Fluorine-boron compound, preparation method and application thereof, and I-type photosensitizer

Abstract

The invention provides a fluorine-boron compound which contains an anthraquinone group and can efficiently generate anion free radicals with strong oxidizing property after being excited by light, so that the fluorine-boron compound has relatively low semi-inhibition concentration, relatively strong inhibition effect and relatively strong phototoxicity and can kill cancer cells in a relatively short time; meanwhile, the generated superoxide anion free radicals can specifically oxidize FADH2 coenzyme in a mitochondrial electron transfer chain, and the function of the coenzyme is inactivated by oxidizing an isoxazinyl ring structure of the FADH2 coenzyme, so that the electron transfer process of mitochondria is further realized, the energy metabolism of cancer cells is inhibited, and the proliferation activity of the cancer cells is effectively inhibited.

Description

Technical Field

[0001] The present invention relates to the technical field of biomaterials, and in particular to a fluoroboron compound, a preparation method thereof, an application, and a type I photosensitizer. Background Art

[0002] Cancer is one of the diseases with the highest mortality rate worldwide, and the number of people dying from cancer globally increases rapidly every year. So far, chemotherapy and radiotherapy are two main methods for clinical cancer treatment, but both of these therapies can cause serious physiological toxic side effects, such as hair loss, bone marrow suppression, vomiting, nausea, etc. In contrast, phototherapy includes two therapies, photodynamic therapy (PDT) and photothermal therapy (PTT), which are new therapies that can reduce invasiveness and have specific targeting.

[0003] Under visible light or near-infrared (NIR) light irradiation, a photosensitizer generates reactive oxygen species (ROS) to induce apoptosis of tumor cells and eliminate tumor cells. After the photosensitizer absorbs photons and transitions from the ground state (S0) to the singlet state (S1), it converts to the triplet state (T1) by means of intersystem crossing (ISC), and then undergoes a photochemical reaction with a biological substrate through either a type I or type II pathway to generate ROS to kill tumor cells. In type I PDT, an electron transfer process mainly occurs, and the photosensitizer in the T1 state transfers electrons to the surrounding biological substrate to generate hydroxyl radicals (OH·) and superoxide anions (O2 -· ) etc., to kill tumor cells. In type II PDT, it is an energy transfer process, and the photosensitizer in the T1 state directly transfers energy to the surrounding O2 to convert it into cytotoxic singlet oxygen ( 1 O2), to kill tumor cells. Because the energy transfer process is relatively simple and the generation efficiency of 1 O2 is relatively high, most photosensitizers are more likely to exert their effects through this pathway. However, a hypoxic microenvironment often appears in solid tumors, which will reduce the therapeutic effect of PDT. Compared with the type II pathway, type I PDT has a lower dependence on O2, which benefits from the participation of O2-· species in disproportionation reactions and Fenton and Haber-Weiss reactions. These processes can not only regenerate oxygen to relieve hypoxia, but also stimulate the formation of other ROS species. Therefore, type I PDT shows great potential in the treatment of hypoxic cancers and has received increasing attention in recent years.

[0004] Although type I PDT has theoretical advantages, there are still obvious technical bottlenecks in the currently reported type I photosensitizers. Literature studies have shown (J. Am. Chem. Soc. 2023, 145, 8130 - 8140; Angew. Chem. Int. Ed. 2021, 60, 19912 - 19920; Angew. Chem. Int. Ed. 2024, 63, e202318783.) that type I photosensitizer systems generally have defects such as insufficient phototoxicity and long treatment cycles. For example, some materials require multiple administrations to achieve effective tumor suppression (J. Am. Chem. Soc. 2021, 143, 20828 - 20836; Angew. Chem. Int. Ed. 2023, 62, e202300162.), while high-dose use is prone to cause aggregation of photosensitizer molecules, resulting in reduced activity and increasing the metabolic burden on the liver and kidneys. Summary of the Invention

[0005] The object of the present invention is to provide a fluoroboron compound aiming at the problems of insufficient phototoxicity and long treatment cycle of existing type I photosensitizers. On the basis of retaining the optical advantages of traditional materials, the specific generation of type I ROS is achieved through precise regulation of the molecular structure, and superoxide anion radicals can be efficiently generated under white light excitation through a hypoxia-dependent photosensitization mechanism, thereby improving the inhibitory effect, having strong phototoxicity and a short treatment cycle.

[0006] According to the first aspect of the object of the present invention, a fluoroboron compound is provided, which is denoted as AQTPE and has a structural formula as shown in Formula I;

[0007]

[0008] According to the second aspect of the object of the present invention, a preparation method of the aforementioned fluoroboron compound is provided, including the following steps:

[0009] 1-Aminoanthraquinone and 1-(4-bromophenyl)-1,2,2-triphenylethylene in a toluene medium, under the conditions of (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (BINAP), tris(dibenzylideneacetone) dipalladium (Pd2(dba)3), and sodium tert-butoxide as additives, obtain an intermediate through Buchwald-Hartwig cross-coupling reaction;

[0010] The intermediate in a 1,2-dichloroethane medium, with boron trifluoride diethyl ether and triethylamine as additives, generates the fluoroboron compound AQTPE through a cyclization reaction.

[0011] As an alternative embodiment, the molar ratio of 1-(4-bromophenyl)-1,2,2-triphenylethylene, 1-aminoanthraquinone, BINAP, Pd2(dba)3, and sodium tert-butoxide is 1:(1 - 1.15):(0.005 - 0.015):(0.01 - 0.02):(1.5 - 2.5).

[0012] As an alternative embodiment, the molar ratio of the intermediate, boron trifluoride diethyl etherate, and triethylamine is 1:(10 - 50):(5 - 10).

[0013] As an alternative embodiment, the process for obtaining the intermediate includes:

[0014] Add 1-aminoanthraquinone and 1-(4-bromophenyl)-1,2,2-triphenylethylene to toluene, stir evenly under a nitrogen atmosphere, then sequentially add BINAP, Pd2(dba)3, and sodium tert-butoxide. Stir and heat the mixed solution to 80 - 110°C, react for 10 - 20 h, distill off the solvent under reduced pressure. After the reaction ends, remove the solvent, and obtain the intermediate by column chromatography.

[0015] As an alternative embodiment, in a 1,2-dichloroethane medium, using boron trifluoride diethyl etherate and triethylamine as additives, the intermediate undergoes a cyclization reaction to generate the fluoroborate compound AQTPE. The specific process includes:

[0016] Add the intermediate to 1,2-dichloroethane, stir until dissolved, slowly add triethylamine to the mixed solution, continue to stir at room temperature, then slowly add the boron trifluoride diethyl etherate solution, stir and heat to 40 - 50°C, react for 6 - 8 h, distill off the solvent under reduced pressure, extract with dichloromethane, and purify by column chromatography to obtain the purple solid AQTPE.

[0017] According to the third aspect of the object of the present invention, there is provided an application of the aforementioned fluoroborate compound in the preparation of an anti-tumor photosensitizer.

[0018] According to the fourth aspect of the object of the present invention, there is provided a type I photosensitizer prepared using the aforementioned fluoroborate compound.

[0019] According to the fifth aspect of the object of the present invention, there is provided a preparation method of the aforementioned type I photosensitizer. Dissolve the aforementioned fluoroborate compound in tetrahydrofuran, add it to ultrapure water containing DSPE-PEG 2000 under ultrasonic conditions, stir the reaction to completion, remove tetrahydrofuran, and filter to obtain a purple clear AQTPE nanoparticle solution, thereby obtaining the type I photosensitizer.

[0020] As an alternative embodiment, the mass ratio of AQTPE to DSPE-PEG 2000 is 1:(10 - 20), and stir at room temperature for 24 - 48 h.

[0021] As can be seen from the above technical solutions of the present invention, the fluoro-boron compound AQTPE proposed by the present invention contains an anthraquinone group, which can efficiently generate strongly oxidizing anion radicals after photoexcitation, and the generation efficiency of superoxide anion radicals reaches 2.9 times that of the commercial type I photosensitizer crystal violet, with a low half-inhibitory concentration (IC 50 <20 μg / mL), showing a strong inhibitory effect, having stronger phototoxicity, and being able to kill cancer cells in a shorter time;

[0022] At the same time, the generated superoxide anion radicals can specifically oxidize the FADH2 coenzyme (the reduced form of flavin adenine dinucleotide) in the mitochondrial electron transport chain, inactivate the coenzyme function by oxidizing its isoalloxazine ring structure, and then disrupt the electron transport process of the mitochondria and inhibit the energy metabolism of cancer cells, thereby effectively inhibiting the proliferation activity of cancer cells;

[0023] In this way, by efficiently killing cancer cells and combining with the ability to achieve continuous growth inhibition by disrupting the mitochondrial function of tumor cells under single-treatment conditions, it provides an innovative solution to overcome the hypoxia problem commonly existing in the treatment of solid tumors. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 It is the synthesis route diagram of the fluoro-boron compound AQTPE of the present invention.

[0025] Figure 2 It is the 1 1H-NMR spectrum of compound AQTPE in the examples of the present invention.

[0026] Figure 3 It is the 13 13C-NMR spectrum of compound AQTPE in the examples of the present invention.

[0027] Figure 4 It is the mass spectrum of compound AQTPE in the examples of the present invention.

[0028] Figure 5 It is the test diagram of the dynamic light scattering particle size distribution of AQTPE nanoparticles in the examples of the present invention.

[0029] Figure 6 It is the diagram of the change of the size of AQTPE nanoparticles over time in the examples of the present invention.

[0030] Figure 7 It is the ultraviolet absorption spectrum diagram of AQTPE nanoparticles in dichloromethane solvent in the examples of the present invention.

[0031] Figure 8In the example of the present invention, after the AQTPE nanoparticles are mixed with dihydrorhodamine 123, the fluorescence intensity change diagram of dihydrorhodamine 123 under white light irradiation conditions.

[0032] Figure 9 In the example of the present invention, after the crystal violet nanoparticles are mixed with dihydrorhodamine 123, the fluorescence intensity change diagram of dihydrorhodamine 123 under white light irradiation conditions.

[0033] Figure 10 In the example of the present invention, the relationship between the fluorescence intensity difference of AQTPE nanoparticles and crystal violet nanoparticles before and after light irradiation and the light irradiation time.

[0034] Figure 11 In the example of the present invention, after the AQTPE nanoparticles are mixed with FADH2, the absorption intensity change diagram of FADH2 under white light irradiation conditions.

[0035] Figure 12 In the example of the present invention, the relative survival rate of different concentrations of AQTPE nanoparticles incubated with mouse breast cancer cells (4T1) for 24 hours under light or dark conditions.

[0036] Figure 13 In the example of the present invention, the correlation curve between the mouse tumor volume and time after different treatment methods. Detailed implementation mode

[0037] In order to better understand the technical content of the present invention, specific embodiments are hereby given and described in conjunction with the accompanying drawings as follows.

[0038] In the present disclosure, aspects of the present invention are described with reference to the accompanying drawings, in which many illustrative embodiments are shown. The embodiments of the present disclosure are not necessarily intended to include all aspects of the present invention. It should be understood that the various concepts and embodiments introduced above, as well as those concepts and embodiments described in more detail below, can be implemented in any of many ways.

[0039] Borondipyrromethene (BODIPY)-based photosensitizers have shown unique advantages in the field of tumor phototherapy due to their excellent photostability and strong phototoxicity. However, the current type I BODIPY-based photosensitizers still have difficulty in effectively overcoming the technical bottlenecks of insufficient phototoxicity and long treatment cycles of existing type I photosensitizers.

[0040] Therefore, the present invention proposes a breakthrough design strategy for BODIPY-based photosensitizers, and creatively constructs a new photosensitizing treatment system based on the synergistic effect of type I photodynamic mechanism and coenzyme-targeted oxidation. On the basis of retaining the optical advantages of traditional materials, the specific generation of type I ROS is achieved through precise molecular structure regulation. This system not only has a low IC 50Value (<20 μg / mL), killing tumor cells in a short time, thus having the clinical advantage of inhibiting tumor growth with a single treatment. Moreover, through the synergistic mechanism of specifically oxidizing FADH2, it inhibits the proliferation activity of cancer cells, thereby enhancing the ROS killing effect while causing mitochondrial dysfunction.

[0041] Fluoroboron compounds

[0042] As the fluoroboron compound in an exemplary embodiment of the present invention, this compound is denoted as AQTPE, and its structural formula is shown in Formula I;

[0043]

[0044] Preparation

[0045] In another exemplary embodiment of the present invention, a preparation method of the aforementioned fluoroboron compound is provided. Using 1-(4-bromophenyl)-1,2,2-triphenylethylene, 1-aminoanthraquinone, sodium tert-butoxide, boron trifluoride diethyl etherate, and triethylamine as raw materials, the reaction is carried out according to Figure 1 the reaction route for preparation.

[0046] In one optional implementation manner, the preparation method of the fluoroboron compound includes the following steps:

[0047] 1-Aminoanthraquinone and 1-(4-bromophenyl)-1,2,2-triphenylethylene in a toluene medium, under the conditions of (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (BINAP), tris(dibenzylideneacetone) dipalladium (Pd2(dba)3), and sodium tert-butoxide as additives, obtain intermediate (Compound 1) through Buchwald-Hartwig cross-coupling reaction;

[0048] The intermediate in a 1,2-dichloroethane medium, using boron trifluoride diethyl etherate and triethylamine as additives, generates the fluoroboron compound AQTPE through a cyclization reaction.

[0049] As an optional example, the process of obtaining the intermediate includes:

[0050] Add 1-aminoanthraquinone and 1-(4-bromophenyl)-1,2,2-triphenylethylene to toluene, stir evenly under a nitrogen atmosphere, then sequentially add BINAP, Pd2(dba)3, and sodium tert-butoxide. Stir and heat the mixed solution to 80 - 110 °C, react for 10 - 20 h, remove the solvent by reduced pressure distillation after the reaction ends, and obtain the intermediate by column chromatography.

[0051] As an alternative example, the molar ratio of 1-(4-bromophenyl)-1,2,2-triphenylethylene, 1-aminoanthraquinone, BINAP, Pd2(dba)3, and sodium tert-butoxide is 1:(1 - 1.15):(0.005 - 0.015):(0.01 - 0.02):(1.5 - 2.5).

[0052] As an alternative example, in a 1,2-dichloroethane medium, using boron trifluoride diethyl ether and triethylamine as additives, through a cyclization reaction, a fluoroborate compound AQTPE is generated. The specific process includes:

[0053] Add the intermediate to 1,2-dichloroethane, stir until dissolved, slowly add triethylamine to the mixed solution, continue to stir at room temperature, then slowly add the boron trifluoride diethyl ether solution, stir and heat to 40 - 50 °C, react for 6 - 8 h, then remove the solvent by distillation under reduced pressure, extract with dichloromethane, and purify by column chromatography to obtain the purple solid AQTPE.

[0054] As an alternative example, the molar ratio of the intermediate, boron trifluoride diethyl ether, and triethylamine is 1:(10 - 50):(5 - 10).

[0055] The fluoroborate compound AQTPE of the present invention has a clear chemical structure, a simple synthesis process, is easy to purify, and has a high yield.

[0056] Application

[0057] In another embodiment of the present invention, there is provided an application of the aforementioned fluoroborate compound in the preparation of an anti-tumor photosensitizer.

[0058] In one example, there is provided a type I photosensitizer prepared using the aforementioned fluoroborate compound. Under white light irradiation, this photosensitizer can oxidize FADH2 and efficiently generate a large amount of ROS in tumor cells, killing tumor cells in a shorter time.

[0059] In another example, there is provided a preparation method of the aforementioned type I photosensitizer. Dissolve the aforementioned fluoroborate compound in tetrahydrofuran, and under ultrasonic conditions, add it to ultrapure water containing DSPE-PEG 2000 After stirring and reacting, remove tetrahydrofuran and filter to obtain a purple and clear AQTPE nanoparticle solution, thereby obtaining the type I photosensitizer.

[0060] As an alternative example, the mass ratio of AQTPE and DSPE-PEG 2000 is 1:(10 - 20), and stir at room temperature for 24 - 48 h.

[0061] As an alternative example, the particle size of the type I photosensitizer is 100 ± 3.5 nm.

[0062] The type I photosensitizer of the present invention has good photophysical properties. The maximum absorption wavelength in the ultraviolet absorption spectrum of its nanoparticle solution reaches 624 nm. At the same time, the type I photosensitizer of the present invention has the advantages of small molecular weight and excellent solubility, and has great application prospects in biological imaging, photodynamic therapy, etc. In particular, it is conducive to the construction and application of the type I photosensitizer photodiagnosis and treatment system, realizes efficient tumor treatment, and has strong practicability and wide applicability.

[0063] For better understanding, the present invention will be further described below in conjunction with several specific examples, but the preparation process is not limited thereto, and the content of the present invention is not limited thereto.

[0064] Unless otherwise specified, the materials in the examples are prepared according to existing methods or directly purchased from the market.

[0065] Example 1

[0066] [Synthesis of Intermediate]

[0067] Add 1-(4-bromophenyl)-1,2,2-triphenylethylene (1.641 g, 4 mmol), 1-aminoanthraquinone (0.981 g, 4.4 mmol), and anhydrous dry toluene (50 mL) into a dry 250 mL two-necked flask. After stirring well under a nitrogen atmosphere, successively add BINAP (0.025 g, 0.04 mmol), Pd2(dba)3 (0.055 g, 0.06 mmol), and sodium tert-butoxide (0.768 g, 8 mmol). The mixed solution is stirred and heated to 80 °C. After reacting for 16 h, the solvent is removed by distillation under reduced pressure. After the reaction ends, the solvent is removed, and column chromatography is used to obtain a dark red solid compound 1 (1.738 g, 72.3%).

[0068] 1 H NMR (400 MHz, CDCl3): δ (ppm) = 11.33 (s, 1H), 8.31 (d, J = 7.9 Hz, 1H), 8.27 (d, J = 7.3 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.77 - 7.74 (m, 1H), 7.71 (t, J = 5.5 Hz, 1H), 7.48 (d, J = 3.1 Hz, 2H), 7.17 - 7.14 (m, 6H), 7.11 - 7.07 (m, 7H), 7.05 (t, J = 6.4 Hz, 6H).

[0069] 1313C NMR (100 MHz, CDCl3): δ (ppm) = 185.7, 183.4, 149.7, 144.6, 144.4, 141.9, 141.4, 140.9, 138.4, 135.7, 135.3, 134.9, 134.1, 133.8, 133.3, 132.1, 128.4, 127.6, 127.3, 123.6, 121.0, 118.7, 115.0.

[0070] It can be determined from the above that the chemical structural formula of Compound 1 is as shown in Formula II:

[0071]

[0072] [Synthesis of AQTPE]

[0073] Under a nitrogen atmosphere, Compound 1 (0.553 g, 1 mmol) was added to 1,2-dichloroethane and stirred until dissolved. After slowly adding triethylamine (0.607 g, 6 mmol) to the mixed solution, stirring was continued at room temperature. Subsequently, boron trifluoride diethyl ether solution (9.256, 30 mmol) was slowly added dropwise, and the mixture was stirred and heated to 50 °C. After reacting for 6 h, the solvent was removed by distillation under reduced pressure, and the residue was extracted with dichloromethane and purified by column chromatography (dichloromethane:petroleum ether = 1:10) to obtain purple solid AQTPE (0.366, 66.2%).

[0074] As Figure 2 shown, 1 1H NMR (400 MHz, CDCl3): δ (ppm) = 8.50 - 8.48 (m, 1H), 8.33 (t, J = 4.6 Hz, 1H), 7.85 (t, J = 4.3 Hz, 2H), 7.68 (d, J = 6.7 Hz, 1H), 7.51 (dd, = 9.2, 7.3 Hz, 1H), 7.17 - 7.12 (m, 12H), 7.12 - 7.07 (m, 7H), 6.81 (d, J = 9.2 Hz, 1H)

[0075] As Figure 3 shown, 13 13C NMR (100 MHz, CDCl3) δ (ppm) = 181.0, 173.1, 154.8, 143.7, 143.6, 143.3, 142.9, 141.9, 140.1, 139.6, 137.5, 135.3, 134.6, 133.8, 132.6, 131.9, 131.4, 131.3, 131.3, 131.1, 128.1, 127.9, 127.8, 127.7, 127.6, 126.7, 126.6, 123.6, 121.7, 109.3.

[0076] As Figure 4 shown, MALDI-TOF MS (m / z): Calcd for C 33 H 27 BF2N3S2 [M+H] + : 602.211, found 602.191.

[0077] It can be determined from the above that the chemical structural formula of AQTPE is as shown in Formula I:

[0078]

[0079] Example 2

[0080] [Preparation of Type I Photosensitizer]

[0081] Take 2 mg of the compound AQTPE prepared in Example 1 and dissolve it in 2 mL of tetrahydrofuran. Under ultrasonic conditions (power 200 W, frequency 40 kHz), inject it into 10 mL of ultrapure water containing DSPE-PEG 2000 (10 mg) by syringe, stir for 36 h to remove tetrahydrofuran in the solution, and filter through a 200-μm filter head to obtain a purple and clear AQTPE nanoparticle solution.

[0082] As Figure 5 shown, the test result of the dynamic light scattering particle size distribution of AQTPE nanoparticles shows that the hydrated particle size is about 100 nm, and nanoparticles of this size can be effectively enriched in tumor cells through the enhanced permeability and retention (EPR) effect.

[0083] Example 3

[0084] [Stability Test of AQTPE Nanoparticles]

[0085] Measure the particle size of the AQTPE nanoparticle solution every three days. As Figure 6 shown, the particle size of AQTPE nanoparticles hardly changes within two weeks, indicating that AQTPE nanoparticles have excellent size stability.

[0086] Example 4

[0087] [Photophysical Property Test of AQTPE Nanoparticles]

[0088] In a quartz cuvette for UV testing, add the AQTPE nanoparticle solution (2.5 mL) prepared in Example 2, with a concentration of 200 μg / mL, and test its UV absorption spectrum. The results are as Figure 7 shown.

[0089] From Figure 7 it can be seen that the maximum UV absorption peak wavelength of the AQTPE nanoparticles is 624 nm.

[0090] From the above results, it can be seen that the AQTPE nanoparticles prepared by the present invention have good photophysical properties.

[0091] Example 5

[0092] [Photodynamic Performance Test of AQTPE Nanoparticles]

[0093] (1) Add the aqueous solution of AQTPE nanoparticles (0.25 mM, 2 mL) prepared in Example 2 to a cuvette, and then add 40 μL of an aqueous solution of dihydrorhodamine 123 (DHR 123) with a concentration of 1 mM (DHR 123 is a superoxide anion radical probe, which can react with superoxide anion radicals, resulting in an increase in the characteristic absorption peak of DHR 123). Irradiate intermittently with white light, with each irradiation for 10 s, and monitor the change in the fluorescence intensity at the characteristic peak of DHR 123 at 525 nm. The results are as Figure 8 shown.

[0094] From Figure 8 it can be seen that the fluorescence emission value at the characteristic peak of DHR 123 (525 nm) continuously increases with the increase of irradiation time, indicating that the AQTPE nanoparticles have good ability to generate superoxide anion radicals.

[0095] (2) Add the aqueous solution of commercial type I photosensitizer crystal violet nanoparticles (0.25 mM, 2 mL) to a cuvette, and then add 40 μL of an aqueous solution of dihydrorhodamine 123 (DHR 123) with a concentration of 1 mM (DHR 123 is a superoxide anion radical probe, which can react with superoxide anion radicals, resulting in an increase in the characteristic absorption peak of DHR 123). Irradiate intermittently with white light, with each irradiation for 10 s, and monitor the change in the fluorescence intensity at the characteristic peak of DHR 123 at 525 nm. The results are as Figure 9 shown.

[0096] From Figure 9 it can be seen that the fluorescence emission value at the characteristic peak of DHR 123 (525 nm) continuously increases with the increase of irradiation time, indicating that the crystal violet nanoparticles can also generate superoxide anion radicals.

[0097] From Figure 10It can be seen that the superoxide anion radical generation efficiency of AQTPE nanoparticles is 2.9 times higher than that of crystal violet, indicating that the AQTPE nanoparticles of the present invention can efficiently generate strongly oxidizing anion radicals.

[0098] Example 6

[0099] [Test on the ability of AQTPE nanoparticles to oxidize FADH2]

[0100] Add the aqueous solution of AQTPE nanoparticles prepared in Example 2 (0.25 mM, 2 mL) into a cuvette, and then add 20 μL of an aqueous solution of FADH2 with a concentration of 1 mM (FADH2 can react with superoxide anion radicals to produce FAD (flavin adenine dinucleotide), resulting in an increase in the characteristic absorption peak (450 nm) of FAD). Irradiate intermittently with white light, with each irradiation for 15 s, and monitor the change in absorbance at the FAD characteristic peak of 450 nm. The results are as Figure 11 shown.

[0101] From Figure 11 it can be seen that the absorbance at the characteristic absorption peak (450 nm) of FAD continuously increases with the increase of irradiation time, indicating that AQTPE nanoparticles have the ability to oxidize FADH2.

[0102] Example 7

[0103] [Cytotoxicity experiment of AQTPE nanoparticles]

[0104] Inoculate 4T1 cells into two 96-well cell culture plates at a density of 5.0×10 3 cells per well, and incubate at 37 °C, 5% CO2, and in a dark environment for 24 h.

[0105] Use the AQTPE nanoparticles prepared in Example 2 to prepare AQTPE nanoparticles with different concentrations (0, 1, 2, 5, 10, 15, 20, 30, 40, 50 μg / mL) and add them to the wells for co-incubation for 12 h. After incubation, irradiate one of the well plates with white light for 10 min at room temperature, and keep the other well plate in the dark to test the dark cytotoxicity of AQTPE nanoparticles.

[0106] After the irradiation is completed, continue to culture the well plates in the dark for 12 h, then add 20 μL of MTT solution to each well and treat for 4 h. Remove the culture medium in the well plates, add 150 μL of dimethyl sulfoxide (DMSO) to dissolve the purple formazan crystals, and read the absorbance data at 490 nm with an enzyme-linked immunosorbent assay (ELISA) reader to calculate the survival rate of 4T1 cells under different concentrations of photosensitizer. The calculation formula for the cell survival rate is: average absorbance of the treatment group / average absorbance of the control group × 100%.

[0107] As Figure 12 shown, with the increase of the administration concentration, the cell viability decreased significantly, and the half-inhibitory concentration (IC 50 50) of AQTPE nanoparticles for 4T1 cells was 15.5 μg / mL; while in the dim light group, the cell viability remained at a high level at higher concentrations, showing lower dark toxicity.

[0108] This indicates that under white light irradiation, AQTPE nanoparticles have a low half-inhibitory concentration, strong phototoxicity, and can effectively kill tumor cells.

[0109] Example 8

[0110] [Tumor Therapy Experiment of AQTPE Nanoparticles]

[0111] Balb / c mice with 4T1 tumor cells injected into the armpit were selected as the tumor model, and 16 nude mice were randomly divided into 4 groups.

[0112] When the tumor volume was about 100 mm 3 , in the first group (saline), saline was injected through the tail vein; in the second group (saline + light), saline was injected into the mice through the tail vein; in the third group (AQTPE nanoparticle solution), AQTPE nanoparticle solution was injected into the mice through the tail vein (the preparation method was the same as that of AQTPE nanoparticles, 100 μg / mL, 100 μL); in the fourth group (AQTPE nanoparticle solution + light): AQTPE nanoparticle solution (100 μg / mL, 100 μL) was injected into the mice through the tail vein. 12 h after injection, the tumors of the mice in the third and fourth groups were irradiated with white light (80 mW / cm 2 2) for 10 min, and the first and second groups were not irradiated.

[0113] The above process was carried out only once. The tumor size and mouse body weight were measured every 2 days for a total of 14 days, and the results are as Figure 13 shown.

[0114] From Figure 13 it can be seen that in the first and second groups, the tumor volume of the mice increased over time, while in the fourth group, after treatment and irradiation, the tumor volume of the mice increased slowly. In the third group, the mice were not irradiated, and the growth trend of their tumor volume was similar to that of the control groups (the first and second groups), indicating that AQTPE nanoparticles have excellent photodynamic therapy effects on living tumors.

[0115] As can be seen from the above, the present invention has successfully prepared the fluoroboron compound AQTPE. Under white light irradiation, the fluoroboron compound AQTPE can efficiently generate superoxide anion radicals, thereby having a lower half-inhibitory concentration and stronger phototoxicity, killing tumor cells in a shorter time. At the same time, the generated superoxide anion radicals oxidize FADH2, effectively inhibiting the proliferation activity of cancer cells. In this way, the high-efficiency treatment of tumors is achieved synergistically, with strong practicability and wide applicability.

[0116] Although the present invention has been disclosed above with preferred embodiments, it is not intended to limit the present invention. Those with ordinary knowledge in the technical field to which the present invention pertains can make various changes and modifications without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention shall be subject to what is defined by the claims.

Claims

1. A fluoro-boron compound, characterized in that, The compound is denoted as AQTPE, and its structural formula is shown in Formula I; 2. A method for preparing the fluoroboron compound according to claim 1, characterized in that, It includes the following steps: 1-Aminoanthraquinone and 1-(4-bromophenyl)-1,2,2-triphenylethylene in a toluene medium, under the conditions of (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (BINAP), tris(dibenzylideneacetone) dipalladium (Pd2(dba)3), and sodium tert-butoxide as additives, obtain an intermediate through Buchwald-Hartwig cross-coupling reaction; The intermediate in a 1,2-dichloroethane medium, with boron trifluoride diethyl ether and triethylamine as additives, generates the fluoroborate compound AQTPE through a cyclization reaction.

3. The preparation method of the fluoro-boron compound according to claim 2, wherein The molar ratio of 1-(4-bromophenyl)-1,2,2-triphenylethylene, 1-aminoanthraquinone, BINAP, Pd2(dba)3, and sodium tert-butoxide is 1:(1 - 1.15):(0.005 - 0.015):(0.01 - 0.02):(1.5 - 2.5).

4. The preparation method of the fluoro-boron compound according to claim 2, wherein The molar ratio of the intermediate, boron trifluoride diethyl ether, and triethylamine is 1:(10 - 50):(5 - 10).

5. The preparation method of the fluoro-boron compound according to claim 2, wherein, The process of obtaining the intermediate includes: Add 1-aminoanthraquinone and 1-(4-bromophenyl)-1,2,2-triphenylethylene to toluene, stir evenly under a nitrogen atmosphere, then successively add BINAP, Pd2(dba)3, and sodium tert-butoxide, stir and heat the mixed solution to 80 - 110 °C, react for 10 - 20 h, distill off the solvent under reduced pressure, and after the reaction ends, remove the solvent, and obtain the intermediate by column chromatography.

6. The preparation method of the fluoro-boron compound according to claim 2, wherein, The intermediate in a 1,2-dichloroethane medium, with boron trifluoride diethyl ether and triethylamine as additives, generates the fluoroborate compound AQTPE through a cyclization reaction. The specific process includes: Add the intermediate to 1,2-dichloroethane, stir until dissolved, slowly add triethylamine to the mixed solution, continue to stir at room temperature, then slowly add boron trifluoride diethyl ether solution, stir and heat to 40 - 50 °C, react for 6 - 8 h, distill off the solvent under reduced pressure, extract with dichloromethane, and purify by column chromatography to obtain the purple solid AQTPE.

7. Use of the fluoroborate compound according to claim 1 in the preparation of an anti-tumor photosensitizer.

8. A type I photosensitizer prepared using the fluoroborate compound according to claim 1.

9. A method for preparing the type I photosensitizer according to claim 8, characterized in that, Dissolve the fluoroborate compound described in claim 1 in tetrahydrofuran, and add it to ultrapure water containing DSPE-PEG 2000 under ultrasonic conditions. After the stirring reaction is completed, remove the tetrahydrofuran and filter to obtain a purple clear AQTPE nanoparticle solution, and then a type I photosensitizer can be obtained.

10. The preparation method of the type I photosensitizer according to claim 9, wherein, The mass ratio of AQTPE and DSPE-PEG 2000 is 1:(10 - 20), and stir at room temperature for 24 - 48 h.

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