water) and 60 mL of tetrahydrofuran were added to a 150 mL two-necked flask, and the mixture was heated to 80 °C and reacted for 12 hours. After the reaction was stopped, the reaction was quenched with water, then extracted with dichloromethane and dried with anhydrous magnesium sulfate. After the solution was concentrated, it was purified by silica gel column chromatography using a mixed solvent of petroleum ether and ethyl acetate (volume ratio of petroleum ether to ethyl acetate is 1:1) as the eluent, and dried to obtain compound M6 with a yield of 69%. The results of MS and elemental analysis indicated that the obtained compound was the target product.

[0081] (7) Preparation of 4,4’-(10-(2-ethylhexyl)-10H-dithieno[3,2-a:2',3'-c][1,2,3]triazolo[4,5-i]phenazine-2,5-diyl)bis(N,N-diphenylaniline) (M7)

[0082] Under an argon atmosphere, compound M5 (2.09 g, 5 mmol) and compound M6 (3.89 g, 5.5 mmol) were added to 60 mL of glacial acetic acid, and the reaction was carried out at 110 °C for 24 hours. The reaction was stopped, quenched with water, extracted with dichloromethane and dried over anhydrous magnesium sulfate. After concentration of the solution, it was purified by silica gel column chromatography using a mixed solvent of petroleum ether and dichloromethane (volume ratio of petroleum ether to dichloromethane was 2:3) as the eluent, and dried to obtain compound M7 with a yield of 55%. The results of MS and elemental analysis showed that the obtained compound was the target product.

[0083] (8) Preparation of target compound XQ1

[0084] Under an argon atmosphere, compound M7 (1.09 g, 1 mmol), 4-dimethylaminostyrene (0.44 g, 3 mmol), tetrakis(triphenylphosphine)palladium (57.8 g, 0.05 mmol) and an aqueous solution of potassium carbonate with a mass fraction of 50% (1.10 g, 8 mmol / 1.1 mL deionized water) were added to 20 mL of toluene, and the reaction was carried out at 125 °C for 24 hours. After the reaction was completed, the mixture was poured into 100 mL of water, extracted with dichloromethane and dried over anhydrous magnesium sulfate. After concentration of the solution, it was purified by silica gel column chromatography using a mixed solvent of petroleum ether and ethyl acetate (volume ratio of petroleum ether to ethyl acetate was 3:1) as the eluent, and dried to obtain compound XQ1. The high-resolution mass spectrum is shown in Figure 1 , and the test result showed that the molecular weight of the compound was 1222.68, which matched the theoretical result (C 80 H 71 N9S2, 1221.53), indicating that compound XQ1 was successfully synthesized.

[0085] Example 2. Preparation of compound XQ2

[0086] The reaction formula of the preparation process is as follows:

[0087]

[0088] (1) Preparation of 2,7-bis(4-(bis(4-(tert-butyl)phenyl)amino)phenyl)benzo[2,1-b:3,4-b']dithiophene-4,5-dione (M8)

[0089] Under an argon atmosphere, 2,7-dibromobenzo[2,1-b:3,4-b']dithiophene-4,5-dione (1.13 g, 3 mmol), 4-(tert-butyl)-N-(4-(tert-butyl)phenyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)aniline (3.62 g, 7.5 mmol), tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol), 50% aqueous potassium carbonate solution (3.31 g, 24 mmol / 3.31 mL deionized water), and 60 mL of tetrahydrofuran were added to a 150 mL two-necked flask. The mixture was heated to 80 °C and reacted for 12 hours. After stopping the reaction, the reaction was quenched with water, extracted with dichloromethane, and dried over anhydrous magnesium sulfate. After concentration of the solution, it was purified by silica gel column chromatography using a mixed solvent of petroleum ether and ethyl acetate (volume ratio of petroleum ether to ethyl acetate was 2:1) as the eluent, and dried to obtain compound M8 with a yield of 76%. The results of MS and elemental analysis indicated that the obtained compound was the target product.

[0090] (2) Preparation of 4,4'-(8,12-dibromo-10-(2-ethylhexyl)-10H-dithieno[3,2-a:2',3'-c][1,2,3]triazolo[4,5-i]phenazine-2,5-diyl)bis(N,N-bis(4-(tert-butyl)phenyl)aniline) (M9)

[0091] Under an argon atmosphere, compound M5 (2.09 g, 5 mmol) and compound M8 (5.12 g, 5.5 mmol) were added to 60 mL of glacial acetic acid and reacted at 110 °C for 24 hours. After stopping the reaction, the reaction was quenched with water, extracted with dichloromethane, and dried over anhydrous magnesium sulfate. After concentration of the solution, it was purified by silica gel column chromatography using a mixed solvent of petroleum ether and dichloromethane (volume ratio of petroleum ether to dichloromethane was 1:1) as the eluent, and dried to obtain compound M9 with a yield of 68%. The results of MS and elemental analysis indicated that the obtained compound was the target product.

[0092] (3) Preparation of the target compound XQ2

[0093] Under an argon atmosphere, compound M9 (1.13 g, 1 mmol), 4-dimethylaminostyrene (0.44 g, 3 mmol), tetrakis(triphenylphosphine)palladium (57.8 g, 0.05 mmol), and an aqueous solution of potassium carbonate with a mass fraction of 50% (1.10 g, 8 mmol / 1.1 mL deionized water) were added to 20 mL of toluene, and the reaction was carried out at 125 °C for 24 hours. After the reaction was completed, the mixture was poured into 100 mL of water, extracted with dichloromethane, and dried over anhydrous magnesium sulfate. After the solution was concentrated, it was purified by silica gel column chromatography, and a mixed solvent of petroleum ether and ethyl acetate (volume ratio of petroleum ether to ethyl acetate was 3:1) was used as the eluent. After drying, compound XQ2 was obtained. The high-resolution mass spectrum is shown in Figure 2 , and the test result showed that the molecular weight of the compound was 1446.88, which matched the theoretical result (C 96 H 103 N9S2, 1445.78), indicating that compound XQ2 was successfully synthesized.

[0094] Example 3. Characterization of Compounds XQ1 and XQ2

[0095] (1) Particle Size Test

[0096] Compounds XQ1 and XQ2 are oil-soluble. The inventors learned through solubility tests that in a tetrahydrofuran solvent, the solubilities of compounds XQ1 and XQ2 were 4.6 mg / mL and 7.5 mg / mL, respectively.

[0097] To adapt to the complex aqueous environment in the body, the oil-soluble compounds XQ1 and XQ2 were respectively prepared into water-soluble nanoparticles, which specifically included the following steps: 10 mg of compound XQ1 or XQ2 and 100 mg of amphiphilic polymer F127 (an amphiphilic triblock polymer formed by ethoxy-propoxy) were completely dissolved in 3 mL of tetrahydrofuran solvent. Under ultrasonic conditions, the mixed system was quickly added to 20 mL of ultrapure water, and ultrasonic treatment was continued for 25 min to make the system evenly dispersed. Then, nitrogen was bubbled into the sample to remove tetrahydrofuran, and finally, it was stored in a 4 °C refrigerator for later use.

[0098] The apparent concentration of the prepared water-soluble XQ1 nanoparticles (XQ1 NPs) or XQ2 nanoparticles (XQ2 NPs) was 500 μg / mL. The size was measured using a Malvern laser particle size analyzer (model Mastersizer 3000). The results showed that the particle size of XQ1 NPs was 63 nm, and the polydispersity index PDI was 0.22; the particle size of XQ2 NPs was 55 nm, and the polydispersity index PDI was 0.20.

[0099] (2) Ultraviolet-Visible Absorption Spectroscopy Test

[0100] The water-soluble XQ1 nanoparticles or XQ2 nanoparticles with an apparent concentration of 500 μg / mL prepared in (1) were subjected to ultraviolet-visible absorption spectroscopy tests.

[0101] Figure 3 This is the ultraviolet-visible absorption spectrum of XQ1 NPs. It can be seen from the figure that its absorption range is 400 - 1260 nm, which is within the second near-infrared region (1000 - 1700 nm). And the absorption peak intensity at 1064 nm (the wavelength of the commonly used second near-infrared laser light source) is 0.923, which is 78% of the strongest absorption peak intensity (1.177). It can be seen that XQ1 NPs have a strong absorption light response in the second near-infrared region.

[0102] Figure 4 This is the ultraviolet-visible absorption spectrum of XQ2 NPs. It can be seen from the figure that its absorption edge redshifts to 1285 nm, and it has a strong absorption response in the second near-infrared region (1000 - 1700 nm). And under the same concentration condition, the absorption intensity of XQ2 NPs is stronger than that of XQ1 NPs; the absorption peak intensity at 1064 nm (the wavelength of the commonly used second near-infrared laser light source) is 1.199, which is 91% of the strongest absorption peak intensity (1.319). It can be seen that XQ2 NPs also have a strong absorption light response in the second near-infrared region, and the absorption intensity at 1064 nm is stronger, which is more conducive to obtaining better photothermal conversion performance.

[0103] Compounds XQ1 and XQ2 contain the same molecular skeleton, and the introduction of tert-butyl in compound XQ2 improves its solubility. Comparing the ultraviolet-visible absorption spectra of XQ1 NPs and XQ2 NPs, it can be seen that the flexible tert-butyl group contained in compound XQ2 can enhance the push-pull effect of electrons within the molecule, cause the ultraviolet-visible absorption spectrum and fluorescence spectrum to redshift, and can weaken the pushing between molecules and the rotation within the molecule, enhance fluorescence, and improve photothermal conversion performance.

[0104] (3) Aggregation-induced emission performance test

[0105] Compounds XQ1 and XQ2 contain helical triphenylamine and N,N-dimethylaniline fragments, which can undergo intramolecular rotation restriction and intramolecular vibration restriction, and have typical aggregation-induced emission (AIE) performance. This is demonstrated by the following experiment:

[0106] Using compound XQ1 or XQ2 as the solute and tetrahydrofuran as the solvent, a stock solution with a concentration of 10 -3 mol / L was prepared, and then it was diluted to a concentration of 10 -5mol / L, a series of solutions with water contents (v / v) of 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, and 99% were obtained respectively. After ultrasonic treatment for 30 s in an ultrasonic instrument, their emission spectra were collected using a fluorescence spectrometer. In a pure tetrahydrofuran solution (i.e., water content is 0%, 10 -5 mol / L), the fluorescence emission peaks of XQ1 and XQ2 are at 1186 nm and 1226 nm respectively, and the changes in the strongest fluorescence intensity at different water contents were analyzed. The specific results are as Figure 5 . The fluorescence spectra of XQ1 in tetrahydrofuran / water systems with different water contents (0%, 60%, 99%) are shown in Figure 6 , and the fluorescence spectra of XQ2 in tetrahydrofuran / water systems with different water contents (0%, 60%, 99%) are shown in Figure 7 .

[0107] From Figure 5 it can be seen that when the water content is in the range of 0 - 60%, the fluorescence intensities of XQ1 and XQ2 gradually decrease; when the water content exceeds 70%, the fluorescence intensities of the two compounds gradually increase. This phenomenon indicates that XQ1 and XQ2 have typical AIE properties. The difference is that when the water content is the same, compared with XQ1, XQ2 has a larger I / I0 ratio (I is the strongest value of the fluorescence spectrum at different water contents; since the fluorescence intensity is the weakest when the water content is 60%, therefore, based on the fluorescence intensity under this condition as the standard, I0 is the strongest fluorescence value when the water content is 60%). This is because XQ2 contains a tert-butyl chain and has a large steric hindrance, which can effectively inhibit the π-π stacking interaction in the aggregated state, thereby inhibiting the aggregation-induced quenching effect in the aggregated state, and finally showing more obvious AIE properties.

[0108] (4) Type I photodynamic performance test

[0109] The type I photodynamic performance of XQ1 nanoparticles and XQ2 nanoparticles was characterized by dihydrorhodamine 123 (DHR 123). If XQ1 and XQ2 nanoparticles generate superoxide anions under 1064 nm laser irradiation, DHR123 in the system is gradually oxidized to rhodamine 123, and then the fluorescence of the system increases. If XQ1 and XQ2 nanoparticles cannot generate superoxide anions under 1064 nm laser irradiation, the fluorescence intensity of the system remains unchanged. The following experiment was conducted for testing:

[0110] Take 3 mL of dimethyl sulfoxide, add a certain amount of XQ1 nanoparticles or XQ2 nanoparticles and DHR123 thereto, where the concentrations of XQ1 and XQ2 nanoparticles are 60 μg / mL and the concentration of DHR123 is 50 μmol / L to obtain a test sample; then irradiate the test sample with a 1064 nm laser (5 min, 1.0 W / cm 2 ) and test the change of the fluorescence intensity of the sample with time. When testing, the spectral range for collecting the spectrum is 500 - 650 nm and the spectral peak is 525 nm.

[0111] Figure 6 Figures are the graphs of the fluorescence intensity of DHR123 versus time under the irradiation of a 1064 nm laser (5 min, 1.0 W / cm 2 ). It can be seen from the figures that as the irradiation time changes, the fluorescence of the system increases, showing time dependence. After 5 min of irradiation treatment, the fluorescence intensity increases by different amplitudes. For the sample containing XQ1 nanoparticles, the fluorescence intensity increases by 4.35 times; for the sample containing XQ2 nanoparticles, it increases by 8.10 times. This result confirms that the compounds XQ1 and XQ2 are effective phototherapeutic agents, which can generate superoxide anion radicals under the irradiation of a 1064 nm laser for photodynamic therapy.

[0112] (5) Photothermal performance test

[0113] Dilute the water-soluble XQ1 nanoparticles and XQ2 nanoparticles with an apparent concentration of 500 μg / mL prepared in (1) to a concentration of 50 μg / mL with ultrapure water. Then, take 1 mL of the sample solution with a concentration of 50 μg / mL and place it in a centrifuge tube, and irradiate it with a 1064 nm laser (5 min, 1.0 W / cm 2 ). Meanwhile, use a Fluke infrared thermal imager to collect the sample temperature at the set time.

[0114] Figure 7 Figures are the photothermal conversion curves of XQ1 and XQ2 nanoparticles. It can be seen from the figures that when the concentration of XQ2 nanoparticles is 50 μg / mL and under the irradiation of a 1064 nm laser (5 min, 1.0 W / cm 2 ), the sample temperature can rise by 27.7 °C and the maximum temperature can be maintained at 54.7 °C, slightly higher than that of XQ1 nanoparticles. This shows that both of them have good photothermal conversion ability.

[0115] It can be known from the tests of the photodynamic performance and photothermal performance that: Compound XQ has photosensitization and photothermal performance under the action of a 1064nm laser. Compared with phototherapeutic agents that obtain photosensitization performance and photothermal performance under the action of different light sources, the compound XQ of the present invention can obtain photosensitization and photothermal effects under the action of a single light source, with simple operation and easy implementation.

[0116] (6) Photothermal-photodynamic therapy cell performance test

[0117] The cell biocompatibility of XQ2 nanoparticles and the photothermal-photodynamic therapy effect on GL261 cells were detected by the CCK-8 method. The specific experimental steps are as follows:

[0118] 1) Dilute the XQ2 nanoparticles with an apparent concentration of 500 μg / mL prepared in (1) to concentrations of 10 μg / mL, 30 μg / mL, 50 μg / mL, 70 μg / mL, and 90 μg / mL with complete medium (DMEM, containing 10% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin).

[0119] 2) Digest the GL261 cells in the logarithmic growth phase with 0.25% trypsin and evenly dilute the cells to a concentration of 5×10 4 cells / mL.

[0120] 3) Add the cell solution to a 96-well plate, 100 μL per well. After gently shaking evenly, place it in an incubator at 37°C and 5% CO2 for 24 h.

[0121] 4) Add the complete medium containing different concentrations of XQ2 nanoparticles to the 96-well plate, 100 μL per well. Set 10 wells for each concentration, with 5 wells in each group, a total of 2 groups, namely the light irradiation group and the non-light irradiation group. Set 0 μg / mL as the control group. And place the 96-well plate in the incubator and incubate for 12 h.

[0122] 5) Take out the 96-well plate of the light irradiation group, irradiate it with a 1064nm laser for 5 min (1.0 W / cm 2 ), and place it back in the incubator and continue to incubate for 12 h. The 96-well plate of the non-light irradiation group does not need to be irradiated. Directly culture for 24 h.

[0123] 6) Wash out the culture medium waste liquid in the 96-well plates of the light irradiation group and the non-light irradiation group. Add 100 μL of complete medium containing 10% CCK-8 to each well, and then place it back in the incubator and culture for 1 h.

[0124] 7) Place the 96-well plates of the light irradiation group and the non-light irradiation group in an enzyme-labeling instrument, measure the absorbance of the absorption peak at 450 nm for each well, calculate the average value and standard deviation of the absorbance of 5 wells in each group, and calculate the cancer cell survival rate. The CCK-8 test results are shown inFigure 8 。

[0125] As can be seen from Figure 8 , under the condition of no light illumination, the survival rate of GL261 cells can be maintained above 93% for XQ2 nanoparticles with different concentrations. This shows that XQ2 nanoparticles exhibit excellent biocompatibility under the condition of no 1064nm laser illumination. Under the condition of 1064nm laser illumination, the survival rate of cells is related to the concentration of XQ2 nanoparticles. The greater the concentration of XQ2 nanoparticles, the lower the cell survival rate, that is, the stronger the killing effect on cells. At a concentration of 10μg / mL, XQ2 nanoparticles can kill 9.5% of GL261 cells; at a concentration of 30μg / mL, XQ2 nanoparticles can kill 20.7% of GL261 cells; at a concentration of 50μg / mL, XQ2 nanoparticles can kill 39.5% of GL261 cells; at a concentration of 70μg / mL, XQ2 nanoparticles can kill 44.7% of GL261 cells; at a concentration of 90μg / mL, XQ2 nanoparticles can kill 65.9% of GL261 cells. This shows that XQ2 nanoparticles have excellent photothermal-photodynamic therapy effects on GL261 cells.

[0126] To observe the effect of XQ2 NPs on the activity of GL261 cells after being irradiated by 1064nm laser, a control group of XQ2 NPs, a control group of 1064nm laser irradiation, and an experimental group of XQ2 NPs and 1064nm laser irradiation were set up, and then a live / dead cell staining kit was used to characterize the apoptotic and necrotic conditions of GL261 cells. Among them, the intracellular esterase in live cells causes Calcein-AM to decompose to produce Calcein, which produces green fluorescence under the action of 490nm laser. After the PI staining agent penetrates through the cell membrane that has lost its selective permeability, it binds to nucleic acid substances in the nucleus region to form red fluorescence. The specific operations are as follows:

[0127] (1) Digest GL261 cells in the logarithmic growth phase with 0.25% trypsin, and evenly dilute the cells to a concentration of 1×10 6 cells / mL, add 500μL to each well of a 12-well plate, and incubate in a cell culture incubator for 24h.

[0128] (2) The control group and the experimental group of XQ2 NPs were incubated with cell culture medium containing XQ2 NPs (concentration of 90μg mL -1 ) for 24h; the control group of 1064nm laser irradiation was incubated with cell culture medium without XQ2 NPs.

[0129] (3) Use 1064nm laser to irradiate the control group of 1064nm laser irradiation and the experimental group, and the irradiation intensity is 1.00W cm-2 The irradiation duration was 5 min. The XQ2 NPs control group was not treated with light irradiation.

[0130] (4) After completion, the cell culture medium was removed, and the cells were gently washed with PBS; PBS solution containing a stain (Calcein-AM: 2 μL / mL -1 , PI: 1 μL / mL -1 ) was added, and the cells were incubated in an incubator for 15 - 20 min. Then, cell imaging was observed using an inverted fluorescence microscope and a ZEN imaging system.

[0131] The experimental results of live / dead cell double staining are shown in Figure 9 . It can be seen from the figure that cells treated with XQ2 NPs alone or 1064 nm laser light irradiation showed strong green fluorescence, indicating that the vast majority of the cells were live cells; while cells treated with both XQ2 NPs and 1064 nm laser showed red fluorescence, indicating that the cells underwent necrosis or apoptosis after optical treatment and were dead cells. This can be intuitively reflected that under 1064 nm laser light irradiation, XQ2 NPs showed good photothermal / photodynamic therapy effects.

[0132] Therefore, the compounds represented by XQ1 and XQ2 prepared in the present invention are expected to become highly efficient phototherapeutic agents for near-infrared fluorescence imaging-mediated photothermal-photodynamic combined therapy for deep tumors (such as glioblastoma).

[0133] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. A compound for near-infrared fluorescence imaging and photothermal-photodynamic synergistic therapy, named XQ, and its chemical structure is shown in formula (Ⅰ): Among them, R2 is hydrogen or a straight-chain or branched-chain alkyl group with 1 to 30 carbon atoms; R1 is a straight-chain or branched-chain alkyl group with 1 to 30 carbon atoms.

2. The compound for near-infrared fluorescence imaging and photothermal-photodynamic synergistic therapy according to claim 1, characterized in that, In formula (Ⅰ), R2 is hydrogen or a straight-chain or branched-chain alkyl group with 1 to 10 carbon atoms; and / or R1 is a straight-chain or branched-chain alkyl group with 4 to 22 carbon atoms.

3. The compound for near-infrared fluorescence imaging and photothermal-photodynamic synergistic therapy according to claim 2, wherein In formula (Ⅰ), R2 is hydrogen or a straight-chain or branched-chain alkyl group with 1 to 6 carbon atoms; and / or R1 is a straight-chain or branched-chain alkyl group with 8 to 16 carbon atoms.

4. The compound for near-infrared fluorescence imaging and photothermal-photodynamic synergistic therapy according to claim 3, wherein In formula (Ⅰ), R2 is hydrogen or a straight-chain or branched-chain alkyl group with 4 carbon atoms; and / or R1 is a straight-chain or branched-chain alkyl group with 8 carbon atoms.

5. The preparation method of the compound for near-infrared fluorescence imaging and photothermal-photodynamic synergistic therapy according to any one of claims 1-4, characterized in that: The preparation route of the compound of formula (Ⅰ) is as follows: Among them, the R2 and R1 groups are the same as those in claims 1-4.

6. The preparation method according to claim 5, characterized in that, It includes the following steps: (1) 4,7-Dibromo-2,1,3-benzothiadiazole reacts at 140 °C for 24 hours under the action of iron powder and glacial acetic acid to undergo a ring-opening reaction to obtain compound M1; (2) Compound M1 reacts at 25 °C for 12 hours under the action of glacial acetic acid and sodium nitrite to undergo a ring-closure reaction to obtain compound M2; (3) Compound M2 is dissolved in N,N-dimethylformamide and undergoes an alkylation reaction with alkyl bromide R1-Br under the action of potassium carbonate, reacting at 110 °C for 12 hours to obtain compound M3; (4) Compound M3 undergoes a nitration reaction in a concentrated nitric acid and concentrated sulfuric acid system, reacting at 100 °C for 12 hours to obtain compound M4; (5) Compound M4 undergoes a reduction reaction under the action of iron powder and glacial acetic acid, reacting at 140 °C for 20 hours to obtain compound M5; (6) 2,7-Dibromobenzo[2,1-b:3,4-b']dithiophene-4,5-dione and 4',4'-diR2-yl-4-boronic acid pinacol ester triphenylamine are dissolved in tetrahydrofuran and undergo a Suzuki coupling reaction under the action of potassium carbonate and tetrakis(triphenylphosphine)palladium, reacting at 80 °C for 12 hours to obtain compound M6; (7) Compound M5 reacts with compound M6 under the action of glacial acetic acid to undergo a condensation reaction, reacting at 110 °C for 24 hours to obtain compound M7; (8) Compound M7 and 4-dimethylaminostyrene are dissolved in toluene and undergo a Mizoroki-Heck coupling reaction under the action of potassium carbonate and tetrakis(triphenylphosphine)palladium, reacting at 125 °C for 24 hours to obtain compound XQ.

7. According to the preparation method described in claim 6, it is characterized in that: In step (1), the molar ratio of 4,7-dibromo-2,1,3-benzothiadiazole to iron powder is 1:0.02 to 0.1, and the molar amount of 4,7-dibromo-2,1,3-benzothiadiazole to the volume of glacial acetic acid is 1:5 to 10, with the unit of mol / L; In step (2), the molar ratio of compound M1 to sodium nitrite is 1:2 to 6, and the molar amount of compound M1 to the volume of glacial acetic acid is 1:4 to 10, with the unit of mol / L; In step (3), the molar ratio of compound M2, alkyl bromide R1-Br, and potassium carbonate is 1:1 to 1.5:4 to 10, and the molar amount of compound M2 to the volume of N,N-dimethylformamide is 1:5 to 15, with the unit of mol / L; In step (4), the molar amount of compound M3 to the volume of concentrated nitric acid is 1:5 to 10, with the unit of mol / L; the volume ratio of concentrated nitric acid to concentrated sulfuric acid is 1:0.5 to 5; In step (5), the molar ratio of compound M4 to iron powder is 1:0.05 to 0.15, and the molar amount of compound M4 to the volume of glacial acetic acid is 1:10 to 20, with the unit of mol / L; In step (6), the molar ratio of 2,7-dibromobenzo[2,1-b:3,4-b']dithiophene-4,5-dione, 4',4'-diR2-yl-4-boronic acid pinacol ester triphenylamine, tetrakis(triphenylphosphine)palladium, and potassium carbonate is 1:2 to 4:0.01 to 0.1:5 to 10, and the molar amount of 2,7-dibromobenzo[2,1-b:3,4-b']dithiophene-4,5-dione to the volume of tetrahydrofuran is 1 mmol:(10 to 30) mL; In step (7), the molar ratio of compound M5 to compound M6 is 1:1 to 1.5, and the molar amount of compound M5 to the volume of glacial acetic acid is 1:10 to 15, with the unit of mol / L; In step (8), the molar ratio of compound M7, 4-dimethylaminostyrene, tetrakis(triphenylphosphine)palladium, and potassium carbonate is 1:2 to 4:0.01 to 0.1:5 to 10, and the molar amount of compound M7 to the volume of toluene is 1 mmol:(10 to 30) mL.

8. The preparation method according to claim 7, wherein: In step (1), the molar ratio of 4,7-dibromo-2,1,3-benzothiadiazole to iron powder is 1:0.05, and the molar amount of 4,7-dibromo-2,1,3-benzothiadiazole to the volume of glacial acetic acid is 1:8, with the unit of mol / L; In step (2), the molar ratio of compound M1 to sodium nitrite is 1:4, and the molar amount of compound M1 to the volume of glacial acetic acid is 1:5, with the unit of mol / L; In step (3), the molar ratio of compound M2, alkyl bromide R1-Br, and potassium carbonate is 1:1.1:6, and the molar amount of compound M2 to the volume of N,N-dimethylformamide is 1:10, with the unit of mol / L; In step (4), the molar amount of compound M3 to the volume of concentrated nitric acid is 1:8, with the unit of mol / L; the volume ratio of concentrated nitric acid to concentrated sulfuric acid is 1:1; In step (5), the molar ratio of compound M4 to iron powder is 1:0.1, and the molar amount of compound M4 to the volume of glacial acetic acid is 1:16, with the unit of mol / L; In step (6), the molar ratio of 2,7-dibromobenzo[2,1-b:3,4-b']dithiophene-4,5-dione, 4',4'-bis(R2)-4-boronic acid pinacol ester triphenylamine, tetrakis(triphenylphosphine)palladium, and potassium carbonate is 1:2.5:0.05:8, and the molar amount of 2,7-dibromobenzo[2,1-b:3,4-b']dithiophene-4,5-dione to the volume of tetrahydrofuran is 1 mmol:20 mL; In step (7), the molar ratio of compound M5 to compound M6 is 1:1.1, and the molar amount of compound M5 to the volume of glacial acetic acid is 1:12, with the unit of mol / L; In step (8), the molar ratio of compound M7, 4-dimethylaminostyrene, tetrakis(triphenylphosphine)palladium, and potassium carbonate is 1:3:0.05:8, and the molar amount of compound M7 to the volume of toluene is 1 mmol:20 mL.

9. A phototherapeutic agent, comprising the compound XQ according to any one of claims 1-4 or the compound XQ prepared by the method according to any one of claims 5-8.

10. Use of the compound XQ according to any one of claims 1-4 or the compound XQ prepared by the method according to any one of claims 5-8 in the preparation of a phototherapeutic agent for NIR-II region fluorescence imaging and / or combined photothermal-photodynamic therapy of tumors; preferably, the tumor is a deep tumor; preferably, the tumor is glioblastoma multiforme.

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