Aggregation-induced luminescence material, nanoparticles, preparation method and application thereof

Abstract

The present invention discloses an aggregation-induced luminescence material, nanoparticles, a preparation method and an application thereof, and relates to the technical field of luminescent materials. The structural formula of the aggregation-induced luminescence material is: wherein R is selected from one of the following structures: represents a connection site. The present invention uses 6,7-di(thiophene-2-yl)-[1,2,5]thiadiazole[3,4-g]quinoxaline as a strong electron acceptor, introduces benzene or 2,3-dihydrothiophene[3,4-b][1,4]dioxin at both ends as a rich electron donor / π bridge, and increases the dihedral angle with the acceptor as a large steric group, making the overall molecular skeleton more distorted, thereby ensuring its aggregation-induced luminescence characteristics. At the same time, dimethylbenzene or trimethylbenzene is used as an electron donor to extend the absorption and emission wavelengths. The aggregation-induced luminescence material can be used as a rotary motor for thermal energy conversion, has good photothermal conversion ability and reactive oxygen generation ability, and can be used for multimodal diagnosis and treatment of cancer.

Description

Technical Field

[0001] The present invention relates to the field of luminescent materials, and in particular to an aggregation-induced luminescence material, nanoparticles, and a preparation method and application thereof. Background Art

[0002] In fields such as bioimaging and optoelectronic devices, materials are often used in the form of aggregates. However, traditional luminescent molecules generally have the problem of aggregation fluorescence quenching (ACQ), which results in the overall luminescence of the aggregate being worse than that of the individual. Fortunately, aggregation-induced emission (AIE) materials emit almost no light in dilute solutions, but their luminescence is significantly enhanced in the aggregated state, making them a powerful tool to overcome the fluorescence quenching effect of traditional fluorescent molecules. When in the excited state, the energy of aggregation-induced emission materials can be dissipated through multiple pathways. By regulating radiative transitions, non-radiative transitions and intersystem crossing, the generation of fluorescence, photothermal energy and photodynamic energy is balanced to maximize the utilization of excited state energy, while generating multifunctionality. It can be used for fluorescence-photoacoustic-photothermal imaging (FLI-PAI-PTI) synergistically guided photothermal-photodynamic synergistic therapy (PTT-PDT).

[0003] Therefore, the development of aggregation-induced emission materials is crucial. Summary of the Invention

[0004] Based on the above-mentioned deficiencies of the prior art, the purpose of the present invention is to provide an aggregation-induced luminescence material, nanoparticles, preparation method and application, aiming to provide more aggregation-induced luminescence materials, enrich the aggregation-induced luminescence material library, and achieve the treatment of diseases.

[0005] The technical solutions of the present invention are as follows:

[0006] In a first aspect of the present invention, an aggregation-induced emission material is provided, wherein the structural formula of the aggregation-induced emission material is:

[0007]

[0008] Wherein, R is selected from one of the following structures:

[0009]

[0010] Indicates the junction site.

[0011] A second aspect of the present invention provides a method for preparing the aggregation-induced emission material of the present invention, comprising the following steps:

[0012] adding Br-R-Br, N,N-diphenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)aniline, a catalyst and a base into a solvent, stirring and refluxing, and reacting to obtain the aggregation-induced emission material;

[0013] Wherein, R is selected from one of the following structures:

[0014]

[0015] Indicates the junction site.

[0016] Optionally, the catalyst comprises tetrakistriphenylphosphine palladium;

[0017] The base includes potassium carbonate;

[0018] The solvent includes at least one of toluene and water.

[0019] Optionally, the stirring and reflux temperature is 120° C., and the stirring and reflux time is 12 to 24 hours.

[0020] Optionally, the molar ratio of Br-R-Br to N,N-diphenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)aniline is 1:(2-3);

[0021] The molar ratio of Br-R-Br to the catalyst is (8-12):1;

[0022] The molar ratio of Br-R-Br to the base is 1:(4-6).

[0023] The third aspect of the present invention provides a nanoparticle, wherein the nanoparticle comprises the aggregation-induced emission material of the present invention as described above and / or the aggregation-induced emission material prepared by the preparation method of the present invention as described above, and a carrier material coating the aggregation-induced emission material.

[0024] Optionally, the carrier material comprises distearoylphosphatidylethanolamine-polyethylene glycol 2000.

[0025] A fourth aspect of the present invention provides a method for preparing the nanoparticles of the present invention as described above, comprising the following steps:

[0026] adding the aggregation-induced emission material of the present invention as described above and / or the aggregation-induced emission material prepared by the preparation method of the present invention as described above to a first solvent to obtain a first mixture;

[0027] adding the support material to a second solvent to obtain a second mixture;

[0028] mixing the first mixture and the second mixture to obtain a third mixture;

[0029] The third mixture is subjected to ultrasonic treatment and then dialyzed to obtain the nanoparticles.

[0030] In a fifth aspect, the present invention provides the use of the aggregation-induced luminescence material as described above, the aggregation-induced luminescence material prepared by the preparation method as described above, the nanoparticles as described above, or the nanoparticles prepared by the preparation method as described above in the preparation of multimodal integrated diagnosis and treatment reagents.

[0031] Optionally, the multimodal integrated diagnosis and treatment reagent is used to treat cancer.

[0032] Beneficial Effects: The present invention uses a donor / π-bridge engineering approach to construct a strong electron donor (D)-electron-withdrawing acceptor (A)-strong electron donor (D) structure and a distorted conformation to achieve a red-shift in the absorption and emission wavelengths and prevent close intermolecular stacking. The present invention uses 6,7-di(thiophen-2-yl)-[1,2,5]thiadiazole[3,4-g]quinoxaline as a strong electron acceptor and introduces an electron-rich donor motif. Specifically, benzene or 2,3-dihydrothiophene[3,4-b][1,4]dioxin is introduced at both ends of the motif through the donor / π-bridge engineering approach. Benzene or 2,3-dihydrothiophene[3,4-b][1,4]dioxin acts as a rich electron donor / π-bridge on the one hand, and as a large steric hindrance group on the other hand, increasing the dihedral angle with the acceptor, making the overall molecular skeleton more distorted and ensuring its aggregation-induced emission properties. At the same time, dimethylaniline or trimethylaniline is used as an electron donor to connect to benzene or 2,3-dihydrothiophene [3,4-b] [1,4] dioxin, extending the absorption and emission wavelengths (to the near-infrared region II). Due to the highly twisted conformation of dimethylaniline or trimethylaniline with multiple σ-bonds, it becomes an effective rotor. The aggregation-induced luminescence material of the structure provided by the present invention has a low electronic band gap and can be used as a rotary motor for thermal energy conversion. It has good photothermal conversion ability and reactive oxygen species (ROS) generation capacity, and can be used for multimodal diagnosis and treatment of cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of TPA-TTQ prepared in Example 1 in tetrahydrofuran.

[0034] Figure 2 This is the carbon NMR spectrum of TPA-TTQ prepared in Example 1 in tetrahydrofuran.

[0035] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of TPATO-TTQ prepared in Example 2 in tetrahydrofuran.

[0036] Figure 4 This is the carbon NMR spectrum of TPATO-TTQ prepared in Example 2 in tetrahydrofuran.

[0037] Figure 5 This is the hydrogen nuclear magnetic resonance spectrum of TPAT-TTQ prepared in Comparative Example 1 in tetrahydrofuran.

[0038] Figure 6 This is the mass spectrum of TPAT-TTQ prepared in Comparative Example 1 in tetrahydrofuran.

[0039] Figure 7 The UV absorption spectra of TPA-TTQ in Example 1, TPAT-TTQ in Comparative Example 1, and TPATO-TTQ in Example 2 in tetrahydrofuran are shown.

[0040] Figure 8 Graphs showing fluorescence emission spectra of TPA-TTQ in Example 1, TPAT-TTQ in Comparative Example 1, and TPATO-TTQ in Example 2 in tetrahydrofuran.

[0041] Figure 9 Graphs showing fluorescence emission spectra of TPA-TTQ in Example 1, TPAT-TTQ in Comparative Example 1, and TPATO-TTQ in Example 2 in a mixed solvent of tetrahydrofuran and water.

[0042] Figure 10 This is a diagram of the photothermal conversion efficiency of TPATO-TTQ NPs under 808 nm laser irradiation in Example 3.

[0043] Figure 11 Graph showing the ROS generation ability of TPATO-TTQ NPs in Example 3.

[0044] Figure 12 This is a diagram showing the dark toxicity and photothermal-photodynamic synergistic killing effect of TPATO-TTQ NPs on 4T1 cells in Example 3.

[0045] Figure 13 This is a diagram showing the photothermal-photodynamic synergistic treatment effect of TPATO-TTQ NPs on in situ breast cancer in Example 3.

[0046] Figure 14 Schematic diagram of the integrated multimodal diagnosis and treatment of TPATO-TTQ NPs in Example 3. DETAILED DESCRIPTION

[0047] The present invention provides an aggregation-induced luminescence material, nanoparticles, and preparation methods and applications. To clarify the objectives, technical solutions, and effects of the present invention, the present invention is described in further detail below. It should be understood that the specific embodiments described herein are intended only to illustrate the present invention and are not intended to limit the present invention.

[0048] Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0049] Currently, many methods for constructing multimodal optical diagnostic and therapeutic materials have been reported. Traditional multimodal optical diagnostic and therapeutic materials rely primarily on combining several separate components into a single whole. Due to the inherent complexity and poor reproducibility of their construction, their clinical application prospects are limited. In contrast, materials with diverse optical diagnostic and therapeutic properties in a single component are gaining increasing attention due to their clear compositional structure, simple preparation, high purity, good reproducibility, and excellent biocompatibility.

[0050] Aggregation-induced emission materials can regulate the balance between radiative transitions and non-radiative transitions in the energy dissipation process through molecular design to maximize the utilization of excited state energy while generating multifunctionality. Materials with aggregation-induced emission properties, due to their unique flexible propeller-like molecular configuration, easily modified chemical structure and a large number of mobile groups, have single-molecule multifunctionality that is difficult for traditional organic molecules to possess, and are ideal templates for constructing multimodal diagnostic and therapeutic materials. Therefore, aggregation-induced emission materials are expected to develop into a class of photodiagnostic agents with clinical translation prospects, and have broad application potential in tumor diagnosis and treatment. Currently reported multimodal photodiagnostic and therapeutic agents based on aggregation-induced emission materials have problems such as insufficient construction strategies, insufficient penetration depth and short emission wavelength.

[0051] Based on this, an embodiment of the present invention provides an aggregation-induced emission material (specifically, an aggregation-induced emission material regulated by an electron donor), wherein the structural formula of the aggregation-induced emission material is:

[0052]

[0053] Wherein, R is selected from one of the following structures:

[0054]

[0055] Indicates the junction site.

[0056] The present invention uses a donor / π-bridge engineering approach to construct a strong electron donor (D)-electron-withdrawing acceptor (A)-strong electron donor (D) structure and a distorted conformation to achieve a red-shift in the absorption and emission wavelengths and prevent close intermolecular stacking. The present invention uses 6,7-di(thiophen-2-yl)-[1,2,5]thiadiazole[3,4-g]quinoxaline as a strong electron acceptor and introduces an electron-rich donor motif. Specifically, benzene or 2,3-dihydrothiophene[3,4-b][1,4]dioxin is introduced at both ends of the molecule through the donor / π-bridge engineering approach. Benzene or 2,3-dihydrothiophene[3,4-b][1,4]dioxin acts as a rich electron donor / π-bridge on the one hand, and as a large steric hindrance group on the other hand, increasing the dihedral angle with the acceptor, further distorting the overall molecular skeleton and ensuring its aggregation-induced emission properties. At the same time, dimethylaniline or trimethylaniline is used as an electron donor to connect to benzene or 2,3-dihydrothiophene [3,4-b] [1,4] dioxin, extending the absorption and emission wavelengths (to the near-infrared region II). Due to the highly twisted conformation of dimethylaniline or trimethylaniline with multiple σ-bonds, it becomes an effective rotor. The aggregation-induced luminescence material of the structure provided by the present invention has a low electronic band gap and can be used as a rotary motor for thermal energy conversion. It has good photothermal conversion ability and reactive oxygen species generation capacity, and can be used for multimodal cancer diagnosis and treatment.

[0057] Compared with the aggregation-induced luminescence material molecules in the visible light (400-700nm) and near-infrared region I (NIR-I, 700-900nm) that have been widely studied, the aggregation-induced luminescence material molecules have the characteristics of low background interference, deep tissue penetration and low light scattering in the near-infrared region II window (NIR-II, 1000-1700nm), and show more excellent performance in in vivo biological imaging. It is very meaningful to develop NIR-II aggregation-induced luminescence material molecules with integrated multimodal diagnosis and treatment. However, due to the limited number of luminescent molecule donors and acceptors available, the emission wavelength of the aggregation-induced luminescence material is difficult to exceed 900nm, which makes the design and synthesis of NIR-II aggregation-induced luminescence material molecules challenging. However, the aggregation-induced luminescence material provided by the present invention effectively solves the above problems. It belongs to NIR-II aggregation-induced luminescence material and can be used for multimodal diagnosis and treatment of cancer.

[0058] An embodiment of the present invention further provides a method for preparing the aggregation-induced emission material of the present invention, which comprises the following steps:

[0059] adding Br-R-Br, N,N-diphenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)aniline, a catalyst and a base into a solvent, stirring and refluxing, and reacting to obtain the aggregation-induced emission material;

[0060] Wherein, R is selected from one of the following structures:

[0061]

[0062] Indicates the junction site.

[0063] The preparation method provided by the present invention has a simple synthetic route and low cost. The prepared aggregation-induced luminescence material has good biocompatibility, a low electronic band gap, can be used as a rotary motor for thermal energy conversion, has good photothermal conversion ability and ROS generation ability, and can be used for multimodal diagnosis and treatment of cancer.

[0064] In some embodiments, the catalyst includes tetrakistriphenylphosphine palladium, but is not limited thereto.

[0065] In some embodiments, the base includes potassium carbonate, but is not limited thereto.

[0066] In some embodiments, the solvent includes at least one of toluene and water, but is not limited thereto.

[0067] In some embodiments, the stirring and reflux temperature is 120° C., and the stirring and reflux time is 12 to 24 hours (for example, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours, etc.). Specifically, the stirring and reflux is performed under the protection of an inert gas.

[0068] In some embodiments, the molar ratio of Br-R-Br to N,N-diphenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)aniline is 1:(2-3), for example, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9 or 1:3, etc.

[0069] In some embodiments, the molar ratio of Br-R-Br to the catalyst is (8-12):1, for example, 8:1, 9:1, 10:1, 11:1 or 12:1.

[0070] In some embodiments, the molar ratio of Br-R-Br to the base is 1:(4-6), for example, 1:4, 1:5, or 1:6.

[0071] In some embodiments, after the reaction and before obtaining the aggregation-induced emission material, the method further comprises the following steps:

[0072] The reaction solution obtained after the reaction was cooled to room temperature, and then extracted with dichloromethane (to remove some impurities), and the organic phases in the extracted reaction solution were combined; the reaction solution after the combined organic phases was dried using anhydrous sodium sulfate, and the dried reaction solution was concentrated under reduced pressure to obtain a crude product;

[0073] The crude product is purified by silica gel column chromatography using a mixed solution of petroleum ether and dichloromethane as an eluent (to remove impurities such as reaction raw materials that cannot be removed by extraction) to obtain the aggregation-induced emission material.

[0074] In this embodiment, in the mixed solution of petroleum ether and dichloromethane, the volume ratio of petroleum ether to dichloromethane is (1-5):(1-10), for example, it can be 1:1, 1:2, 1:3, 1:5, 1:8, 1:10, 2:1, 2:5, 2:10, 3:1, 3:5, 3:10, 4:1, 4:5, 4:10, 5:1, 5:6 or 5:10, etc.

[0075] An embodiment of the present invention further provides a nanoparticle, wherein the nanoparticle comprises the aggregation-induced emission material of the present invention as described above and / or the aggregation-induced emission material prepared by the preparation method of the present invention as described above, and a carrier material coating the aggregation-induced emission material.

[0076] The nanoparticles provided in this embodiment have a core-shell structure, wherein the core material is the aggregation-induced emission material, and the shell material is a carrier material. The nanoparticles have excellent photothermal conversion capabilities, with a photothermal conversion efficiency of up to 41.57% under 808nm laser irradiation. The nanoparticles also have good ROS generation capabilities and can be used as nano-diagnostic and therapeutic agents to achieve synergistic photothermal and photodynamic therapy for cancers (such as breast cancer).

[0077] In some embodiments, the carrier material includes distearoylphosphatidylethanolamine-polyethylene glycol 2000, but is not limited thereto.

[0078] An embodiment of the present invention further provides a method for preparing the nanoparticles of the present invention as described above, comprising the following steps:

[0079] S1. Adding the aggregation-induced emission material of the present invention as described above and / or the aggregation-induced emission material prepared by the preparation method of the present invention as described above to a first solvent (such as tetrahydrofuran, etc.) to obtain a first mixture;

[0080] S2, adding the carrier material to a second solvent (such as water) to obtain a second mixture;

[0081] S3, mixing the first mixture and the second mixture to obtain a third mixture;

[0082] S4. Subjecting the third mixture to ultrasonic treatment and then to dialyze to obtain the nanoparticles.

[0083] The preparation method provided by the present invention is simple, and the prepared nanoparticles have excellent photothermal conversion ability and ROS generation ability. The nanoparticles can achieve photothermal and photodynamic synergistic treatment of cancer (such as breast cancer).

[0084] Embodiments of the present invention also provide the use of the aggregation-induced luminescence material described above, the aggregation-induced luminescence material prepared using the preparation method described above, the nanoparticles described above, or the nanoparticles prepared using the preparation method described above, in preparing a multimodal diagnostic and therapeutic reagent. The aggregation-induced luminescence material and nanoparticles provided by the present invention have excellent photothermal conversion capabilities and ROS generation capabilities, and can be used in multimodal diagnosis and treatment of cancer.

[0085] In some embodiments, the multimodal integrated diagnosis and treatment reagent is used to treat cancer, specifically breast cancer.

[0086] The present invention will be further described below with reference to specific examples.

[0087] In the following examples, unless otherwise specified, the raw materials used are all commercially available products.

[0088] The synthesis routes of the aggregation-induced emission materials in the following examples are as follows:

[0089]

[0090] Example 1

[0091] This embodiment provides a method for preparing an aggregation-induced emission material, comprising the following steps:

[0092] According to the above synthetic route, under the protection of N2, 100 mg of Br-R-Br (wherein R is ), 148 mg of N,N-diphenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, 22 mg of tetrakistriphenylphosphine palladium and 138 mg of potassium carbonate were added sequentially to 12 mL of a mixed solvent of toluene and water (the volume ratio of toluene and water was 3:1), stirred and refluxed at 120° C. for 24 h, and cooled to room temperature after completion of the reaction. The mixture was then extracted with dichloromethane, and the organic phases in the extracted reaction solution were combined. The reaction solution after the combined organic phases was then dried over anhydrous sodium sulfate, and the dried reaction solution was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography using petroleum ether and dichloromethane (the volume ratio of petroleum ether and dichloromethane can be 2:1 to 1:3, and 2:1 is used in this example) as eluents to obtain 126 mg of a dark green powdery solid product, i.e., aggregation-induced emission material (denoted as TPA-TTQ), with a yield of 75%.

[0093] The H NMR spectrum and C NMR spectrum of TPA-TTQ in tetrahydrofuran are shown in Figure 2. Figure 1 and Figure 2 shown.

[0094] Example 2

[0095] This embodiment provides a method for preparing an aggregation-induced emission material, comprising the following steps:

[0096] According to the above synthetic route, under the protection of N2, 28 mg of Br-R-Br (wherein R is ), 33 mg of N,N-diphenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, 4 mg of tetrakistriphenylphosphine palladium and 24 mg of potassium carbonate were added sequentially to a mixed solvent of 12 mL of toluene and water (the volume ratio of toluene and water was 3:1), stirred and refluxed at 120 ° C. for 17 hours, and cooled to room temperature after the reaction was complete. Then, it was extracted with dichloromethane, and the organic phases in the reaction solution after extraction were combined. Then, the reaction solution after the combined organic phases was dried over anhydrous sodium sulfate, and the dried reaction solution was concentrated under reduced pressure. Petroleum ether and dichloromethane (the volume ratio of petroleum ether and dichloromethane can be 1:1 to 1:10, and 1:1 is taken in this embodiment) were used as eluents. After purification by silica gel column chromatography, 29 mg of dark green powdery solid product, i.e., aggregation-induced emission molecule (denoted as TPATO-TTQ), was obtained, and its yield was 83%.

[0097] The H NMR spectrum and C NMR spectrum of TPATO-TTQ in tetrahydrofuran are shown in Figures 1 and 2. Figure 3 and Figure 4 shown.

[0098] Comparative Example 1

[0099] This embodiment provides a method for preparing an aggregation-induced emission quenching material, comprising the following steps:

[0100] According to the above synthetic route, under the protection of N2, 40 mg of Br-R-Br (wherein R is ), 45 mg of N,N-diphenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, 7 mg of tetrakistriphenylphosphine palladium and 42 mg of potassium carbonate were added sequentially to 12 mL of a mixed solvent of toluene and water (the volume ratio of toluene and water was 3:1), stirred and refluxed at 120 ° C. for 12 hours, cooled to room temperature after the reaction was complete, and then extracted with dichloromethane. The organic phases in the reaction solution after extraction were combined, and then the reaction solution after the combined organic phases was dried over anhydrous sodium sulfate. The dried reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography using petroleum ether and dichloromethane (the volume ratio of petroleum ether and dichloromethane can be 4:1 to 1:1, and 4:1 is used in this comparative example) as eluents to obtain 34 mg of a dark green powdery solid product, i.e., aggregation-induced emission material (denoted as TPAT-TTQ), with a yield of 57%.

[0101] The H NMR spectrum and mass spectrum of TPAT-TTQ in tetrahydrofuran are shown as follows: Figure 5 and Figure 6 shown.

[0102] test:

[0103] The ultraviolet absorption spectra of TPA-TTQ in Example 1, TPAT-TTQ in Comparative Example 1 and TPATO-TTQ in Example 2 in tetrahydrofuran are shown in FIG. Figure 7 As shown, where ε represents the molar absorption coefficient, it can be seen that the wavelength corresponding to the absorption peak of TPA-TTQ is 630 nm, the wavelength corresponding to the absorption peak of TPAT-TTQ is 715 nm, and the wavelength corresponding to the absorption peak of TPATO-TTQ is 785 nm.

[0104] The fluorescence emission spectra of TPA-TTQ in Example 1, TPAT-TTQ in Comparative Example 1 and TPATO-TTQ in Example 2 in tetrahydrofuran are shown in FIG. Figure 8 As shown, the wavelength corresponding to the fluorescence emission peak of TPA-TTQ is 850 nm, the wavelength corresponding to the fluorescence emission peak of TPAT-TTQ is 980 nm, and the wavelength corresponding to the fluorescence emission peak of TPATO-TTQ is 1025 nm.

[0105] The fluorescence emission spectra of TPA-TTQ in Example 1, TPAT-TTQ in Comparative Example 1, and TPATO-TTQ in Example 2 in a mixed solvent of tetrahydrofuran and water (the volume content of water in the mixed solvent is 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, and 90%, respectively) are shown in FIG. Figure 9 As shown, where I represents the luminescence intensity in a solution with a certain water content, and I0 represents the luminescence intensity in pure tetrahydrofuran, it can be seen that TPA-TTQ and TPATO-TTQ have the property of aggregation-induced emission and are aggregation-induced emission materials, while TPAT-TTQ in Comparative Example 1 has the property of aggregation-induced quenching.

[0106] Example 3

[0107] The TPATO-TTQ used in this example was prepared in Example 2, and DSPE-mPEG2000, namely distearoylphosphatidylethanolamine-polyethylene glycol 2000, has the structural formula:

[0108]

[0109] This embodiment provides a method for preparing nanoparticles, comprising the following steps:

[0110] A tetrahydrofuran solution containing TPATO-TTQ (1 mg / 1 mL) was directly mixed with ultrapure deionized water containing DSPE-mPEG2000 (10 mg / 9 mL) in a beaker to obtain a mixture. Subsequently, the beaker containing the mixture was placed in cold water (to maintain a low temperature environment) and the mixture was ultrasonically stirred using an ultrasonicator at a power output of 45% for 2 minutes. After ultrasonic treatment, the mixture was placed in a dialysis bag with a molecular weight cutoff of 3500 and dialyzed in ultrapure water for 24 hours. During the dialysis stage, the water was changed every 4 hours to remove tetrahydrofuran. Finally, a suspension of nanoparticles (referred to as TPATO-TTQ NPs) was obtained by ultrafiltration concentration.

[0111] test:

[0112] (1) The photothermal conversion efficiency of TPATO-TTQ NPs (100 μM) in Example 3 was tested under 808 nm laser irradiation. The results are as follows: Figure 10 As shown, where θ represents the temperature change (ΔT) and the maximum temperature change (ΔT max It can be seen that its photothermal conversion efficiency is 41.57%, indicating that it has excellent photothermal conversion ability.

[0113] (2) Testing the ROS production ability of TPATO-TTQ NPs in Example 3 under 808 nm laser irradiation, the specific steps are as follows:

[0114] 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) was used as a ROS indicator to detect the ROS at 808 nm laser (0.8 W·cm -2 ) irradiation by TPATO-TTQ NPs in solution to investigate ROS generation. First, a 1 mM ethanol solution of DCFH-DA (0.5 mL) was added to 2 mL of NaOH solution (0.01 M) and stirred at room temperature for 30 minutes to hydrolyze DCFH-DA to DCFH. The hydrolysis product was then neutralized with 10 mL of 1× PBS (pH 7.4) to obtain an activated ROS indicator (40 μM, 12.5 mL). The solution was stored at 4°C in the dark until ready for use. The activated ROS indicator (40 μM) was then mixed with TPATO-TTQ NPs in PBS to a final concentration of 1 μM for both the ROS indicator and TPATO-TTQ NPs. After irradiation with an 808 laser for various durations, the fluorescence intensity of DCFH, triggered by ROS generation from TPATO-TTQ NPs, was measured using a fluorescence spectrometer to reflect ROS generation. The excitation wavelength was 488 nm, and the fluorescence signals were collected in the range of 490–600 nm.

[0115] The results are as follows Figure 11 As shown, I represents the fluorescence intensity of DCFH triggered by ROS generated by TPATO-TTQ NPs, and I0 represents the fluorescence intensity of DCFH without light. It can be seen that the fluorescence intensity of DCFH after 808 nm laser irradiation for 30 minutes is enhanced by nearly 400 times, indicating that it has good ROS generation ability.

[0116] (3) The dark toxicity and photothermal killing effects of TPATO-TTQ NPs (at concentrations of 0 μM, 5 μM, 10 μM, 20 μM, 40 μM, 60 μM, and 80 μM) on 4T1 cells in Example 3 were tested. The specific steps are as follows:

[0117] 4T1 cells were seeded in 96-well plates at an initial density of 5 × 10 3 cells / well and incubated for 24 hours. The cells were then treated with different concentrations of TPATO-TTQ NPs. After incubation for 12 hours, the cells were directly exposed to 808 nm laser (0.8 W·cm -2 ) and irradiated for 5 minutes. Simultaneously, cells without laser irradiation were used for dark toxicity assays. Subsequently, cells were further incubated for 12 hours before adding CCK-8. Finally, cell viability was recorded using a microplate reader at a detection wavelength of 450 nm.

[0118] The results are as follows Figure 12The results are shown as the survival percentage of cells after various treatments relative to the control cells without any treatment. TPATO-TTQ NPs still have low dark cytotoxicity in the range of 80 μM and have excellent photothermal killing ability of 4T1 cells.

[0119] (4) The synergistic photothermal / photodynamic therapy experiment of TPATO-TTQ NPs for in situ breast cancer in Example 3 specifically includes the following steps:

[0120] 4T1 tumor-bearing mice were randomly divided into four groups (n=5 in each group) for different treatments, namely, the “PBS” group, the “PBS+L” group, the “TPATO-TTQ NPs” group, and the “TPATO-TTQ NPs+L” group.

[0121] For the “PBS+L” group, mice were injected with PBS (200 μL) via the tail vein on day 0 and exposed to 808 nm laser (0.8 W·cm -2 ) Continuous irradiation for 10 minutes;

[0122] For the “PBS” group, mice were injected with PBS (200 μL) via the tail vein on day 0 without light exposure, serving as the control group for the “PBS + L” group;

[0123] For the “TPATO-TTQ NPs+L” group, mice were injected with TPATO-TTQ NPs (200 μL, 1.5 mM) via the tail vein on day 0 and exposed to 808 nm laser (0.8 W·cm -2 ) Continuous irradiation for 10 minutes;

[0124] For the “TPATO-TTQ NPs” group, mice were injected with TPATO-TTQ NPs (200 μL, 1.5 mM) via the tail vein on day 0 without light exposure, serving as the control group for the “TPATO-TTQ NPs+L” group;

[0125] The tumor volume of mice was recorded every 3 days during the treatment period and calculated as V = a × b 2 / 2. (a: tumor length; b: tumor width). Relative tumor volume (RTV) was calculated as RTV=V / V0, where V0 is the initial tumor volume.

[0126] The results are as follows Figure 13 As shown, it can be seen that TPATO-TTQ NPs can effectively perform photothermal / photodynamic therapy on in situ breast cancer tumors. After the third day, the tumors in the treatment group "TPATO-TTQ NPs+L" group completely disappeared.

[0127] The schematic diagram of TPATO-TTQ NPs used for fluorescence (FLI) / photoacoustic (PAI) / photothermal (PTT) synergistically guided photothermal / photodynamic (PDT) synergistic treatment effect in Example 3 is shown in FIG. Figure 14 As shown, the upper left part is a schematic diagram of using DSPE-mPEG2000 to coat hydrophobic TPATO-TTQ.

[0128] In summary, the present invention provides an aggregation-induced luminescence material, nanoparticles, preparation methods, and applications. This invention utilizes a donor / π-bridge engineering approach to construct a strong electron donor (D)-electron-withdrawing acceptor (A)-strong electron donor (D) structure and a distorted conformation to achieve a red-shift in absorption and emission wavelengths while preventing close intermolecular packing. The present invention utilizes 6,7-di(thiophen-2-yl)-[1,2,5]thiadiazo[3,4-g]quinoxaline as a strong electron acceptor and introduces an electron-rich donor motif. Specifically, benzene or 2,3-dihydrothiophene[3,4-b][1,4]dioxin is introduced at both ends of the 6,7-di(thiophen-2-yl)-[1,2,5]thiadiazo[3,4-g]quinoxaline motif through the donor / π-bridge engineering approach. Benzene or 2,3-dihydrothiophene[3,4-b][1,4]dioxin acts as a rich electron donor / π-bridge and, as a large steric group, increases the dihedral angle with the acceptor, further distorting the overall molecular framework and ensuring its aggregation-induced luminescence properties. At the same time, dimethylaniline or trimethylaniline is used as an electron donor to connect to benzene or 2,3-dihydrothiophene [3,4-b] [1,4] dioxin, extending the absorption and emission wavelengths (to the near-infrared region II). Furthermore, due to the highly twisted conformation of dimethylaniline or trimethylaniline with multiple σ-bonds, it becomes an effective rotor. Therefore, the aggregation-induced luminescence material of the structure provided by the present invention has a low electronic band gap and can be used as a rotary motor for thermal energy conversion. It has good photothermal conversion ability and ROS generation ability, and can be used for multimodal diagnosis and treatment of cancer.

[0129] It should be understood that the application of the present invention is not limited to the above examples. For those skilled in the art, improvements or changes can be made based on the above description. All these improvements and changes should fall within the scope of protection of the claims attached to the present invention.

Claims

1. An aggregation-induced emission material, characterized in that: The structural formula of the aggregation-induced emission material is: Wherein, R is selected from one of the following structures: Indicates the attachment site.

2. A method for preparing the aggregation-induced emission material according to claim 1, characterized in that: The steps include: adding Br-R-Br, N,N-diphenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)aniline, a catalyst and a base into a solvent, stirring and refluxing, and reacting to obtain the aggregation-induced emission material; Wherein, R is selected from one of the following structures: Indicates the attachment site.

3. The preparation method according to claim 2, characterized in that The catalyst includes tetrakistriphenylphosphine palladium; The base includes potassium carbonate; The solvent includes at least one of toluene and water.

4. The preparation method according to claim 2, characterized in that The stirring and reflux temperature is 120° C., and the stirring and reflux time is 12 to 24 hours.

5. The preparation method according to claim 2, characterized in that The molar ratio of Br-R-Br to N,N-diphenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)aniline is 1:(2-3); The molar ratio of Br-R-Br to the catalyst is (8-12):1; The molar ratio of Br-R-Br to the base is 1:(4-6).

6. A nanoparticle, characterized in that: The nanoparticles include the aggregation-induced emission material according to claim 1 and / or the aggregation-induced emission material prepared by the preparation method according to any one of claims 2 to 5, and a carrier material coating the aggregation-induced emission material.

7. The nanoparticles according to claim 6, characterized in that The carrier material includes distearoylphosphatidylethanolamine-polyethylene glycol 2000.

8. A method for preparing nanoparticles according to claim 6, characterized in that: The steps include: adding the aggregation-induced emission material according to claim 1 and / or the aggregation-induced emission material prepared by the preparation method according to any one of claims 2 to 5 to a first solvent to obtain a first mixture; adding the support material to a second solvent to obtain a second mixture; mixing the first mixture and the second mixture to obtain a third mixture; The third mixture is subjected to ultrasonic treatment and then dialyzed to obtain the nanoparticles.

9. Use of the aggregation-induced luminescence material according to claim 1, the aggregation-induced luminescence material prepared by the preparation method according to any one of claims 2 to 5, the nanoparticles according to any one of claims 6 to 7, or the nanoparticles prepared by the preparation method according to claim 8 in the preparation of multimodal integrated diagnosis and treatment reagents.

10. The use according to claim 9, characterized in that The multimodal integrated diagnosis and treatment reagent is used to treat cancer.

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