CN111084881B - Vascular blocking agent bonded BODIPY derivative and preparation method and application thereof - Google Patents

Vascular blocking agent bonded BODIPY derivative and preparation method and application thereof Download PDF

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CN111084881B
CN111084881B CN201911219720.6A CN201911219720A CN111084881B CN 111084881 B CN111084881 B CN 111084881B CN 201911219720 A CN201911219720 A CN 201911219720A CN 111084881 B CN111084881 B CN 111084881B
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董晓臣
陈大鹏
邵进军
司伟丽
张琪
黄维
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Abstract

The invention discloses a blood vessel blocking agent bonded BODIPY derivative, which is formed by covalently bonding BODIPY serving as a near-infrared photosensitizer and 2, 5-pentoxifylline serving as a blood vessel blocking agent. Meanwhile, the invention also discloses a nano diagnosis and treatment reagent obtained by self-assembling the derivative and an electron-rich amphiphilic polymer methoxy-poly (ethylene glycol) -poly (2-diisopropylamino) methyl methacrylate and application of the nano diagnosis and treatment reagent in type I photodynamic synergistic vascular block therapy in tumor treatment. The target product of the invention has definite structure and simple synthesis process, the diagnosis and treatment reagent based on the target product has I-type photodynamic and pH responsive vascular blocking agent release performance, and under the passive targeting action and fluorescence imaging mediation, the nano diagnosis and treatment reagent can accurately reach tumor parts, block tumor blood vessels and kill tumor cells, thereby effectively preventing the recurrence and metastasis of tumors.

Description

Vascular blocking agent bonded BODIPY derivative and preparation method and application thereof
Technical Field
The invention belongs to the field of near-infrared dyes and nano-medicines, and particularly relates to a blood vessel blocking agent bonded BODIPY derivative and a preparation method thereof, and application of the blood vessel blocking agent bonded BODIPY derivative in preparation of a fluorescence imaging mediated I-type photodynamic/blood vessel blocking synergistic tumor treatment medicine.
Background
During the development of cancer, when the diameter of the tumor reaches 2-3 mm, oxygen and nutrients in the tumor are not enough to support further growth of the tumor, so that Vascular Endothelial Growth Factor (VEGF) in a tumor microenvironment is induced to be up-regulated, and new blood vessels are generated to provide oxygen and nutrients for the tumor. When the tumor develops to a certain extent, the surrounding immune system is attacked, and a large amount of free cancer cells and exosomes containing oncogenes enter normal tissues through the blood vessels, resulting in tumor metastasis. In order to prevent tumor metastasis, treatment methods such as surgery, chemotherapy, radiotherapy and the like have been widely used clinically. However, conventional therapy may cause upregulation of VEGF in the focal region after surgery, leading to new tumor angiogenesis, and may not prevent tumor metastasis and recurrence from its source.
Compared with the traditional treatment method, the vascular occlusion therapy is a novel and more effective tumor treatment method, and can cut off the metastasis channel of the tumor efficiently and prevent the tumor metastasis. Among them, DMXAA in a clinical phase II trial is a widely used vascular occlusion agent at present. However, the poor water solubility and cell membrane penetration of DMXAA limit its potency. In addition, because the blood vessel blocking therapy mainly acts on tumor blood vessels, only the apoptosis of cells close to the blood vessels in the tumor can be induced, and cancer cells at the edge of the tumor cannot be killed. Under autophagy and the supply of nutrients to surrounding tissues, these surviving cancer cells rapidly induce angiogenesis and promote tumor metastasis. Therefore, the development of a tumor-targeting vascular blocking agent capable of killing marginal cancer cells is particularly urgent.
Photodynamic therapy, as a non-invasive therapy, has the advantages of low side effects, high selectivity, high therapeutic effect, and the like. Traditional photodynamic therapy is a type II photodynamic mechanism, and mainly depends on singlet oxygen generated by a photosensitizer under the condition of illumination to kill tumor cells. However,the production of singlet oxygen is closely related to the oxygen concentration, and when the oxygen concentration in the tumor is reduced in the treatment process, the photodynamic effect is rapidly reduced, thus hindering the clinical application of the photodynamic therapy. Unlike conventional photodynamic therapy, type I photodynamic therapy generates superoxide anion radicals (O) primarily through electron transport and proton transfer2 ●-) Hydroxyl radical (OH)●) And the like, generates cytotoxicity, has lower oxygen dependence and can effectively kill hypoxic tumor cells. The combination of type I photodynamic therapy and vascular blocking therapy not only can treat hypoxic tumors, but also can block tumor blood vessels and prevent the recurrence and metastasis of tumors.
Disclosure of Invention
The invention aims to form a hydrophilic diagnosis and treatment reagent by covalent bonding of a blood vessel blocking agent and a BODIPY photosensitizer and self-assembly of an electron-rich polymer. On one hand, the tumor targeting and the blood vessel blocking efficiency of the blood vessel blocking agent are improved; on the other hand, under the action of I-type photodynamic, tumor cells are effectively killed, and accurate and efficient tumor treatment is realized.
The aim of the invention is realized by the following technical scheme:
a blood vessel blocking agent bonded fluoboric pyrrole derivative (BDPVDA for short) has a structure shown in a formula I:
Figure BDA0002300465460000021
the chemical name of BDPVDA is (4- (3, 7-bis (E) -4- (dimethylamine) -styrene) -5, 5-difluoro-1, 9-dimethyl-5H-4 lambda4、5λ4-dipyrrole [1,2-c:2 ', 1' -f][1,3,2]Dinitrogen boron) -phenol) bis (5, 6-dimethyl-9-oxo-9H-ton-4-yl) acetic acid ethyl ester.
The blood vessel blocking agent bonded BODIPY derivative is formed by covalently bonding BODIPY serving as a near-infrared photosensitizer and DMXAA serving as a blood vessel blocking agent.
The synthetic route of the blood vessel blocking agent bonded BODIPY derivative is as follows:
Figure BDA0002300465460000022
the preparation method of the blood vessel blocking agent bonded BODIPY derivative comprises the following steps:
dissolving 4-hydroxybenzaldehyde and 2, 4-dimethylpyrrole in tetrahydrofuran by taking tetrahydrofuran as a reaction solvent, sequentially adding trifluoroacetic acid, 2, 3-dichloro-5, 6-dicyano-p-benzoquinone (DDQ), triethylamine and boron trifluoride diethyl etherate for reaction, and purifying to obtain a compound 1;
dissolving the compound 1 in dimethylformamide, heating to react under the catalytic action of acetic acid and piperidine, and purifying to obtain a compound 2;
step (3), carrying out an acyl chlorination reaction on DMXAA and thionyl chloride to obtain acyl chlorinated DMXAA; and reacting the compound 2 with acyl-chlorinated DMXAA to obtain BDPVDA under the catalysis of triethylamine by using acetonitrile as a reaction solvent.
In the step (1), the molar ratio of the 4-hydroxybenzaldehyde to the 2, 4-dimethylpyrrole, the 2, 3-dichloro-5, 6-dicyano-p-benzoquinone, the boron trifluoride diethyl etherate and the triethylamine is 1:2-3:1-2:50-100:50-100, and preferably 1:2.2:1:50: 50.
Preferably, taking a tetrahydrofuran solution as a reaction solvent, adding 4-hydroxybenzaldehyde, 2, 4-dimethylpyrrole and trifluoroacetic acid, reacting at room temperature for 10-18 hours, adding a tetrahydrofuran solution of 2, 3-dichloro-5, 6-dicyan-p-benzoquinone, and reacting at room temperature for 3-8 hours; adding triethylamine and boron trifluoride diethyl etherate into the reaction solution under the ice bath condition, and continuing to react for 12-24 hours; removing tetrahydrofuran by rotary evaporation; purifying by column chromatography to obtain compound 1.
Preferably, the column chromatography adopts a silica gel chromatographic column, and the eluent is dichloromethane and petroleum ether which are 1:1 (V/V).
Chemical name of compound 1: 4- (5, 5-difluoro-1, 3,7, 9-tetramethyl-5H-4. lambda4、5λ4-dipyrrole [1,2-c:2 ', 1' -f][1,3,2]Dinitrogen boron) -phenol.
In the step (2), the molar ratio of the acetic acid, the piperidine, the 4-N, N-dimethylaminobenzaldehyde and the compound 1 is 1-20:1-20:2-3:1, preferably 8.5-9:5-5.5:2.4: 1.
The reaction temperature is 110-130 ℃, preferably 120 ℃, and the reaction time is 3-8 hours, preferably 4 hours.
Preferably, after the reaction is finished, water is added into the reaction liquid, dichloroethane is extracted, and the organic phase is purified by column chromatography to obtain the compound 2.
The column chromatography adopts a silica gel chromatographic column, and an eluent is ethyl acetate and petroleum ether in a ratio of 1:3 (V/V).
Chemical name of compound 2: 4- (3, 7-bis (E) -4- (dimethylamine) -styrene) -5, 5-difluoro-1, 9-dimethyl-5H-4 lambda4、5λ4-dipyrrole [1,2-c:2 ', 1' -f][1,3,2]Dinitrogen boron) -phenol.
In the step (3), the mol ratio of the thionyl chloride to the DMXAA is 2-3:1, and preferably 2: 1.
The acyl chlorination reaction: thionyl chloride is added to the ice bath, stirred for 10 to 30 minutes, preferably 10 minutes, and then reacted at room temperature (25 ℃) for 1 to 4 hours, preferably 1 hour.
The molar ratio of the DMXAA to the compound 2 is 1:1-1.2, and preferably 1: 1.
The molar ratio of the triethylamine to the compound 2 is 5:1-2, preferably 5: 1.
The reaction temperature of acyl-chlorinated DMXAA and the compound 2 is 50-60 ℃, and the reaction time is 5-8 hours.
It is another object of the present invention to provide mPEG-PPDA coated BDPVDA nanoparticles PBVNPs to obtain BDPVDA nanoparticles having type I photodynamic properties.
The mPEG-PPDA coated BDPVDA nano-particles PBVNPs are prepared by the following method: BDPVDA and an electron-rich amphiphilic polymer methoxy-poly (ethylene glycol) -poly (2-diisopropylamino) methyl methacrylate (mPEG-PPDA) are dissolved in a tetrahydrofuran solution, the tetrahydrofuran solution is quickly injected into water under the ultrasonic condition, and the tetrahydrofuran is removed under reduced pressure to obtain the PBVNPs.
In mPEG-PPDA, mPEG has a molecular weight of 2000 and PPDA has a degree of polymerization of 80, according to the reference[1]The molecular structure of the compound is shown as a formula II:
Figure BDA0002300465460000041
the mass ratio of BDPVDA to mPEG-PPDA is 1:20-50, preferably 1: 25. The volume ratio of the tetrahydrofuran to the water is 1: 8-16.
Compared with the prior art, the invention has the beneficial effects that:
(1) the BODIPY derivative bonded by the vascular disrupting agent has a definite structure, a simple synthesis method and high yield;
(2) the BDPVDA nano diagnosis and treatment reagent PBVNPs have good water dispersibility, can reach the tumor part of a mouse under the passive targeting action through intravenous injection, and realizes accurate tumor treatment;
(3) the PBVNPs can target and deliver the vascular blocking agent to the tumor part to cut off tumor blood vessels;
(4) the PBVNPs can generate superoxide anion free radicals under the stimulation of near-infrared illumination, so that the high-efficiency treatment of the hypoxic tumors is realized, and the PBVNPs have wide application prospects.
Drawings
FIG. 1 is of BDPVDA1H-NMR spectrum with chemical shift on the abscissa and intensity on the ordinate.
FIG. 2 is of BDPVDA13C-NMR spectrum with chemical shift on the abscissa and intensity on the ordinate.
FIG. 3 shows a MALDI-TOF-Mass spectrum of BDPVDA with molecular weight on the abscissa and intensity on the ordinate.
FIG. 4 is a diagram of the UV absorption spectrum of PBV NPs with wavelength on the abscissa and intensity on the ordinate.
FIG. 5 is a graph of the particle size distribution of PBV NPs, with particle size on the abscissa and intensity on the ordinate.
FIG. 6 is a graph of the release of the vascular blocking agent from PBV NPs at different pH's, with time on the abscissa and cumulative release on the ordinate.
FIG. 7 is a plot of superoxide radical production from PBV NPs characterized by ethidium dihydrogen, wavelength on the abscissa and fluorescence intensity of the probe on the ordinate.
FIG. 8 shows the uptake of PBV NPs by 4T1 cells characterized by confocal laser, with the following scale: 10 μm.
FIG. 9 shows the PBV NPs in the hypoxic state (2% O) under different conditions characterized by flow cytometry2) A diagram of the mechanism causing apoptosis of 4T1 cells, i) 0. mu.g/mL PBV NPs + light, ii) 3.90. mu.g/mL PBV NPs + dark light, iii) 3.90. mu.g/mL PBV NPs + light, iv) 20. mu.g/mL PBV NPs + light.
Fig. 10 is a performance test of PBV NPs vascular blockade by vascular venous endothelial cell detection, with a coordinatometer: 100 μm.
FIG. 11 is a photograph of fluorescence images of PBV NPs in BALB/c mice inoculated with 4T1 tumor.
FIG. 12 shows the change in tumor volume of BALB/c mice inoculated with 4T1 tumor after receiving PBV NPs light treatment.
Detailed Description
The technical solution of the present invention is further illustrated by the following examples.
Example 1
Vascular blocker-linked BDPVDA synthesis
(1) In a 500mL flask, 4-methoxybenzaldehyde (0.37g,3.0mmol) and 2, 4-dimethylpyrrole (0.63g,6.6mmol) were dissolved in 90mL of tetrahydrofuran, and 0.1mL of trifluoroacetic acid was added thereto, followed by reaction with stirring at room temperature for 12 hours; adding 12 ml of 2, 3-dichloro-dicyano-p-benzoquinone (0.68g,3.0mmol) tetrahydrofuran solution into the reaction solution, and continuing to react at room temperature for 4 hours; under the ice bath condition, 18mL of triethylamine and 18mL of boron trifluoride ethyl ether are added into the reaction solution drop by drop, and the reaction is continued for 12 hours; after the reaction was completed, tetrahydrofuran was removed by rotary evaporation, and purified by silica gel chromatography (dichloromethane: petroleum ether ═ 1:1, V/V) to obtain an orange solid product (compound 1, 0.459g, yield about 45%) having the following structural formula:
Figure BDA0002300465460000051
the chemical name of the compound 1 is: 4- (5, 5-difluoro-1, 3,7, 9-tetramethyl-5H-4. lambda4、5λ4-two pyridinePyrrole [1,2-c:2 ', 1' -f][1,3,2]Dinitrogen boron) -phenol.
(2) In a 50mL round-bottom flask, compound 1(0.34g,1.0mmol) and 4-dimethylaminobenzaldehyde (0.33g,2.4mmol) were dissolved in 20mL dimethylformamide, and 0.5mL acetic acid and 0.5mL piperidine were added and reacted at 120 ℃ for 4 hours. After the reaction was complete, 100mL of water was added and extracted with dichloromethane and the organic phase was purified by silica gel chromatography (ethyl acetate: petroleum ether ═ 1:3, V/V) to give the product as a dark green solid (compound 2, 0.252g, 42% yield) of the formula:
Figure BDA0002300465460000061
the chemical name of compound 2 is: 4- (3, 7-bis (E) -4- (dimethylamine) -styrene) -5, 5-difluoro-1, 9-dimethyl-5H-4 lambda4、5λ4-dipyrrole [1,2-c:2 ', 1' -f][1,3,2]Dinitrogen boron) -phenol.
(3) In a 20mL round-bottom flask, DMXAA (56.4mg,0.2mmol) was dissolved in 10mL anhydrous dichloromethane, 1mL thionyl chloride was added in an ice bath, and then the mixture was warmed to room temperature to react for 1 hour, and after the reaction was completed, dichloromethane and thionyl chloride were removed under reduced pressure; compound 2(120mg, 0.2mmol) in acetonitrile was added in 10mL, 5 equivalents (101mg, 1mmol) of triethylamine was added, and the mixture was stirred at 50 ℃ for 5 hours and purified by silica gel chromatography (ethyl acetate: petroleum ether ═ 1:1, V/V) to obtain BDPVDA represented by formula i (60.6mg, yield 35%) as a black solid. Of BDPVDA1The H-NMR spectrum is shown in figure 1,13the C-NMR spectrum is shown in FIG. 2, and the MALDI-TOF-Mass spectrum is shown in FIG. 3.
1H NMR(400MHz,CDCl3):δppm 8.241(dd,J＝1.6Hz,8.0Hz,1H,Ar-H),8.020(d,J＝8.0Hz,1H,Ar-H),7.656(dd,J＝1.6Hz,7.2Hz,1H,Ar-H),7.468(d,J＝7.2Hz,2H,-C＝CH-),7.422(d,J＝8.8Hz,4H,Ar-H),7.314(t,J 7.6Hz,15.2Hz,1H,Ar-H),7.225(d,J＝8.8Hz,2H,Ar-H),7.135(d,J＝8.4Hz,1H,Ar-H),7.117(t,J＝4.0Hz,8.4Hz,2H,Ar-H)；7.067(d,J＝11.6Hz,2H,-C＝CH-),6.626(d,J＝8.8Hz,4H,Ar-H),6.492(s,2H,pyrrole-H),4.169(s,2H,-CH2-),2.935(s,12H,-N-CH3),2.427(s,3H,Ar-CH3),2.383(s,3H,Ar-CH3),1.338(s,6H,pyrrole-CH3).
13C NMR(100MHz,d-THF):δppm 176.331,171.301,160.101,158.908,154.818,154.475,151.475,144.392,136.206,130.406,129.008,125.948,125.754,125.712,125.518,123.489,121.988,120.245,116.096,115.482,112.422,59.993,46.363,40.301,39.765,35.592,30.171,27.176,25.694,23.094,20.049,14.576,14.080,11.172.
MALDI-TOF-MS(m/z):calcd for[C54H49BF2N4O4-H]+:865.82；found,865.21.
Example 2
Preparation of mPEG-PPDA coated BDPVDA nanoparticles (PBV NPs)
100mg of mPEG-PPDA (mPEG having a molecular weight of 2000 and a PPDA degree of polymerization of 80) and 4mg of BDPVDA were dissolved in 5mL of tetrahydrofuran, stirred for 5 minutes, added dropwise to 80mL of deionized water under sonication (200W), and sonicated for 30 minutes. Removing tetrahydrofuran by vacuum rotary evaporation, and filtering by a 220nm filter head to obtain PBV NPs.
As shown in FIG. 4, in the UV-visible absorption spectrum of PBV NPs, the PBV NPs have a strong absorption peak in the wavelength range of 570nm-850nm, and the highest absorption peak is 733nm, which indicates that the PBV NPs have excellent near-infrared absorption performance. Meanwhile, as shown in FIG. 5, the particle size distribution test showed that the particle size distribution of PBV NPs was 60.7. + -. 5.1 nm.
Example 3
Acid-stimulated response release performance of vascular blocking agent DMXAA
20mL of phosphate buffer solution containing PBV NPs (50. mu.g/mL) were placed in dialysis bags (molecular weight cut-off: 1000) and slowly released by placing in phosphate buffers at various pH values (5.0,6.5,7.4), and the release was measured by recording the absorption of DMXAA at various time points. As shown in fig. 6, the cumulative DMXAA release rate increased with decreasing pH, indicating that PBV NPs have good acid-stimulated responsiveness, which would facilitate the delivery of the drug with tumor microacid stimulation.
Example 4
PBV NPs superoxide radical Generation Performance
The superoxide radical generation performance of PBV NPs is detected by using a superoxide radical fluorescent probe ethidium Dihydrogen (DHE), and the fluorescence change of the DHE is detected at intervals of one minute under the irradiation of 730nm laser. As shown in fig. 7, the fluorescence of DHE gradually increased with the increase of the illumination time, indicating that PBV NPs have excellent superoxide radical generating properties.
Example 5
Tumor cell uptake and apoptosis assay for PBV NPs
Uptake experiments were performed using 4T1 breast cancer cells, as follows: 4T1 cells were incubated in a confocal dish containing 2mL1640 medium at 37 ℃ with 5% carbon dioxide for 24 hours, and incubation was continued for 24 hours with the addition of PBV NPs (final concentration of PBV NPs in medium of 2.3. mu.g/mL). The medium was removed, washed 3 times with physiological saline, and the uptake of PBV NPs by the cells was observed by confocal laser fluorescence microscopy. As shown in FIG. 8, 4T1 cells have obvious fluorescence signals of PBV NPs, which indicates that PBV NPs can be taken up by tumor cells, and has important guiding significance for in vivo treatment.
To explore the mechanism of apoptosis after PBV NPs, 4T1 breast cancer cells were tested by flow cytometry, as follows: 4T1 cells were incubated in a six-well plate containing 2mL1640 medium at 37 ℃ in a 5% carbon dioxide environment for 24 hours, followed by hypoxic conditions (2% O)2) 4T1 cells were treated differently: i)0 μ g/mL PBV NPs + light; ii)3.90 μ g/mL PBV NPs + dim light; iii) 3.90. mu.g/mL PBV NPs + light; iv) 20. mu.g/mL PBV NPs + light and detection by flow cytometry. Wherein the light dose of the light group is 0.05W/cm2And the illumination time is 5 minutes. As shown in FIG. 9, PBV NPs have low dark toxicity and high phototoxicity, IC50The value was about 3.9. mu.g/mL and caused cell death primarily by late apoptotic means.
Example 6
PBVNPs vascular occlusion Performance test
Human umbilical vein endothelial cells were cultured on Matrix gel containing Matrix at 37 ℃ in 5% carbon dioxide, and after 12 hours, vessels were formed, after which 2mL of 1640 medium containing PBV NPs (10. mu.g/mL) was added and morphological changes of the vessels were recorded by electron microscopy at different time points. As shown in fig. 10, PBV NPs were able to effectively block generated blood vessels after 4 hours of administration, and the blocking effect was more significant with time, indicating that PBV NPs had excellent vascular blocking properties.
Example 7
In vivo fluorescence imaging Performance of PBV NPs
PBV NPs solution with the concentration of 20 mug/mL is prepared by using physiological saline.
Injecting 100 mu L of PBV NPs solution into a tumor-bearing mouse, observing the dynamic distribution of the PBV NPs in the mouse by a living body fluorescence imaging instrument at different time points, taking out tumor tissues and normal organs after 36 hours, and observing the tissue distribution of the PBVNPs. As shown in fig. 11a, the fluorescence of PBV NPs at the tumor site gradually increased with time, reached the maximum at 18 hours, and began to gradually decrease thereafter, indicating that PBV NPs can effectively enrich in the tumor and reach the maximum concentration at 18 hours. Meanwhile, as shown in fig. 11b, the fluorescence at the tumor site is strongest compared to other normal organs, indicating that the PBV NPs have excellent tumor targeting.
Example 8
Tumor therapeutic Properties of PBVNPs
Referring to the method of example 2, nano-particles BDP NPs of compound 2 coated with mPEG-PPDA were prepared by replacing BDPVDA with an equal mass of compound 2.
PBV NPs were dissolved in physiological saline to prepare a PBV NPs solution with a concentration of 20. mu.g/mL. BDP NPs are dissolved by physiological saline to prepare BDP NPs solution with the concentration of 20 mu g/mL.
Selecting 20 BALB/c mice inoculated with 4T1 tumor cells subcutaneously as tumor models, randomly dividing into 4 groups, and obtaining a tumor volume of 100-150mm3At the time, once every two days, tail vein drug injections received different treatments: the first group was normal saline + light control group, the second group was BDP NPs + light control group, the third group was PBV NPs + dark light control group, and the fourth group was PBV NPs + light treatment group. Wherein the injection dosage of the second, third and fourth groups is 100 μ L, and the first group isEqual amount of physiological saline. After the injection of the drugs, 4 groups were treated with dark light, and at 18 hours, the first group, the second group and the fourth group received light with the dose of 0.1W/cm 28 minutes; the third group does not receive any illumination.
As shown in fig. 12, the fourth group of mouse tumor models had almost no tumor after 5 treatments, showed superior therapeutic effects of the synergy of type I photodynamic therapy and vascular occlusion therapy compared to the second group of compound 2 and the third group, and showed that BDPVDA has better antitumor activity than compound 2, and could completely eliminate tumors.
Reference to the literature
[1]Z.Xu,P.Xue,Y.E.Gao,S.Liu,X.Shi,M.Hou,Y.Kang,pH-responsive polymeric micelles based on poly(ethyleneglycol)b-poly(2-(diisopropylamino)ethyl methacrylate)block copolymer for enhanced intracellular release of anticancer drugs.J.Colloid.Interface Sci.2017,490,511-519.

Claims (16)

1. A blood vessel blocking agent bonded BODIPY derivative has a structure shown in formula I:
Figure FDA0003395247730000011
2. the process for preparing a vascular disrupting agent-bonded fluoroborole derivative as claimed in claim 1, comprising the steps of:
dissolving 4-hydroxybenzaldehyde and 2, 4-dimethylpyrrole in tetrahydrofuran by taking tetrahydrofuran as a reaction solvent, sequentially adding trifluoroacetic acid, 2, 3-dichloro-5, 6-dicyano-p-benzoquinone, triethylamine and boron trifluoride diethyl etherate for reaction, and purifying to obtain a compound 1;
heating and reacting the compound 1 with 4-N, N-dimethylaminobenzaldehyde under the catalytic action of acetic acid and piperidine to obtain a compound 2;
step (3), carrying out an acyl chlorination reaction on DMXAA and thionyl chloride to obtain acyl chlorinated DMXAA; acetonitrile is used as a reaction solvent, and the compound 2 reacts with acyl-chlorinated DMXAA under the catalysis of triethylamine to obtain BDPVDA shown in a formula I.
3. The method for preparing a vascular disrupting agent-bonded fluoroborole derivative as claimed in claim 2, wherein in step (1), the molar ratio of 4-hydroxybenzaldehyde to 2, 4-dimethylpyrrole, 2, 3-dichloro-5, 6-dicyano-p-benzoquinone, boron trifluoride diethyl etherate, triethylamine is 1:2-3:1-2:50-100: 50-100.
4. The method for preparing a vascular disrupting agent-bonded fluoroborole derivative as claimed in claim 3, wherein in step (1), the molar ratio of 4-hydroxybenzaldehyde to 2, 4-dimethylpyrrole, 2, 3-dichloro-5, 6-dicyano-p-benzoquinone, boron trifluoride diethyl etherate, triethylamine is 1:2.2:1:50: 50.
5. The method for preparing a vascular disrupting agent-bonded fluoroboropyrrole derivative according to claim 2, wherein in the step (1), 4-hydroxybenzaldehyde, 2, 4-dimethylpyrrole and trifluoroacetic acid are added to a tetrahydrofuran solution as a reaction solvent, and the mixture is reacted at room temperature for 10-18 hours, and a 2, 3-dichloro-5, 6-dicyan-p-benzoquinone tetrahydrofuran solution is added to the mixture and reacted at room temperature for 3-8 hours; adding triethylamine and boron trifluoride diethyl etherate into the reaction solution under the ice bath condition, and continuing to react for 12-24 hours; removing tetrahydrofuran by rotary evaporation; purifying by column chromatography to obtain compound 1.
6. The method for preparing a vascular disrupting agent-bonded fluoroboropyrrole derivative according to claim 2, wherein in step (2), the molar ratio of acetic acid, piperidine, 4-N, N-dimethylaminobenzaldehyde, compound 1 is 1-20:1-20:2-3: 1;
the reaction temperature is 110-130 ℃, and the reaction time is 3-8 hours.
7. The method for preparing a vascular disrupting agent-bonded fluoroboropyrrole derivative according to claim 6, wherein in step (2), the molar ratio of acetic acid, piperidine, 4-N, N-dimethylaminobenzaldehyde and compound 1 is 8.5-9:5-5.5:2.4: 1.
8. The method for preparing a vascular disrupting agent-bonded fluoroboropyrrole derivative according to claim 6, wherein in the step (2), the reaction temperature is 120 ℃ and the reaction time is 4 hours.
9. The method for preparing a vascular disrupting agent-bonded fluoroborole derivative as claimed in claim 2, wherein in step (3), the molar ratio of thionyl chloride to DMXAA is 2-3: 1.
10. The method for preparing a vascular disrupting agent-bonded fluoroborole derivative as claimed in claim 9, wherein in step (3), the molar ratio of thionyl chloride to DMXAA is 2: 1.
11. The method for preparing a vascular disrupting agent-bonded fluoroborole derivative as claimed in claim 2, wherein in step (3), the molar ratio of DMXAA to compound 2 is 1:1 to 1.2;
the molar ratio of the triethylamine to the compound 2 is 5: 1-2;
the reaction temperature of acyl-chlorinated DMXAA and the compound 2 is 50-60 ℃, and the reaction time is 5-8 hours.
12. The method for preparing a vascular blocker-bonded fluoroborole derivative according to claim 11, wherein in step (3), the molar ratio of DMXAA to compound 2 is 1: 1.
13. The method for preparing a vascular disrupting agent-bonded fluoroboropyrrole derivative according to claim 11, wherein the molar ratio of triethylamine to compound 2 in step (3) is 5: 1.
14. The BDPVDA nano particle coated by methoxy-poly (ethylene glycol) -poly (2-diisopropylamino) methyl methacrylate is characterized by being prepared by the following method: dissolving the vascular blocking agent bonded BODIPY derivative of claim 1 and mPEG-PPDA in a tetrahydrofuran solution, injecting the tetrahydrofuran solution into water under ultrasonic conditions, and removing the tetrahydrofuran under reduced pressure to obtain the mPEG-PPDA coated BDPVDA nanoparticles.
15. The mPEG-PPDA coated BDPVDA nanoparticle according to claim 14, characterized in that the mass ratio of BDPVDA to methoxy-poly (ethylene glycol) -poly (2-diisopropylamino) methyl methacrylate is 1: 25; the volume ratio of the tetrahydrofuran to the water is 1: 8-16.
16. The use of the vascular disrupting agent-linked BODIPY derivative of claim 1 in the preparation of a tumor treatment drug with type I photodynamic/vascular disrupting synergistic effect mediated by fluorescence imaging.
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