Porphyrin derivative boron complex, nano particle, preparation method and application in thrombolytic therapy

Abstract

The invention provides a porphyrin derivative boron complex, nanoparticles, a preparation method and application in thrombolytic therapy, and belongs to the technical field of chemical synthesis and biomedicine. The structural formula of the porphyrin derivative boron complex is as shown in formula 1. The method comprises the following steps: dissolving 2, 5-dihydroxy terephthalaldehyde in ethanol, dropwise adding a TPP-NH2 ethanol solution for reaction to obtain 2TPP, and then performing reflux reaction on the 2TPP and manganese dichloride under the action of a solvent to obtain a porphyrin derivative 2TPP-Mn; and finally, adding the 2TPP-Mn into triethylamine, and then adding BF3. OEt2 for reaction to obtain the porphyrin derivative boron complex. The invention also provides nanoparticles prepared from the porphyrin derivative boron complex. The nanoparticles prepared by the method have the combined thrombolysis effect of photodynamic, photo-thermal and nitric oxide gas release.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis and biomedicine, and specifically relates to a porphyrin derivative boron complex, nanoparticles and a preparation method thereof, and application thereof in thrombolytic therapy. Background Art

[0002] Thrombosis-related diseases, such as ischemic stroke, acute myocardial infarction, and deep vein thrombosis, remain the leading causes of death or disability worldwide. Given the high morbidity and mortality of thrombotic diseases, the rational design of efficient and safe novel therapeutic strategies has always been a top priority for clinical antithrombotic therapy. Currently, clot-disrupting drugs represented by fibrinolytic drugs are widely used in clinical practice. However, traditional antithrombotic drugs have long suffered from unsatisfactory therapeutic effects and high bleeding risks due to the shortcomings of off-target biodistribution, poor thrombus penetration, and narrow therapeutic window. The subsequent life-threatening bleeding risks and complex physical monitoring also indicate the clinical limitations of this treatment. Near-infrared (NIR) light-mediated nanomedicines rapidly convert light energy into thermal therapy through the Landau damping effect, providing a new therapeutic strategy for thrombotic treatment. Photothermal photosensitizers (PSs) have been widely studied for near-infrared (NIR) thrombus imaging and hyperthermic thrombolysis. There is increasing evidence that a sharp increase in the temperature of thrombus tissue can effectively loosen the thrombus by destroying the non-covalent interaction of fibrin, which can not only produce high-temperature thrombolysis but also promote the deep penetration of antithrombotic drugs in the thrombus. More importantly, photodynamic therapy (PDT) targeting the fibrin trunk of the blood clot mediated by reactive oxygen species (ROS) produced by photosensitizers under light conditions can effectively avoid subsequent embolism caused by fragments after photothermal treatment. PTT / PDT dual-mode treatment has been recognized as an effective thrombolytic treatment method. It is worth noting that photothermal penetration of deep thrombi is a safe and non-invasive thrombus penetration method. Combined photothermal / photodynamic therapy can significantly improve the thrombolytic effect and prevent secondary embolism of larger fragments. In addition, studies have shown that healthy vascular endothelial cells continuously produce low concentrations of NO to prevent thrombosis. As an important vascular protective molecule, nitric oxide (NO) plays a key role in maintaining vascular homeostasis, inhibiting platelet activation, and regulating vasodilation.

[0003] Porphyrin and its porphyrin derivatives are used as phototherapy agents due to their absorption in the red light region. In addition, transition metal materials are favored because of their rich excited state properties, such as high luminescence quantum efficiency, ultra-long luminescence lifetime, high stability luminescence, and multicolor luminescence. In addition, transition metals form porphyrin metal rings, which can not only improve the photothermal performance, but also utilize the variable valence characteristics of transition metals to further consume hydrogen peroxide and reactive oxygen. Previous studies have confirmed that exogenous supplementation of l-arginine (LA) can react with reactive oxygen species (ROS) and nitric oxide synthase to produce nitric oxide (NO), which plays an important role in cardiovascular and cerebrovascular diseases by improving endothelial function, reducing oxidative stress, and regulating vasodilation. In 2022, Professor Han Heyou's team at Huazhong Agricultural University first proposed a porphyrin COF engineered melanin nanoplatform, which performs non-invasive thrombolytic therapy through heat therapy and ROS under near-infrared light irradiation. Therefore, porphyrin boron complexes may serve as a new generation of phototherapy materials, opening up a new path with clinical development potential for thrombolytic therapy. Summary of the invention

[0004] The present invention provides a porphyrin derivative boron complex, nanoparticles, a preparation method and an application of the porphyrin derivative boron complex in thrombolytic therapy. The porphyrin derivative boron complex 2TPP-Mn-B of the present invention introduces Mn metal to achieve the effects of photothermal and photodynamic synergistic therapy. At the same time, the valence-changing characteristics of manganese metal are utilized to eliminate inflammation at the thrombus site.

[0005] The present invention first provides a porphyrin derivative boron complex, the structural formula of which is shown in Formula 1:

[0006]

[0007] The present invention also provides a method for preparing a porphyrin derivative boron complex, comprising the following steps:

[0008] Step 1: dissolving 2,5-dihydroxyterephthalaldehyde in a solvent, slowly adding TPP-NH2 ethanol solution dropwise, heating under reflux reaction, and obtaining a bisporphyrin Schiff base ligand 2TPP;

[0009] Step 2: subjecting the biporphyrin Schiff base ligand 2TPP and manganese dichloride in step 1 to a reflux reaction under the action of a solvent to obtain a porphyrin derivative 2TPP-Mn;

[0010] Step 3: dissolve the porphyrin derivative 2TPP-Mn obtained in step 2 in a solvent, cool in an ice bath, add triethylamine and stir, then add BF3·OEt2 and stir to obtain a porphyrin derivative boron complex 2TPP-Mn-B.

[0011] Preferably, the reaction temperature in step 1 is 75° C.-85° C., and the reaction time is 8-10 h.

[0012] Preferably, the molar ratio of 2,5-dihydroxyterephthalaldehyde and TPP-NH2 in step 1 is 1:2.

[0013] Preferably, the molar ratio of the biporphyrin Schiff base ligand 2TPP and manganese dichloride in step 2 is 1:(3-5).

[0014] Preferably, the temperature of the reflux reaction in step 2 is 120° C.-130° C., and the reaction time is 6-8 h.

[0015] Preferably, the molar ratio of 2TPP to manganese dichloride in step 2 is 1:(3-5).

[0016] The present invention also provides a nanoparticle prepared from the porphyrin derivative boron complex shown in Formula 1.

[0017] The present invention also provides a method for preparing nanoparticles, comprising:

[0018] The porphyrin derivative boron complex and distearoylphosphatidylethanolamine-polyethylene glycol shown in formula 1 are dissolved in a solvent respectively, then the two are mixed and added into water, and L-arginine solution is added to dissolve and ultrasonicate, and then stirred, and finally RGD targeting peptide is added and stirred to obtain nanoparticles.

[0019] The present invention also provides the use of the nanoparticles in preparing medicines for treating thrombotic diseases.

[0020] Beneficial effects of the present invention

[0021] The present invention provides a porphyrin derivative boron complex, nanoparticles, a preparation method and an application in thrombolytic therapy. The porphyrin derivative boron complex has a structural formula as shown in Formula I. The method comprises the following steps: firstly dissolving 2,5-dihydroxyterephthalaldehyde in ethanol, adding TPP-NH2 ethanol solution dropwise to react, obtaining a purple solid 2TPP, and then subjecting it to a reflux reaction with manganese dichloride under the action of a solvent. After the reaction is completed, a porphyrin derivative 2TPP-Mn is obtained; finally, 2TPP-Mn and triethylamine are stirred, and BF3·OEt2 is added to obtain a porphyrin derivative boron complex 2TPP-Mn-B. Test results show that 2TPP-Mn-B NPs have good photothermal capacity and excellent active oxygen generation capacity under 635nm laser irradiation, which indicates that the material can have a good dual-mode PTT / PDT therapeutic effect on thrombolysis.

[0022] The present invention also provides nanoparticles formed by encapsulating a porphyrin derivative boron complex and a nitric oxide (NO) release precursor L-arginine into an amphiphilic polymer distearoylphosphatidylethanolamine-polyethylene glycol. The nanoparticles of the present invention have excellent photothermal and photodynamic properties, release nitric oxide in response to reactive oxygen species (ROS), and can perform photothermal / photodynamic, nitric oxide gas therapy multi-mode thrombolysis. The prepared nanoparticles have a combined thrombolytic effect of photodynamic, photothermal and nitric oxide gas release. The nanoassembly designed by the present invention has multiple advantages such as simple preparation, strong drug co-loading capacity, long body circulation, targeted accumulation of thrombus, photothermal enhancement of thrombus penetration and thrombolysis, and has a high therapeutic effect. As expected, 2TPP-Mn-BNPs can not only remove ROS at the thrombus site and eliminate inflammation, but also have a photothermal / antiplatelet synergistic thrombolytic effect in vivo. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The particle size potential diagram of 2TPP-Mn-B NPs prepared in Example 1 of the present invention;

[0024] Figure 2 The ultraviolet absorption spectrum and fluorescence emission spectrum of 2TPP-Mn-B NPs prepared in Example 1 of the present invention in aqueous solution;

[0025] Figure 3 This is a graph of ROS generation in the 2TPP-Mn-B NPs aqueous solution prepared in Example 1 of the present invention;

[0026] Figure 4 This is a photothermal data diagram of 2TPP-Mn-B NPs prepared in Example 1 of the present invention in aqueous solution;

[0027] Figure 5 This is a thermal imaging data diagram of 2TPP-Mn-B NPs prepared in Example 1 of the present invention in an aqueous solution;

[0028] Figure 6 This is a test diagram of the antioxidant capacity of 2TPP-Mn-B NPs prepared in Example 1 of the present invention;

[0029] Figure 7 This is a test graph of nitric oxide release of 2TPP-Mn-B NPs prepared in Example 1 of the present invention;

[0030] Figure 8 This is a hemolysis test diagram of 2TPP-Mn-B NPs prepared in Example 1 of the present invention;

[0031] Fig. 9 This is a graph showing the thrombolysis data of 2TPP-Mn-B NPs prepared in Example 1 of the present invention under different conditions;

[0032] Fig.10 This is an in vivo photothermal imaging test image of 2TPP-Mn-B NPs prepared in Example 1 of the present invention;

[0033] Fig.11 This is the in vivo thrombolytic effect diagram of 2TPP-Mn-B NPs;

[0034] Fig.12 This is a graph showing the in vivo hemodynamic changes of 2TPP-Mn-B NPs prepared in Example 1 of the present invention;

[0035] Fig.13 This is a line graph of the in vivo hemodynamic changes of 2TPP-Mn-B NPs prepared in Example 1 of the present invention;

[0036] Fig.14 The biporphyrin Schiff base ligand 2TPP prepared in Example 1 of the present invention 1 H NMR spectrum.

[0037] Fig.15 This is the mass spectrum of the biporphyrin Schiff base ligand 2TPP prepared in Example 1 of the present invention.

[0038] Fig.16 The mass spectrum of the porphyrin derivative 2TPP-Mn prepared in Example 1 of the present invention (Note: Fig.16 The relative atomic mass of 2TPP-Mn is 1495.37, and the mass spectrum shows M 2TPP-Mn +39 (potassium ion).

[0039] Fig.17 The mass spectrum of the porphyrin derivative boron complex 2TPP-Mn-B prepared in Example 1 of the present invention (Note: Fig.17 The relative atomic mass of 2TPP-Mn-B is 1542.36, and the mass spectrum shows M 2TPP-Mn-B -19 (fluorine atom). DETAILED DESCRIPTION

[0040] The present invention first provides a porphyrin derivative boron complex having a molecular formula of C 96 H 59 BF2Mn2N 10 O2, with a relative molecular mass of 1542.36 g / mol, has a structural formula as shown in Formula 1:

[0041]

[0042] The present invention also provides a method for preparing a porphyrin derivative boron complex, comprising the following steps:

[0043] Step 1: dissolving 2,5-dihydroxyterephthalaldehyde in a solvent, slowly adding an aminoporphyrin (TPP-NH2) ethanol solution dropwise, heating and refluxing to obtain a biporphyrin Schiff base ligand 2TPP;

[0044] Step 2: subjecting the biporphyrin Schiff base ligand 2TPP and manganese dichloride in step 1 to a reflux reaction under the action of a solvent to obtain a porphyrin derivative 2TPP-Mn;

[0045] Step 3: dissolve the porphyrin derivative 2TPP-Mn obtained in step 2 in a solvent, cool in an ice bath, add triethylamine and stir, then add boron trifluoride ether (BF3·OEt2) and stir to obtain the porphyrin derivative boron complex 2TPP-Mn-B.

[0046] The specific reaction process is as follows:

[0047]

[0048] According to the present invention, 2,5-dihydroxyterephthalaldehyde is dissolved in a solvent, then slowly added dropwise to a TPP-NH2 ethanol solution, and heated to reflux for reaction. The reaction temperature is preferably 75°C-85°C, and the reaction time is preferably 8-10 hours. After the reaction is cooled to room temperature, a purple precipitate is precipitated, and the precipitate is washed several times with a large amount of ethanol or other solvents. The solid obtained by drying is the biporphyrin Schiff base ligand 2TPP. The solvent is preferably anhydrous ethanol, and the molar ratio of 2,5-dihydroxyterephthalaldehyde to aminoporphyrin TPP-NH2 is preferably 1:2.

[0049] According to the present invention, the above-obtained biporphyrin Schiff base ligand 2TPP and manganese dichloride are added to a reaction container, and then a solvent is added, the solvent is preferably anhydrous N,N-dimethylformamide, and the reaction is refluxed. The reaction temperature is preferably 120°C-130°C, and the reaction time is preferably 6-8h. When the reaction is completed and cooled to room temperature, the solvent in the system is removed by a rotary evaporator and dried to obtain a green solid, which is 2TPP-Mn. The molar ratio of the biporphyrin Schiff base ligand 2TPP to manganese dichloride is preferably 1: (3-5).

[0050] According to the present invention, the above-obtained 2TPP-Mn is added to a reaction vessel and dissolved in a DMF solvent, and then the mixture is cooled to 0°C in an ice bath, and triethylamine is added dropwise, and then boron trifluoride ether BF3·OEt2 is added dropwise to the reactor for mixed reaction, wherein the reaction temperature is preferably room temperature, and the reaction time is preferably 4-6 hours, and then the product is extracted with dichloromethane and water, and the solvent in the system is removed by a rotary evaporator, and the product is subjected to silica gel column chromatography and dried to obtain a dark green solid product, which is 2TPP-Mn-B. The molar ratio of the 2TPP-Mn, boron trifluoride ether, and triethylamine is preferably 1:(2-5):(2.5-3.5).

[0051] The present invention also provides a nanoparticle prepared from the porphyrin derivative boron complex shown in Formula 1.

[0052] The present invention also provides a method for preparing nanoparticles, comprising:

[0053] The porphyrin derivative boron complex and distearoyl phosphatidylethanolamine-polyethylene glycol shown in formula 1 are dissolved in a solvent, and the solvent is preferably tetrahydrofuran, and then the two are mixed and added to water, and L-arginine solution is added to dissolve and ultrasonic, and the ultrasonic time is preferably 10-15min, and then stirred, and the stirring is preferably stirred and volatilized overnight at room temperature, and finally RGD targeting peptide is added and stirred, and the stirring time is preferably 16h. After the stirring, the nanoparticles are dialyzed with a 1000 molecular weight dialysis membrane and filtered with a filter (0.45 / 0.22μm) to obtain nanoparticles with uniform and stable particle size. The mass g of the porphyrin derivative boron complex shown in formula 1: the mass g of distearoyl phosphatidylethanolamine-polyethylene glycol: the volume mL of the L-arginine solution: the mass g of c (RGDfC) is preferably 0.001:0.002:0.5:0.0015; the concentration of the L-arginine solution is preferably 2mg / mL.

[0054] The present invention also provides the use of the nanoparticles in preparing medicines for treating thrombotic diseases.

[0055] The present invention is further described by way of the following examples, which do not limit the present invention in any way. Without departing from the technical solution of the present invention, any modification or change made to the present invention that is easily implemented by a person of ordinary skill in the art will fall within the scope of the claims of the present invention.

[0056] Example 1

[0057] Add aminoporphyrin (0.2mmol, 0.1258g) to a round-bottom flask filled with 30mL of anhydrous ethanol, add 2,5-dihydroxyterephthalaldehyde ligand (0.1mmol, 0.0166g) dropwise, heat and reflux to react for 8h, wait for the reaction to cool to room temperature, precipitate a purple precipitate and filter it, and wash it several times with a large amount of ethanol or other solvents. The solid obtained by drying is the bisporphyrin Schiff base ligand 2TPP.

[0058] Add the biporphyrin Schiff base ligand 2TPP (0.1mmol, 0.1389g) and manganese dichloride (0.4mmol, 0.0511g) to a 100mL single-mouth bottle, and use 20mL DMF as the solvent of the reaction system to reflux for 8h. After the reaction is completed and cooled to room temperature, the solvent in the system is removed by a rotary evaporator and dried to obtain a green solid, which is 2TPP-Mn.

[0059] 2TPP-Mn (0.1 mmol, 0.1345 g) was added to a 100 mL beaker and dissolved in DMF solvent. The mixture was cooled to 0°C and triethylamine (0.3 mmol, 0.03 g) was added dropwise. Then, boron trifluoride ether (0.3 mmol, 0.0426 g) was added dropwise. Ultra-dry dichloromethane was used as the reaction solvent. The reaction temperature was room temperature. The reaction time was 4 h to obtain the product. The solvent in the system was removed by a rotary evaporator, and the product was dried. The product was purified by silica gel column chromatography to obtain a porphyrin derivative boron complex 2TPP-Mn-B with a yield of 60%. The molecular formula was C 77 H 48 FeIrN7OS2, the relative molecular mass is 1542.36g / mol. The H NMR spectrum of the biporphyrin Schiff base ligand 2TPP prepared in Example 1, the mass spectrum of the biporphyrin Schiff base ligand 2TPP, the mass spectrum of the porphyrin derivative 2TPP-Mn and the mass spectrum of the porphyrin derivative boron complex 2TPP-Mn-B are shown in FIG. Fig.14 , 15 , 16 and 17.

[0060] Example 2

[0061] The preparation process and conditions are the same as those in Example 1, except that the reaction time in step 1 is 10 h.

[0062] Example 3

[0063] The preparation process and conditions are the same as those in Example 1, except that the reaction time in step 2 is 6 h.

[0064] Example 4

[0065] The preparation process and conditions are the same as those in Example 1, except that the reaction temperature in step 1 is 85°C.

[0066] Example 5

[0067] The preparation process and conditions are the same as those in Example 1, except that the reaction temperature in step 2 is 125°C.

[0068] Example 6

[0069] The preparation process and conditions are the same as those in Example 1, except that the reaction time in step 2 is 7 h and the reaction temperature is 130°C.

[0070] The performance of the metal iridium complex prepared in Example 1 was characterized as follows:

[0071] 1. Preparation and properties of metal iridium complex nanoparticles:

[0072] The preparation method of 2TPP, 2TPP-Mn and 2TPP-Mn-B in the present invention is to prepare water-soluble nanoparticles in a simple and convenient manner. The specific operation is as follows: 2TPP (0.0010 g), 2TPP-Mn (0.0010 g), 2TPP-Mn-B (0.0010 g) and distearoylphosphatidylethanolamine-polyethylene glycol (0.0020 g) are added to a 20 mL vial, respectively, and dissolved in 1 ml of tetrahydrofuran, and then added dropwise to the prepared water, and ultrasonically dissolved with L-arginine solution (2 mg / mL, 0.5 mL). Then it was poured into ultrapure water, ultrasonicated (150W) for 10 minutes, stirred and evaporated overnight at room temperature, and then RGD targeting peptide (0.0015 g) was added to the water and stirred for 16 hours. After the stirring, the nanoparticles were dialyzed with a 1000 molecular weight dialysis membrane and filtered with a filter (0.45 / 0.22 μm) to obtain 2TPP NPs, 2TPP-Mn NPs, and 2TPP-Mn-B NPs with uniform particle size and stability, respectively.

[0073] The particle size and potential of 2TPP-Mn-B NPs in the present invention, Figure 1 The 2TPP NPs ( Figure 1 A), 2TPP-MnNPs( Figure 1 B), 2TPP-Mn-B NPs( Figure 1 Particle size and potential diagram (C) Figure 1 D).

[0074] 2. Photophysical properties of metal iridium complexes:

[0075] Figure 2 is the ultraviolet absorption of the 2TPP-Mn-B NPs in aqueous solution ( Figure 2 A) and fluorescence emission ( Figure 2 B), the absorption disappears due to the entry of Mn metal into the porphyrin core, and the emission spectrum is quenched due to the introduction of the metal heteronucleus.

[0076] Figure 3 The 2TPP NPs prepared in the present invention are respectively Figure 3 C) 2TPP-Mn NPs( Figure 3B), 2TPP-Mn-B NPs( Figure 3 A), In vitro singlet oxygen production experiment under light and DPBF conditions and the related kinetic curves ( Figure 3 D) from Figure 3 It can be seen that 2TPP-Mn-B NPs have excellent singlet oxygen generation ability.

[0077] 3. Photothermal properties of metal iridium complexes:

[0078] Figure 4 The photothermal properties of 2TPP-Mn-B NPs were measured. Compared with the control group 2TPP NPs and 2TPP-MnNPs, the drug group 2TPP-Mn-B NPs had better photothermal generation ability ( Figure 4 A), and the concentration dependence at different concentrations ( Figure 4 B), the higher the power, the higher the heat generation and temperature rise ( Figure 4 C), and after five cycles of heating and cooling, it can be seen that the drug has good photothermal cycling ability ( Figure 4 D).

[0079] Figure 5 This is the thermal imaging image of the photothermal data of 2TPP-Mn-B NPs. Under illumination conditions, the solution temperature increases with the extension of illumination time.

[0080] 4. Antioxidant performance experiment of 2TPP-Mn-B NPs:

[0081] Figure 6 The test kit was used to test the antioxidant capacity of 2TPP-Mn-B NPs of the present invention. When the drug concentration reached 200 μg / mL, the consumption rate of DPPH could reach 75.8% ( Figure 6 A). The consumption rate of hydrogen peroxide was detected to be nearly 75.2% ( Figure 6 B). The content of reactive oxygen species, especially hydrogen peroxide, at the thrombus site is much higher than that of normal tissues. The consumption of hydrogen peroxide will effectively improve the maintenance of the thrombus site. At the same time, it proves that 2TPP-Mn-B NPs have good antioxidant and anti-inflammatory capabilities, and can have a good therapeutic effect on inflammation in the body.

[0082] 5. NO release experiment of 2TPP-Mn-B NPs: Figure 7 This is a graph showing the NO release experiment of 2TPP-Mn-B NPs of the present invention. Figure 7 A The concentration of NO measured by the Griess method is positively correlated with the absorption at 540 nm. -2 ) irradiation, Figure 7The Griess method was used to detect that 2TPP-Mn-B NPs can effectively release NO( Figure 7 B) and Figure 7 C test results show that 2TPP-Mn-B NPs basically do not release NO when vitamin C is added and 4°C. Figure 7 The NO produced by the D test showed regular changes with the on and off of laser irradiation, which indicated that the laser-triggered 2TPP-Mn-B NPs could effectively trigger the release of NO from L-arginine and had controllable NO production capability.

[0083] 6. Hemolysis experiment of 2TPP-Mn-B NPs:

[0084] Figure 8 For the hemolysis test of 2TPP-Mn-B NPs of the present invention, different concentrations of 2TPP-Mn-B NPs were co-incubated with red blood cells in hot water at 37°C for 2 hours, the PBS group was the negative control group, and the water group was the positive control group, wherein small figure a) represents the intuitive graph of the corresponding concentration of 2TPP-Mn-B NPs, and small figure b) represents the intuitive graph obtained by centrifugation after the red blood cells of the corresponding concentration of 2TPP-Mn-B NPs were co-incubated in hot water at 37°C for 2 hours, wherein the measured drug hemolysis rate was still less than 5% at 200 μg / mL, having good biosafety.

[0085] 7. In vitro thrombolysis experiment of 2TPP-Mn-B NPs:

[0086] Fig. 9 This is an in vitro thrombolytic test of the 2TPP-Mn-B NPs of the present invention. Fig. 9 A is the size and shape of the thrombus when not illuminated, such as Fig. 9 B and C are the 2TPP-Mn-B NPs group and the control group. The 2TPP NPs, 2TPP-Mn NPs, UK, and PBS groups simultaneously activated PDT / PTT dual-mode thrombolysis under laser irradiation. Compared with the control group, the thrombolysis rate was higher, reaching 70.8%. Fig. 9 D tested the absorbance of fibrin and hemoglobin in the thrombolytic fluid, and further experimental results showed that 2TPP-Mn-B NPs had good in vitro thrombolytic ability.

[0087] 8. In vivo photothermal imaging experiment of 2TPP-Mn-B NPs:

[0088] Fig.10 This is the in vivo photothermal imaging test image of 2TPP-Mn-B NPs. The temperature change of the thrombus site under NIR-II light stimulation was monitored by an infrared thermal imager. The results showed that the temperature of the thrombus site gradually increased with the extension of the light exposure time.

[0089] 9. In vivo thrombolytic experiment of 2TPP-Mn-B NPs:

[0090] Fig.11 The in vivo thrombolytic effect of 2TPP-Mn-B NPs is shown in Figure 2. After successful thrombus formation, drugs were injected into the tail vein and laser (635nm 0.8W cm -2 ) irradiated the thrombus site, and the results showed that it had a good thrombolytic effect.

[0091] 10. In vivo thrombolytic hemodynamics experiment of 2TPP-Mn-B NPs:

[0092] Fig.12 The following is a diagram of the hemodynamic changes of 2TPP-Mn-B NPs in vivo, where the blue diagram is a color diagram of the hemodynamic changes and the gray diagram is the corresponding black and white diagram. After successful thrombus formation, the blood flow at the thrombus site was the lowest as detected by the laser speckle imaging device. As the laser irradiation time increases, the thrombus dissolves and the blood flow gradually recovers. Fig.13 As shown, the thrombolysis rate of the 2TPP-Mn-B NPs group can reach 78%, reflecting that gas therapy has a good synergistic thrombolytic effect.

Claims

1. A porphyrin derivative boron complex, It is characterized in that Its structural formula is shown in Formula 1:

2. A method for preparing a porphyrin derivative boron complex according to claim 1, It is characterized in that The following steps are involved: Step 1: Dissolve 2,5-dihydroxyterephthalaldehyde in solvent and slowly add TPP-NH 2 The ethanol solution is heated to reflux to obtain the bi-porphyrin Schiff base ligand 2TPP; Step 2: subjecting the biporphyrin Schiff base ligand 2TPP and manganese dichloride in step 1 to a reflux reaction under the action of a solvent to obtain a porphyrin derivative 2TPP-Mn; Step 3: Dissolve the porphyrin derivative 2TPP-Mn obtained in step 2 in a solvent, cool in an ice bath, add triethylamine and stir, then add BF 3 ·OEt 2 The mixture was stirred to obtain the porphyrin derivative boron complex 2TPP-Mn-B.

3. A method for preparing a porphyrin derivative boron complex according to claim 2, It is characterized in that The reaction temperature in step 1 is 75°C-85°C, and the reaction time is 8-10h.

4. A method for preparing a porphyrin derivative boron complex according to claim 2, It is characterized in that The 2,5-dihydroxyterephthalaldehyde and TPP-NH 2 The molar ratio is 1:

2.

5. A method for preparing a porphyrin derivative boron complex according to claim 2, It is characterized in that The molar ratio of the biporphyrin Schiff base ligand 2TPP and manganese dichloride in step 2 is 1:(3-5).

6. A method for preparing a porphyrin derivative boron complex according to claim 2, It is characterized in that The temperature of the reflux reaction in step 2 is 120°C-130°C, and the reaction time is 6-8h.

7. A method for preparing a porphyrin derivative boron complex according to claim 2, It is characterized in that The molar ratio of 2TPP to manganese dichloride in step 2 is 1:(3-5).

8. A nanoparticle, It is characterized in that It is prepared from the porphyrin derivative boron complex represented by formula 1 as claimed in claim 1.

9. A method for preparing nanoparticles according to claim 8, It is characterized in that include: The porphyrin derivative boron complex and distearoylphosphatidylethanolamine-polyethylene glycol shown in formula 1 are dissolved in a solvent respectively, then the two are mixed and added into water, and L-arginine solution is added to dissolve and ultrasonicate, and then stirred, and finally RGD targeting peptide is added and stirred to obtain nanoparticles.

10. Use of the nanoparticles according to claim 8 in the preparation of drugs for treating thrombotic diseases.

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