Near-infrared photothermal / photodynamic / chemotherapy combined nano-platform for treating glioblastoma and preparation method of near-infrared photothermal / photodynamic / chemotherapy combined nano-platform

Abstract

The invention discloses a targeted nano delivery system based on curcumin (Cur) and near-infrared aggregation-induced emission (AIE) molecule BDTA and application of the targeted nano delivery system in treatment of glioblastoma (GBM), and belongs to the field of biomedicine. The nano platform is composed of nanoparticles (MPMs (at) Cur-BDTA NPs) modified by a macrophage membrane, curcumin and BDTA are combined by adopting a coprecipitation method, and the targeting property of the nano platform to tumors is enhanced through modification of the macrophage membrane. The nanometer platform combines the functions of photo-thermal therapy (PTT), photodynamic therapy (PDT) and chemotherapy, and can achieve multiple treatment effects. The curcumin improves PTT sensitivity by down-regulating expression of heat shock protein HSP-70 in the platform, and effectively improves photothermal conversion efficiency (87.6%) and singlet oxygen generation amount (1.7 times higher than that of a control group) through a Foster resonance energy transfer (FRET) mechanism. In a glioblastoma in-vitro experiment, the nano platform shows a synergistic treatment effect of photo-thermal, photodynamic and chemotherapy. The invention provides an intelligent treatment platform integrating photo-thermal treatment, photodynamic treatment and chemotherapy, and provides an efficient and safe innovative treatment strategy for precise treatment of glioblastoma.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine, and in particular to a near-infrared photothermal / photodynamic / chemotherapy combined nano-platform for treating glioblastoma and a preparation method thereof. Background Art

[0002] Glioblastoma (GBM) is the most common malignant primary brain tumor in the central nervous system, accounting for approximately 57% of all gliomas and 48% of primary malignant central nervous system tumors. GBM is highly invasive, prone to recurrence after treatment, and has a very poor clinical prognosis, making it one of the most lethal cancers currently.

[0003] Traditional treatments include surgical resection, radiotherapy, and chemotherapy, but the efficacy is limited and the side effects are significant. In recent years, photothermal therapy (PTT) and photodynamic therapy (PDT) combined with chemotherapy have gradually become a new direction for the treatment of glioblastoma. Through the synergistic effect of photothermal / photodynamic diagnosis and treatment technology, the anti-tumor efficacy can be significantly enhanced and multidrug resistance (MDR) can be reduced while reducing the dose of chemotherapy drugs. However, the current multifunctional diagnosis and treatment technology still has problems such as poor repeatability and complex pharmacokinetics, which limit its diagnostic and therapeutic effects. Summary of the invention

[0004] In view of the problems existing in the prior art, the present invention discloses a near-infrared photothermal / photodynamic / chemotherapy combined nano-platform for the treatment of glioblastoma and its preparation method. The present invention provides a combined photothermal / photodynamic / chemotherapy nano-platform based on curcumin and near-infrared aggregation-induced emission molecule BDTA, which achieves multiple therapeutic effects in tumor treatment.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions.

[0006] The present invention discloses a near-infrared aggregation-induced emission molecular compound, wherein the near-infrared aggregation-induced emission molecular compound is named BDTA, and has the structural formula: .

[0007] The present invention also discloses a method for preparing the above-mentioned near-infrared aggregation-induced emission molecule, which is characterized by comprising the following steps: ; Preparation of compound 1: Under nitrogen protection, in a 100 mL two-necked flask, 2-bromo-4-hexylthiophene (1.00 g, 4.05 mmol), 9,10-dihydro-9,9-dimethylacridine (0.85 g, 4.05 mmol), Pd2(dba)3 (0.38 g, 0.41 mmol), P(tBu)3 (0.23 g, 0.41 mmol) and Na t OBu (1.56 g, 16.20 mmol); the device was evacuated by vacuum and filled with dry nitrogen three times to remove air. Then 40 mL of anhydrous toluene was added to the flask, and the reaction was stirred at 120 ° C overnight; after the reaction was completed, it was cooled to room temperature, and an appropriate amount of deionized water was added to the system for quenching, and then extracted with 50 mL of dichloromethane (DCM) three times; the organic phases were combined and dried over anhydrous sodium sulfate; after the solvent was removed by rotary evaporation under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane / petroleum ether (v / v=1 / 10) to obtain the target compound 1; Preparation of compound 2: Under nitrogen protection, n-butyl lithium (n-BuLi, 2.5 mL, 6 mmol, 2.4 M inhexane) was added dropwise to a flask containing compound 1 (0.90 g, 2.40 mmol) and 30 mL of anhydrous tetrahydrofuran (THF); the whole process was kept at -78 °C and stirred for 1 hour; Bu3SnCl (1.86 g, 6 mmol) was added at once; the system was warmed to room temperature and the reaction was continued with stirring for 12 hours; after the reaction was completed, ice-cold deionized water was added to the system to quench the reaction; 50 mL of n-hexane was used for extraction, the organic phases were combined and dried over anhydrous sodium sulfate; the solvent was removed by rotary evaporation to obtain a crude product compound 2; Preparation of compound BDTA: Under nitrogen protection, compound 2 (1.33 g, 2.00 mmol), 4,8-dibromo-benzo[1,2-c:4,5-c']bis[1,2,5]thiadiazole (0.28 g, 0.80 mmol), Pd2(dba)3 (0.38 g, 0.41 mmol), P(tBu)3 (0.23 g, 0.41 mmol) and Na t OBu (1.56 g, 16.20 mmol); under a dry nitrogen atmosphere, 20 mL of anhydrous toluene was added as a solvent; the system was heated to reflux and stirred for 24 hours; after the reaction was completed, it was cooled to room temperature and the solvent was removed by rotary evaporation; the crude product was purified by silica gel column chromatography (dichloromethane / petroleum ether (v / v=1 / 4) to finally obtain the target product BDTA.

[0008] The present invention also discloses an application of the above-mentioned near-infrared aggregation-induced emission molecular compound BDTA in the preparation of a near-infrared photothermal / photodynamic / chemotherapy combined nano-platform.

[0009] Furthermore, the nano-platform has significant photothermal conversion capability and singlet oxygen generation capability under 635nm laser irradiation.

[0010] The present invention also discloses a near-infrared photothermal / photodynamic / chemotherapy combined nano-platform for the treatment of glioblastoma, characterized in that the nano-platform comprises: the aggregation-induced emission molecular compound BDTA described above or the aggregation-induced emission molecular compound BDTA prepared by the preparation method, as well as curcumin and macrophage membrane.

[0011] Furthermore, the BDTA molecule has balanced radiative transition ability, non-radiative transition ability and efficient intersystem crossing ability.

[0012] Furthermore, the Cur and BDTA achieve energy transfer through Förster resonance energy transfer (FRET) and inhibit overexpression of heat shock proteins to enhance the effects of photothermal therapy and photodynamic therapy.

[0013] Furthermore, any of the above-mentioned near-infrared photothermal / photodynamic / chemotherapy combined nanoplatforms for treating glioblastoma is used in the preparation of drugs for treating glioblastoma.

[0014] The present invention also discloses a method for preparing a near-infrared photothermal / photodynamic / chemotherapy combined nano-platform for treating glioblastoma as described in claim 5, characterized in that the method comprises the following specific steps: Step 1: prepare the near-infrared luminescent molecule BDTA: it is composed of benzobithiadiazole (BBT) as an electron acceptor, 9,10-dihydro-9,9-dimethylacridine (DDA) and thiophene (TH) as electron donors, and an alkyl group as a shielding group; Step 2: Using DSPE-mPEG2000 as a template, BDTA and curcumin (Cur) were co-encapsulated to form core nanoparticles by nano-coprecipitation method; Step 3: The extracted cell membrane is modified on the surface of the core nanoparticles by a co-extrusion method to form macrophage membrane-modified Cur-BDTA nanoparticles, namely MPMs@Cur-BDTA NPs.

[0015] Curcumin (Cur) is a plant polyphenol compound extracted from turmeric, which has anti-proliferative, antioxidant and anti-inflammatory biological activities. The potential of curcumin in the treatment of glioblastoma has been confirmed by multiple preclinical studies. Its mechanism of action includes inducing cell cycle arrest, triggering apoptosis, promoting autophagy, and disrupting key molecular signaling pathways. In addition, curcumin, as a heat shock protein inhibitor, can enhance the sensitivity of tumors to photothermal therapy and significantly improve the efficacy.

[0016] Phototherapy is a method of treating diseases and promoting recovery through photochemical or photophysical reactions, with the technical characteristics of precision and minimally invasiveness. However, traditional phototherapy drugs often have problems such as poor photostability and high biological toxicity. Aggregation-induced emission molecules (AIEgens) provide an ideal choice for phototherapy technology due to their excellent luminescence efficiency, photothermal conversion ability and biocompatibility. By optimizing the energy dissipation path of AIEgens through molecular design, the multifunctional integration of photothermal therapy and photodynamic therapy can be achieved.

[0017] Compared with the prior art, the beneficial effects of the present invention are as follows.

[0018] The BDTA molecule disclosed in the present invention is composed of benzobithiadiazole (BBT) as an electron acceptor, 9,10-dihydro-9,9-dimethylacridine (DDA) and thiophene (TH) as electron donors, and an alkyl group as a shielding group, and has balanced radiative transition ability, non-radiative transition ability and efficient intersystem crossing ability.

[0019] The nano-platform provided by the present invention has significant photothermal conversion capability under 635nm laser irradiation, and the photothermal conversion efficiency can reach 87.6%. The singlet oxygen generation of the nano-platform provided by the present invention is 1.7 times that of the control nanoparticles without curcumin encapsulation.

[0020] The present invention provides a nano-platform that combines the AIE molecule BDTA with curcumin and improves its tumor targeting through macrophage membrane modification. At the same time, curcumin can not only downregulate the expression of heat shock protein HSP-70 and improve PTT sensitivity, but also enhance singlet oxygen generation and photothermal conversion efficiency through the Foster resonance energy transfer mechanism, thereby improving the synergistic effect of photothermal and photodynamic therapy. The present invention combines photodiagnosis and treatment with natural small molecules, providing a new idea for the precise treatment of glioblastoma. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 UV-visible absorption and fluorescence spectra of compound BDTA.

[0022] Figure 2 Aggregation-induced emission luminescence spectrum of compound BDTA.

[0023] Figure 3 Transient decay curve of compound BDTA.

[0024] Figure 4 FRET effect between Cur and BDTA.

[0025] Figure 5 Uptake of nanoparticles in C6 cells.

[0026] Figure 6 Nanoplatform photothermal conversion capability. A is the temperature-time curve at different concentrations; B is the temperature-time curve at different powers; C is the photostability curve; and D is the time-Lnθ curve of the cooling curve.

[0027] Figure 7 Singlet oxygen generation capability of the nanoplatform.

[0028] Figure 8 HSP-70 expression.

[0029] Fig. 9 The synergistic therapeutic effect of the nanoplatform in vitro. A is the cell survival rate at different concentrations; B is the cell apoptosis rate detected by flow cytometry. DETAILED DESCRIPTION

[0030] The present invention is further described in detail below with specific embodiments, but it should not be understood that the scope of the above subject matter of the present invention is limited to the following embodiments, and all technologies realized based on the content of the present invention belong to the scope of the present invention.

[0031] Unless otherwise specified, all reagents and materials used in the present invention are commercially available.

[0032] Example 1. Preparation of BDTA.

[0033] 1. The structural formula of BDTA is: .

[0034] 2. The compound synthesis reaction formula of the BDTA molecule of the present invention is as follows: .

[0035] 3. The BDTA molecule preparation process described in the present invention.

[0036] 1. The preparation of compound 1 is as follows: Under nitrogen protection, 2-bromo-4-hexylthiophene (1.00 g, 4.05 mmol), 9,10-dihydro-9,9-dimethylacridine (0.85 g, 4.05 mmol), Pd2(dba)3 (0.38 g, 0.41 mmol), P( t Bu)3 (0.23 g, 0.41 mmol) and Na t OBu (1.56 g, 16.20 mmol). The apparatus was evacuated by vacuum and filled with dry nitrogen three times to remove air. Then 40 mL of anhydrous toluene was added to the flask, and the reaction was stirred at 120 ° C overnight. After the reaction was completed, it was cooled to room temperature, and an appropriate amount of deionized water was added to the system for quenching, followed by extraction with dichloromethane (DCM) three times. The organic phases were combined and dried over anhydrous sodium sulfate. After the solvent was removed by rotary evaporation under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane / petroleum ether (v / v=1 / 10) to obtain the target compound with a yield of 60%.

[0037] 1 H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 1.7 Hz, 1H), 7.46 (d, J = 1.6 Hz,1H), 7.10 (ddd, J = 8.3, 7.2, 1.6 Hz, 2H), 7.04–6.98 (m, 3H), 6.90 (d, J = 1.7 Hz,1H), 6.72 (d, J = 1.3 Hz, 1H), 6.70 (d, J = 1.3 Hz, 1H), 2.69 (t, J = 7.6 Hz, 2H), 1.70 (s, 6H), 1.46–1.28 (m, 8H), 0.96–0.92 (m, 3H).

[0038] 2. The preparation of compound 2 is as follows: Under nitrogen protection, n-butyl lithium (n-BuLi, 2.5 mL, 6 mmol, 2.4 M in hexane) was added dropwise to a flask containing compound 1 (0.90 g, 2.40 mmol) and 30 mL of anhydrous tetrahydrofuran (THF). The whole process was kept at -78 °C and stirred for 1 hour. Subsequently, Bu3SnCl (1.86 g, 6 mmol) was added in one go. The system was warmed to room temperature and the reaction was continued to stir for 12 hours. After the reaction was completed, ice-cold deionized water was added to the system to quench the reaction. Extracted with n-hexane, the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the crude product was directly used in the next step.

[0039] 3. Preparation of compound BDTA, the steps are as follows: Under nitrogen protection, compound 2 (1.33 g, 2.00 mmol), 4,8-dibromo-benzo[1,2-c:4,5-c']bis[1,2,5]thiadiazole (0.28 g, 0.80 mmol), Pd2(dba)3 (0.38 g, 0.41 mmol), P( t Bu)3 (0.23 g, 0.41 mmol) and Na t OBu (1.56 g, 16.20 mmol). Under a dry nitrogen atmosphere, 20 mL of anhydrous toluene was added as a solvent. The system was heated to reflux and stirred for 24 hours. After the reaction was completed, it was cooled to room temperature and the solvent was removed by rotary evaporation. The crude product was purified by silica gel column chromatography (dichloromethane / petroleum ether (v / v=1 / 4) to obtain the target product BDTA with a yield of 33%.

[0040] 1 H NMR (400 MHz, CDCl3) δ 7.47–7.46 (m, 1H), 7.45–7.44 (m, 2H), 7.43(s, 2H), 7.42 (d, J = 1.4 Hz, 1H), 7.24–7.23 (m, 1H), 7.22–7.21 (m, 2H), 7.20(t, J = 1.1 Hz, 1H), 7.07 (d, J = 1.5 Hz, 2H), 7.06 (d, J = 1.4 Hz, 4H), 7.04 (d, J =1.5 Hz, 2H), 1.42 (d, J = 4.9 Hz, 4H), 1.37 (s, 2H), 1.33 (d,J = 2.9 Hz, 2H),1.29 (d, J = 3.3 Hz, 6H), 1.26 (s, 18H), 0.89 (d, J = 6.4 Hz, 2H). 13 C NMR (101MHz, CDCl3) δ 134.14, 130.81, 130.18, 127.64, 77.38, 77.07, 76.75. m / z: calcdforC 56 H 56 N6S4[M+Na], 963.3347; found, 963.3353.

[0041] Example 2. Preparation method of the nanoplatform MPMs@Cur-BDTA NPs described in the present invention.

[0042] 1. Extraction and purification of macrophage membranes The specific steps are as follows: Get RAW264.7 cell suspension and dilute it to 5×10 with TM buffer containing 1% phenylmethylsulfonyl fluoride. 7 / mL, incubate on ice overnight under hypotonic conditions. Then, squeeze the incubated suspension 30 times through a liposome extruder without a polycarbonate membrane into a cell homogenate. Add 1M sucrose solution to the homogenate to a final concentration of 0.25M, centrifuge at 4°C and 2000g for 20 minutes, and take the supernatant. Repeat the centrifugation of the supernatant several times to remove impurities such as residual nuclear organelles, and then centrifuge at 4°C and 3000g to obtain the precipitate, which is the macrophage membrane. Finally, wash the precipitate with ice TM buffer and centrifuge to obtain purified macrophage membranes (MPMs).

[0043] 2. Preparation of the nano-platform. The specific steps are as follows: 1 μmol BDTA and 1 μmol curcumin (Cur) were dissolved in 100 μL tetrahydrofuran (THF), and 20 mg DSPE-mPEG2000 was dissolved in 300 μL THF. The two solutions were mixed, ultrasonically treated, and added dropwise to 5 mL deionized water to form nanoparticles (Cur-BDTA NPs). THF was then completely removed by nitrogen purging and dialyzed for 24 hours to remove unencapsulated free molecules. Finally, the macrophage membrane and Cur-BDTANPs were co-extruded multiple times through a 220 nm polycarbonate membrane to successfully prepare MPMs@Cur-BDTA NPs.

[0044] Example 3 Performance experiment of the nano-platform MPMs@Cur-BDTA NPs described in the present invention.

[0045] 1. Reagents.

[0046] C6 cells and their culture medium, phenylmethanesulfonyl fluoride (PMSF), Cell counting kit-8 (CCK-8), AnnexinV-FITC / PI apoptosis detection kit, hoechst 33342 staining solution, DiI cell membrane red fluorescence staining kit, and phosphate buffered saline (PBS, pH 7.4) were all provided by Wuhan Servicebio. Among them, C6 cells were used as a tumor cell model to study the effect of the nanoplatform in the treatment of glioma; the CCK-8 kit was used to detect cell viability, and the correlation between its color change and the number of living cells was used to quantify the survival of cells under different treatment conditions; the AnnexinV-FITC / PI kit can accurately distinguish between cells in the early and late stages of apoptosis, providing a basis for a deeper understanding of nanoplatform-induced apoptosis. In addition, the rat heat shock protein 70 (HSP-70) ELISA kit was purchased from Shanghai Jonlnbio Company to detect the inhibitory effect of curcumin on HSP-70 expression.

[0047] 2. Methods

[0048] 1. UV-visible absorption spectrum and fluorescence spectrum test.

[0049] a. Weigh 0.0080 g of BDTA to prepare 10 mL of 1×10 -3 mol / L THF solution.

[0050] b. Take 0.5mL of the prepared 1×10 -3 mol / L BDTA solution, prepare 1×10 -5 mol / L tetrahydrofuran solution and tetrahydrofuran solutions with different water contents are used for the determination of optical properties.

[0051] 2. Cellular uptake.

[0052] a. C6 glioma cells were plated at 1×10 5 The cells were seeded in a 12-well plate at a density of 10 cells / mL and cultured overnight under appropriate culture conditions (37°C, 5% CO2) to allow the cells to adhere to the plate and grow well.

[0053] b. Then, the cells were incubated with PBS, 0.2 μg / mL BDTA, Cur-BDTA NPs, or MPMs@Cur-BDTA NPs for 5 min, respectively.

[0054] c. After the incubation, wash the cells twice with PBS to remove unbound materials. Collect the cells, suspend them in an appropriate amount of PBS, and analyze them using a flow cytometer. Flow cytometry accurately quantifies the cell uptake of nanoparticles by detecting specific fluorescent signals emitted by nanoparticles bound to the cell surface or inside, thereby evaluating the differences in the uptake efficiency of different nanomaterials in C6 cells.

[0055] 3. Photothermal performance evaluation method.

[0056] a. To evaluate the photothermal performance of MPMs@Cur-BDTA NPs, aqueous solutions of nanoparticles with different concentrations (10, 25, 50, 100, and 200 μg / mL) were first prepared, and 0.5 mL of each solution was placed in a cuvette.

[0057] b. Using 635nm laser (1.00W / cm 2 ) Nanoparticle solutions of different concentrations were irradiated for 5 minutes. The infrared thermal imager was used to record the changes in the temperature of the solution surface over time in real time and draw temperature-time curves at different concentrations.

[0058] c. A 0.5 mL aqueous solution of MPMs@Cur-BDTA NPs with a fixed concentration of 200 μg / mL was stirred at different power densities (0.25, 0.5, 0.75, 1 W / cm 2 ) for 5 minutes. Use an infrared thermal imager to continuously record the temperature changes during the irradiation process. Based on the temperature change data, draw the temperature-time curve at different powers.

[0059] d. A 0.5 mL aqueous solution of MPMs@Cur-BDTA NPs with a fixed concentration of 200 μg / mL was illuminated by a 635 nm laser (1.0 W / cm 2 ) for 5 on / off cycles. The infrared thermal imager continuously records the temperature changes during the irradiation process. Based on the temperature change data, the temperature-time curve is plotted. The photothermal conversion efficiency is calculated based on the cooling curve.

[0060] 4. Singlet oxygen monitoring.

[0061] a. Prepare solutions of MPMs@BDTA NPs, MPMs@Cur-BDTA NPs and methylene blue (MB) respectively, and adjust the concentration of the solution using a spectrophotometer so that its absorbance at 635 nm is about 0.2.

[0062] b. Add 60 μL of 1.0 mg / mL 1,3-diphenylisobenzofuran (DPBF) to each solution.

[0063] c. Place the sample at a power of 1.00W / cm 2 The samples were irradiated with 635 nm laser for 150 seconds. During the irradiation process, the absorbance at 410 nm was measured every 30 seconds using a spectrophotometer to monitor the oxidation of DPBF. The absorbance data at different time points were collected and analyzed, and the absorbance-time curve was drawn.

[0064] 5. Determination of heat shock protein expression.

[0065] a. The adherent cells were gently washed with pre-cooled PBS, then trypsinized and collected by centrifugation at 1000 g for 5 minutes.

[0066] b. Wash the collected cells 3 times with pre-cooled PBS, 1×10 6 200 μL PBS was added to each cell to resuspend it, and the cells were disrupted by cell disruptor.

[0067] c. Centrifuge the extract at 1500g for 10 minutes at 2°C. Take the supernatant and treat it with rat heat shock protein 70 (HSP-70) ELISA kit to measure the absorbance at 450nm.

[0068] 6. In vitro synergistic therapeutic effect.

[0069] a. Cells were plated at 1×10 5 Cells were seeded in 12-well plates at a density of 10 cells / mL and cultured overnight to promote cell adhesion.

[0070] b. On the next day, the culture medium was replaced with fresh culture medium containing different concentrations of Cur NPs, MPMs@BDTA NPs, or MPMs@Cur-BDTA NPs.

[0071] c. After 6 hours of incubation, the cells were exposed to 635 nm laser (1.0 W / cm 2 ) for 5 minutes.

[0072] d. Cell viability was assessed using CCK-8 assay (n=6).

[0073] e. Flow cytometry was used to quantify cell apoptosis at a nanoparticle concentration of 60 µmol / mL. Flow cytometry can distinguish apoptotic cells, necrotic cells, and live cells by staining cells (Annexin V-FITC / PI staining).

[0074] 3. Conclusion

[0075] BDTA has a significant aggregation-induced emission effect, and its radiative transition rate, non-radiative transition rate, and intersystem crossing rate are 1.8×107 s -1 , 7.0×10 7 s -1 , 9.1×10 7 s -1 . There is a potential Förster resonance energy effect between curcumin and BDTA, which helps to sensitize photothermal therapy and photodynamic therapy. Cell uptake experiments showed that macrophage membrane functionalization enhanced the interaction between nanoparticles and C6 cells and improved the uptake efficiency. In terms of photothermal performance, concentration and laser power had a significant effect on its photothermal conversion, and the photothermal stability was good, with a photothermal conversion efficiency of 87.6%. Singlet oxygen monitoring showed that the singlet oxygen quantum yield of MPMs@Cur-BDTA NPs was higher than that of MPMs@BDTA NPs. In terms of inhibiting heat shock proteins, Cur can effectively inhibit the expression of HSP-70 in C6 cells and enhance the sensitivity of tumors to photothermal therapy. In vitro synergistic treatment experiments showed that the synergistic treatment effects of photothermal, photodynamic and chemotherapy in MPMs@BDTANPs were significant, and the introduction of Cur can effectively improve the treatment effect and reduce the required concentration.

[0076] The above description is only a preferred embodiment of the present invention and is not intended to limit the scope of the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A near-infrared aggregation-induced emission molecular compound, characterized in that: The near-infrared aggregation-induced emission molecule compound is named BDTA, and its structural formula is: 。 2. A method for preparing the near-infrared aggregation-induced emission molecule according to claim 1, characterized in that: The steps include: Preparation of compound 1: Under nitrogen protection, in a 100 mL two-necked flask, 2-bromo-4-hexylthiophene (1.00 g, 4.05 mmol), 9,10-dihydro-9,9-dimethylacridine (0.85 g, 4.05 mmol), Pd2(dba)3 (0.38 g, 0.41 mmol), P(tBu)3 (0.23 g, 0.41 mmol) and Na t OBu (1.56 g, 16.20 mmol); the apparatus was evacuated by vacuum and filled with dry nitrogen three times to remove air; then 40 mL of anhydrous toluene was added to the flask, and the reaction was stirred at 120 ° C overnight; after the reaction was completed, it was cooled to room temperature, and an appropriate amount of deionized water was added to the system for quenching, and then extracted with 50 mL of dichloromethane (DCM) three times; the organic phases were combined and dried over anhydrous sodium sulfate; after the solvent was removed by rotary evaporation under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane / petroleum ether (v / v=1 / 10) to obtain the target compound 1; Preparation of compound 2: Under nitrogen protection, n-butyl lithium (n-BuLi, 2.5 mL, 6 mmol, 2.4 M in hexane) was added dropwise to a flask containing compound 1 (0.90 g, 2.40 mmol) and 30 mL of anhydrous tetrahydrofuran (THF); the whole process was kept at -78 °C and stirred for 1 hour; Bu3SnCl (1.86 g, 6 mmol) was added at once; the system was warmed to room temperature and stirred for 12 hours; after the reaction was completed, ice-cold deionized water was added to the system to quench the reaction; extracted with 50 mL of n-hexane, the organic phases were combined and dried over anhydrous sodium sulfate; the solvent was removed by rotary evaporation to obtain a crude product compound 2; Preparation of compound BDTA: Under nitrogen protection, in a 100 mL dry two-necked flask, compound 2 (1.33 g, 2.00 mmol), 4,8-dibromo-benzo[1,2-c:4,5-c']bis[1,2,5]thiadiazole (0.28 g, 0.80 mmol), Pd2(dba)3 (0.38 g, 0.41 mmol), P( t Bu)3 (0.23 g, 0.41 mmol) and Na t OBu (1.56 g, 16.20 mmol); under a dry nitrogen atmosphere, 20 mL of anhydrous toluene was added as a solvent; the system was heated to reflux and stirred for 24 hours; after the reaction was completed, it was cooled to room temperature and the solvent was removed by rotary evaporation; the crude product was purified by silica gel column chromatography (dichloromethane / petroleum ether (v / v=1 / 4) to finally obtain the target product BDTA.

3. An application of the near-infrared aggregation-induced emission molecular compound BDTA described in claim 1 in the preparation of a near-infrared photothermal / photodynamic / chemotherapy combined nanoplatform.

4. The use according to claim 3, characterized in that: The nanoplatform has significant photothermal conversion ability and singlet oxygen generation ability under 635nm laser irradiation.

5. A near-infrared photothermal / photodynamic / chemotherapy combined nanoplatform for the treatment of glioblastoma, characterized in that: The nano-platform comprises: the aggregation-induced luminescence molecular compound according to claim 1 or the aggregation-induced luminescence molecular compound prepared by the preparation method according to claim 2, curcumin and macrophage membrane.

6. The nanoplatform according to claim 5, characterized in that: The BDTA molecule has balanced radiative transition ability, non-radiative transition ability and efficient intersystem crossing ability.

7. The nanoplatform according to claim 5, characterized in that: The Cur and BDTA achieve energy transfer through Förster resonance energy transfer (FRET) and inhibit overexpression of heat shock proteins, so as to enhance the effects of photothermal therapy and photodynamic therapy.

8. Use of the near-infrared photothermal / photodynamic / chemotherapy combined nanoplatform for treating glioblastoma according to any one of claims 5 to 7 in the preparation of a drug for treating glioblastoma.

9. A method for preparing the near-infrared photothermal / photodynamic / chemotherapy combined nano-platform for treating glioblastoma according to claim 5, characterized in that: The method specifically comprises the following steps: Step 1: prepare the near-infrared luminescent molecule BDTA: it is composed of benzobithiadiazole (BBT) as an electron acceptor, 9,10-dihydro-9,9-dimethylacridine (DDA) and thiophene (TH) as electron donors, and an alkyl group as a shielding group; Step 2: Using DSPE-mPEG2000 as a template, BDTA and curcumin (Cur) were co-encapsulated to form core nanoparticles by nano-coprecipitation method; Step 3: The extracted cell membrane is modified on the surface of the core nanoparticles by a co-extrusion method to form macrophage membrane-modified Cur-BDTA nanoparticles, namely MPMs@Cur-BDTA NPs.

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