A boron-containing preparation capable of increasing boron accumulation in tumors, and its preparation method and application

Abstract

The present invention discloses a boron-containing preparation that can increase intratumoral boron accumulation, as well as its preparation method and application. The boron-containing preparation can be prepared into injectable solutions, nanoparticles, suspensions, and the like that can be diluted as needed. The preparation method is simple, easily repeatable and achievable, and readily marketable. The boron-containing preparation retains the tumor-targeting properties of phenylboronic acid derivatives while reducing their post-cytosolic excretion, demonstrating improved tumor cell uptake. It is a novel boron capture agent that can be used in boron neutron capture therapy to increase boron accumulation in tumor sites.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a boron-containing preparation capable of increasing boron accumulation in tumors, and a preparation method and application thereof. Background Art

[0002] Tumors, especially malignant tumors, are a major threat to human health, placing a heavy burden on patients, their families, and society. Radiotherapy is one of the mainstays of clinical cancer treatment, with over 70% of malignant tumor patients requiring radiotherapy during their disease course. Boron Neutron Capture Therapy (BNCT) is a precision tumor radiotherapy technology that combines the advantages of "biological targeting" and "heavy ion radiotherapy." It has been called the "fifth therapy" after surgery, traditional radiotherapy, chemotherapy, and immunotherapy. Its multiple advantages, including high precision, high efficacy, and a short treatment course, have attracted widespread attention in the radiotherapy field worldwide.

[0003] Boron neutron capture therapy is a binary biological targeted radiotherapy technology based on nuclear capture and nuclear fission reactions. The stable non-radioactive isotope boron 10 ( 10 B) and low-energy thermal neutrons undergo capture reactions, inducing nuclear decay and nuclear fission, producing high-energy α particles ( 4 He) and recoil lithium nuclei ( 7 These particles are all high energy transmission line density rays with a range of only 5 to 9 μm. They have the characteristics of high energy and short range, and their killing range is limited to high uptake. 10 B tumor cells, but no or low uptake 10 B causes minimal damage to normal tissues. It utilizes the formation of a clear boron concentration gradient between tumor cells and normal cells to achieve precise and efficient attack on tumor cells, making it a very promising treatment method.

[0004] The application of BNCT technology requires the following key points: ① Suitable boron delivery agents to enable it to be highly concentrated in tumor tissue. ② Neutron source that can provide neutron beams of a certain energy. ③ Establish an accurate radiation dose measurement model. With the clinical application of accelerator source neutron sources, the limitations of boron delivery agents have become the main shortcoming in BNCT. The development of excellent new boron delivery agents is of great scientific significance. The ideal boron delivery agent should meet the following requirements: low uptake in normal tissues and high uptake in tumor tissues; the boron concentration in tumors should reach about 20μg 10B / g tumor tissue; the boron tumor-normal tissue concentration ratio (tumor-normal tissue, T / N) and the boron tumor-blood concentration ratio (tumor-blood, T / B) cannot be lower than 3; it can be quickly cleared from blood and normal tissues with low systemic toxicity; in addition to being taken up by tumor cells in the dividing stage, it can also be absorbed by hypoxic tumor cells.

[0005] Currently approved boron-trapping agents for clinical use primarily include 4-boronophenylalanine (BPA) and sodium borocaptate (BSH). Although BSH boasts a high boron loading per molecule, its tumor cell affinity and penetration are inferior to BPA. BPA, with its molecular structure containing a phenylalanine backbone containing one boron atom, exhibits a high affinity for the L-type amino acid transporter 1 (LAT1). Therefore, BPA is primarily recognized by the LAT1 amino acid transporter, which is overexpressed in many cancer cells, allowing for efficient cellular internalization. While it exhibits a natural targeting ability for tumor tissue cells with high amino acid requirements, its clinical application is limited by its low boron content, poor water solubility, and short retention time. A possible explanation for the short intracellular retention of BPA is the antiport mechanism of amino acid transporters, including LAT1. While LAT1 imports extracellular substrates (such as BPA) into the cytoplasm, it also exports intracellular substrates. Similarly, if the extracellular BPA concentration decreases, intracellular BPA should be exchanged for extracellular amino acids. Based on this possible mechanism, studies have demonstrated that BPA preparations complexed with polymers can inhibit this efflux, thereby increasing the amount of accumulation and retention time in tumors.

[0006] Traditional boron capture agents have limited tumor-specific distribution and are quickly cleared from the body. The development of boron capture agents that can increase tumor distribution will further promote the BNCT tumor treatment effect and has important scientific research significance and application prospects.

[0007] Given the high clinical dose requirements of BPA and its poor solubility, preliminary work in this study investigated various dosage forms and excipients for BPA delivery in vivo, including vesicles, liposomes, micelles, inclusion complexes, and emulsions. However, BPA solubilization and tumor uptake were suboptimal. Several patents have reported the use of amino-modified polyethylene glycol (PEG) to form amide bonds with carboxyl-containing phenylboronic acid derivatives for PEGylation of glycoproteins, or the use of PEG to modify nanoformulations containing phenylboronic acid derivatives, such as liposomes and silica nanoparticles, to enhance their long-term circulation in vivo. Our research has found that the use of polyethylene glycol (PEG)-based excipients such as polyethylene glycol (PEG), Tween, poloxamer, fatty alcohol polyoxyethylene ether (AEO), polyoxyethylene hydrogenated castor oil, and polyoxyethylene alkyl ether can form reversibly bonded complexes with the borate (-B(OH)2) structure of phenylboronic acid derivatives, including BPA, increasing the solubility of BPA. Compared with chemical bonding, the preparation is simple, the drug can be released through dissociation, and the stability, boron loading capacity, and tumor uptake capacity are all higher, which is expected to achieve more ideal boron delivery in BNCT. Summary of the Invention

[0008] The present invention provides a method for preparing a boron-containing preparation that can increase the amount of boron accumulation in tumors. The obtained boron-containing preparation can increase the distribution and accumulation of boron in tumors, thereby greatly promoting the efficacy of BNCT. The present invention combines a tumor-targeting phenylboronic acid derivative with a polyoxyethylene segment ( The high molecular compound complex (where n represents the number of repeating units -OCH2CH2-) can promote the uptake of boron drugs by tumor cells and reduce the excretion of boron drugs, thereby increasing the accumulation of boron in the tumor.

[0009] The present invention provides a first method for preparing a boron-containing preparation capable of increasing boron accumulation in a tumor: dissolving a phenylboronic acid derivative in a molten or liquid polymer compound containing a polyoxyethylene segment at a pH of 2 to 6, then adding ultrapure water and mixing while maintaining the pH at 2 to 6 to obtain the boron-containing preparation.

[0010] The present invention provides a second method for preparing a boron-containing preparation capable of increasing intratumoral boron accumulation: dissolving a phenylboronic acid derivative and a polymer compound containing a polyoxyethylene segment in a polar solvent, removing the polar solvent by rotary evaporation, dissolving the phenylboronic acid derivative in the polymer compound or forming a thin film with the polymer compound, adding ultrapure water for dilution or hydration, and adjusting the pH to 2 to 8 (preferably 2 to 6) to obtain the boron-containing preparation. The polar solvent may include at least one of methanol, ethanol, dimethyl sulfoxide, and N,N-dimethylformamide.

[0011] The present invention provides a third method for preparing a boron-containing preparation capable of increasing intratumoral boron accumulation: dissolving a phenylboronic acid derivative and a polymer compound containing a polyoxyethylene segment in an organic solvent, transferring the resulting mixture to a dialysis bag, and dialyzing using an aqueous solution having a pH of 2 to 7 as a medium to remove the organic solvent. The dialysis bag fluid is collected and diluted with ultrapure water, and the pH is adjusted to 2 to 8 (preferably 2 to 5) to obtain the boron-containing preparation. The organic solvent may include at least one of methanol, ethanol, dimethyl sulfoxide, and N,N-dimethylformamide.

[0012] The phenylboronic acid derivatives of the present invention have the following structure:

[0013]

[0014] Wherein, R represents one or more optional substituents on the benzene ring, and the substituents may be none, or may be independently selected from substituted or unsubstituted C1-C18 hydrocarbon groups, -OR1, halogen, nitro, hydroxyl, amino, carboxyl, aldehyde, ester or heterocyclic groups. R1 may be a substituted or unsubstituted C1-C18 hydrocarbon group, and the substituents on the hydrocarbon group may be halogen, nitro, hydroxyl, amino, carboxyl, aldehyde, ester or heterocyclic group. The heteroatom in the heterocyclic group may be O, N or S, and the heterocyclic group may be a 3-6 membered ring.

[0015] Furthermore, the phenylboronic acid derivative of the present invention may be 4-boron-L-phenylalanine.

[0016] The weight average molecular weight of the polymer compound containing the polyoxyethylene chain segment of the present invention is 300 to 100,000 g / mol, for example, 300 to 20,000 g / mol.

[0017] The mass percentage of the phenylboronic acid derivative in the boron-containing preparation of the present invention can be 0.1% to 25%.

[0018] The mass ratio of the phenylboronic acid derivative of the present invention to the polymer compound containing a polyoxyethylene chain segment can be 1:2-100.

[0019] In one embodiment, in the boron-containing preparation of the present invention, the ratio of the volume of water to the total volume of the polymer compound containing the polyoxyethylene chain segment is not less than 15:1, which can maintain long-term stability of the boron-containing preparation.

[0020] The polymer compound containing polyoxyethylene chain segments of the present invention may include one or more of polyethylene glycol, Tween, poloxamer, fatty alcohol polyoxyethylene ether, polyoxyethylene hydrogenated castor oil, and polyoxyethylene alkyl ether.

[0021] The present invention also provides a boron-containing preparation prepared by the preparation method.

[0022] The present invention also provides the use of the boron-containing preparation in preparing boron neutron capture therapeutic drugs.

[0023] As a general inventive concept, the present invention also provides a boron neutron capture therapeutic drug, comprising the boron-containing preparation and pharmaceutically acceptable pharmaceutical excipients;

[0024] The boron-containing preparation contains 10 B.

[0025] The pharmaceutical excipients can be used as solubilizers, surfactants, flocculants and the like.

[0026] The pharmaceutical excipient may include at least one of phospholipids, polysaccharides, monosaccharides, benzyl alcohol, and sodium citrate.

[0027] The boron-containing preparation and boron neutron capture therapy drug provided by the present invention can be administered by injection. In addition, those skilled in the art can determine the dosage by referring to the existing dosage of boron neutron capture therapy and dilute it to different concentrations according to individual conditions.

[0028] The boron-containing preparation and boron neutron capture therapy drug of the present invention can be prepared into injectable solutions, nanoparticles, suspensions, etc. that can be diluted as needed. The preparation method is simple, easy to repeat and implement, and easy to promote. The boron-containing preparation and boron neutron capture therapy drug of the present invention retain the tumor-targeting properties of the phenylboronic acid derivative and reduce its post-cellular excretion, demonstrating excellent tumor cell uptake. They are novel boron capture agents that can be used in boron neutron capture therapy to increase boron accumulation in tumor sites.

[0029] In the present invention, the polymer compound containing the polyethylene oxide chain segment can be combined with the boronate ester bond in the phenylboronic acid derivative to increase the solubility of the phenylboronic acid derivative and maintain the in vivo circulation stability to a certain extent, so that after a single intravenous administration, the effect of boron neutron capture therapy is improved by increasing the boron uptake at the tumor site.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] (1) The boron-containing formulation prepared is simple to prepare and has a higher drug loading capacity than most BNCT boron delivery agents;

[0032] (2) The prepared boron-containing preparation has good stability and the dosage can be conveniently adjusted according to needs;

[0033] (3) The boron-containing preparation prepared by compounding a small molecule phenylboronic acid derivative with a high molecular compound containing a polyethylene oxide segment retains the tumor targeting property of the phenylboronic acid derivative and prevents it from being taken into cells and then transported out of the cells, thereby increasing the boron uptake of tumor cells;

[0034] (3) The prepared boron-containing preparation can increase the distribution of boron in the tumor site, and it is expected that after a single injection, the BNCT treatment requirements can be met for subsequent neutron irradiation;

[0035] (4) The prepared boron-containing preparation has good biocompatibility, and further modification can enhance the in vivo circulation stability and target tissue tropism. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 The particle size diagram and transmission electron micrograph of the polyethylene glycol 400-boron phenylalanine complex of Example 1 are shown;

[0037] Figure 2 The particle size diagram and transmission electron microscope photograph of the poloxamer 188-boronophenylalanine complex of Example 2 are shown;

[0038] Figure 3 This is a scanning electron microscope photograph of the poloxamer 188-boronophenylalanine complex of Example 2;

[0039] Figure 4 This is a scanning electron micrograph of the Tween 80-boron phenylalanine complex of Example 3;

[0040] Figure 5 The stability photos of the polyethylene glycol 400-boron phenylalanine complex of Application Example 1 after dilution with ultrapure water at different volume ratios (formulation: water);

[0041] Figure 6 The stability photos of the polyethylene glycol 400-boron phenylalanine complex under different pH conditions in Application Example 1 are shown;

[0042] Figure 7 The transmission electron microscopy morphology comparison photos of the poloxamer 188-1 boron phenylalanine complex of Application Example 2 under acidic and alkaline conditions;

[0043] Figure 8 Graph showing the experimental results of uptake of borophenylalanine-fructose, polyethylene glycol 400-borophenylalanine complex, and poloxamer 188-borophenylalanine complex by GL261 cells in Application Example 4;

[0044] Figure 9 This is a graph showing the in vivo distribution experimental results of the polyethylene glycol 400-boron phenylalanine complex of Application Example 5 in C57 mice bearing GL261 subcutaneous tumors. The horizontal axis in the graph represents time in hours.

[0045] Figure 10 This is a graph showing the experimental results of the boron content ratios of tumor to normal tissue and tumor to blood after administration of polyethylene glycol 400-boron phenylalanine complex to C57 mice bearing GL261 subcutaneous tumors in Application Example 5. The horizontal axis in the graph represents time in hours. DETAILED DESCRIPTION

[0046] The present invention will be further described below in conjunction with the accompanying drawings and specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The operating methods in the following examples where no specific conditions are specified are generally performed under conventional conditions or as recommended by the manufacturer.

[0047] Example 1 Preparation of Polyethylene Glycol 400-Boronic Acid Phenylalanine Complex (PEG400-BPA)

[0048] Method 1: Take 6 ml of polyethylene glycol 400, adjust the pH to approximately 2 with 1 M HCl solution, add 300 mg of 4-borono-L-phenylalanine in portions, and stir magnetically at room temperature until completely dissolved, maintaining the pH between 2 and 5. After dissolution, add 6 ml of ultrapure water adjusted to pH 5 and vortex mix to obtain the boron capture agent PEG400-BPA.

[0049] Method 2: Add 1 ml of polyethylene glycol 400 and 100 mg of 4-borono-L-phenylalanine to 30 ml of methanol and stir at 60°C for 4 hours until completely dissolved. The resulting solution is placed in an eggplant-shaped flask and rotary evaporated to remove the methanol, yielding a pale yellow, translucent paste. To this paste, add 100 μl of 1 M HCl solution dropwise, followed by hydration with 1 ml of ultrapure water. The pH is then carefully adjusted to 5, and the mixture is sonicated in a water bath for 30 minutes. After mixing, the boron capture agent PEG400-BPA is obtained.

[0050] The preparations obtained by the two methods in this example were both in the form of clear solutions with no significant difference and good fluidity. The particle size was measured by a laser particle size analyzer, and the results showed that the particle size distribution was around 2 to 3 nm. Figure 1 The results of particle size test of the preparation prepared by method 1 and the morphology photographed by transmission electron microscopy after dilution 10 times are shown in the figure. As shown in the figure, fine drug particles are distributed in polyethylene glycol 400 to form a composite structure.

[0051] Example 2 Preparation of Poloxamer 188-Boronic Acid Phenylalanine Complex (F68-BPA)

[0052] Heat 2g of poloxamer 188 to 60°C until it melts. Adjust the pH to 2 with 1M hydrochloric acid. Add 50mg of 4-boron-L-phenylalanine and stir for 3 hours to obtain a colorless, clear liquid. Slowly inject this liquid into 3ml of ultrapure water and stir overnight to obtain a colorless, clear solution. Alternatively, quickly mix the liquid with 3ml of ultrapure water, sonicate with a probe for 5 minutes, and adjust the pH to 5 to obtain the boron capture agent F68-BPA.

[0053] The preparation of this embodiment is grayish white or clear depending on the dispersion, and has good fluidity. The particle size is measured by a laser particle size analyzer, and the results show that the particle size distribution is around 200 nm. The morphology is photographed by transmission electron microscopy, and there are round nanoparticles. As the water addition ratio increases, there is a hydration layer with an increased outer diameter around it, which makes the particle size larger under transmission electron microscopy. The particle size detection and transmission electron microscopy results are as follows: Figure 2 shown.

[0054] The preparation of this embodiment was dried and photographed under a scanning electron microscope, where round particles with a particle size of about 100 nm were observed. The test results are as follows: Figure 3 shown.

[0055] Example 3 Preparation of Tween 80-boron phenylalanine complex (T80-BPA)

[0056] Method 1: Add 500 mg of Tween 80 and 50 mg of 4-borono-L-phenylalanine to 30 ml of methanol and stir at 60°C for 4 hours until completely dissolved. The resulting solution is placed in an eggplant-shaped flask and rotary evaporated to remove the methanol, leaving a film of Tween 80 and borono-phenylalanine. Add 1 ml of ultrapure water adjusted to pH 5 to hydrate the solution, and sonicate in a water bath for 2 hours to obtain the boron capture agent T80-BPA.

[0057] Method 2: Add 500 mg of Tween 80 and 50 mg of 4-borono-L-phenylalanine to 30 ml of methanol and stir at 60°C for 4 hours until completely dissolved. Transfer the resulting solution to a dialysis bag and dialyze against a pH 5 aqueous solution to remove the organic solvent. Collect the dialysis bag solution and dilute it with ultrapure water to adjust the pH to 5.

[0058] The preparation of this example is a white suspension in the form of dispersion, and has good redispersibility after sedimentation. The particle size of the preparation prepared using Method 1 was measured using a laser particle size analyzer, and the results showed a particle size distribution of 3264±1028nm and a PDI of 23.57±5.2%. Scanning electron microscopy (SEM) morphology showed a film-like coating of the drug particles, which may be caused by Tween forming a coating on the BPA surface, improving its distribution in water. The SEM results are shown in Figure 2. Figure 4 shown.

[0059] Application Example 1: Stability Study of Polyethylene Glycol 400-Boronic Acid Phenylalanine Complex (PEG400-BPA)

[0060] Add 1 ml of polyethylene glycol 400 and 50 mg of 4-boron-L-phenylalanine to 30 ml of methanol and stir at 60 ° C for 4 hours until completely dissolved. The resulting solution is added to an eggplant-shaped bottle and the methanol is removed by rotary evaporation to obtain a light yellow transparent liquid. The liquid is diluted with ultrapure water in different volume ratios and allowed to stand for several hours to observe the precipitation of the drug and study the stability of the polyethylene glycol 400-boron-phenylalanine complex at different dilution ratios. The preparation condition after standing is as follows Figure 5 As shown, the preparation can remain stable for a long time when the dilution ratio reaches more than 15 times.

[0061] The stability of the preparation at different pH values was further investigated. Under alkaline conditions (pH = 9), the drug precipitated immediately when water was added at a dilution ratio (volume ratio) of 1:1. However, under acidic conditions, when pH = 5, the preparation remained stable when diluted at different ratios as needed. The results are as follows: Figure 6 Preferably, in subsequent application examples, a polyethylene glycol 400-boron phenylalanine complex sample diluted with pure water to a suitable dosage ratio at pH=5 is used.

[0062] Application Example 2: Stability Study of Poloxamer 188-Boronic Acid Phenylalanine Complex (F68-BPA)

[0063] 2 g of poloxamer 188 was heated to 60° C. and melted. The pH was adjusted to 2 with 1 M hydrochloric acid. 50 mg of BPA was added and stirred for 3 h to obtain a colorless clear liquid.

[0064] The effects of different mixing methods on its stability were investigated: slow injection into 3 ml of 60°C ultrapure water using a syringe; rapid mixing with 3 ml of room-temperature ultrapure water and ultrasonication for 5 minutes; and mixing with ultrapure water at 60°C using a microfluidic device at a rate of 12 ml / min. All three mixing methods had little effect on the stability of the poloxamer 188-boronophenylalanine complex solution. After standing overnight, all solutions yielded a pale yellow, clear solution. Electron microscopy revealed no significant differences in morphology or particle size distribution, demonstrating good stability over a week.

[0065] The stability of F68-BPA preparations at different pH values was investigated. The appearance of the preparations remained stable at pH values of 2 to 10. However, transmission electron microscopy revealed significant differences in the morphology of the preparations under acidic (pH = 5) and alkaline (pH = 9) conditions. To maintain the effectiveness of the preparation, the pH value must be kept within the acidic range during use. Figure 7 Preferably, in subsequent application experiments, a poloxamer 188-boronophenylalanine complex sample diluted with pure water to a suitable dosage ratio at pH=5 is used.

[0066] Application Example 3: Stability Optimization of Tween 80-Borophyllaniline Complex

[0067] 500 mg of Tween 80 and 50 mg of 4-borono-L-phenylalanine were added to 30 ml of methanol and stirred at 60°C for 4 hours until completely dissolved. The resulting solution was placed in an eggplant-shaped flask and rotary evaporated to remove the methanol, leaving a film of Tween 80 and borono-phenylalanine. 1 ml of ultrapure water adjusted to pH 5 was added to hydrate the solution, and the solution was sonicated in a water bath for 2 hours to obtain the boron capture agent T80-BPA.

[0068] Different ways to improve its stability were explored:

[0069] (1) The high-pressure homogenization method can effectively reduce the particle size of the composite and improve its storage stability;

[0070] (2) Adding flocculants or deflocculants such as sodium citrate can help reduce sedimentation in a short period of time;

[0071] (3) Adding benzyl alcohol, dextran, etc. can help improve its storage stability.

[0072] Application Example 4 Cellular Uptake Experiment of Polyethylene Glycol 400-Boronic Acid Complex (PEG400-BPA) and Poloxamer 188-Boronic Acid Complex (F68-BPA)

[0073] The experiment used the clinically used boron drug borophenylalanine-fructose (BPA-F) as a control. GL-261 cells in the logarithmic growth phase were taken and 2×10 7 Cells were seeded per well in a six-well plate and cultured at 37°C in a 5 vol% CO2 environment. Once the cells reached approximately 80% confluency, the old culture medium was removed. Using the preferred PEG400-BPA and F68-BPA samples from Application Examples 1 and 2, a drug-containing base containing BPA-F, PEG400-BPA, or F68-BPA at a boron concentration of 30 μg / ml was added to each culture dish. After incubation for 4 hours, the culture medium was discarded and the cells were washed three times with 4°C pre-chilled PBS to remove excess formulation residue. The cells were trypsinized, collected, and carefully counted. Each cell sample was then digested by adding an appropriate amount of a mixed solution of concentrated nitric acid and hydrogen peroxide (V:V = 3:1) and wet-heating at 70°C. When the solution became completely clear, indicating complete digestion, the solution was brought to volume with ultrapure water and filtered through a 0.22 μm microporous membrane. The boron content was determined by ICP-MS, and the per-unit cell boron uptake of each formulation group was calculated.

[0074] BNCT objectively requires that the boron accumulation in tumor tissue is greater than 20 μg (equivalent to at least 10 9 indivual 10 B, about 16.6ng 10 B / 10 6 cells), and the cellular uptake results were as follows. Figure 8 As shown, the results showed that the accumulation of the three preparations in cells was much higher than this requirement. Compared with BPA-F, F68-BPA and PEG400-BPA increased the uptake of GL-261 cells to varying degrees, among which the uptake of PEG400-BPA increased to about twice that of BPA-F.

[0075] Application Example 5: Intratumoral Distribution of Polyethylene Glycol 400-Boronic Acid Phenylalanine Complex (PEG400-BPA)

[0076] A biodistribution study was conducted in C57 mice bearing subcutaneous tumors. First, a tumor-bearing mouse model was constructed by subcutaneous injection of a GL261 cell suspension. After modeling, when the tumor grew to about cubic centimeters, the preferred polyethylene glycol 400-boron phenylalanine complex in Application Example 1 and the control boron phenylalanine-fructose (BPA-F) were injected through the tail vein at a dose of BPA 25 mg / kg. 4 hours and 8 hours after the injection, the mice were euthanized to collect plasma, tumors, and adjacent muscle tissues. The tissue samples were washed with physiological saline, and an appropriate amount of a mixed solution of concentrated nitric acid and hydrogen peroxide (V:V=3:1) was added to each sample. The samples were wet-heated at 80°C for digestion for more than 24 hours. The boron content was determined using ICP-MS, and the boron accumulation in the blood and various tissues was calculated. The results are shown as follows: Figure 9 By calculating the T / N ratio and T / B ratio, the results are as follows Figure 10 As shown in the results, the polyethylene glycol 400-boron phenylalanine complex prepared at 8 h had a better T / N ratio than BPA-fructose, and the T / B ratios of both were greater than 3, which was consistent with the requirements of BNCT treatment.

[0077] In addition, it should be understood that after reading the above description of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for preparing a boron-containing preparation capable of increasing boron accumulation in tumors, characterized in that: The boron-containing preparation is obtained by dissolving a phenylboronic acid derivative in a molten or liquid polymer compound containing a polyoxyethylene chain segment at a pH of 2 to 6, and then adding ultrapure water and mixing while maintaining the pH at 2 to 6. The polymer compound containing a polyoxyethylene chain segment comprises one or more of polyethylene glycol, Tween, poloxamer, fatty alcohol polyoxyethylene ether, polyoxyethylene hydrogenated castor oil, and polyoxyethylene alkyl ether. The weight average molecular weight of the polymer compound is 300 to 100,000 g / mol; The phenylboronic acid derivative is 4-boron-L-phenylalanine.

2. The preparation method according to claim 1, characterized in that The mass percentage of the phenylboronic acid derivative in the boron-containing preparation is 0.1% to 25%.

3. The preparation method according to claim 1, characterized in that The mass ratio of the phenylboronic acid derivative to the polymer compound containing a polyoxyethylene chain segment is 1:2-100.

4. A method for preparing a boron-containing preparation capable of increasing boron accumulation in tumors, characterized in that: Dissolving a phenylboronic acid derivative and a polymer compound containing a polyoxyethylene chain segment in a polar solvent, rotary evaporating to remove the polar solvent, dissolving the phenylboronic acid derivative in the polymer compound or forming a thin film together with the polymer compound, adding ultrapure water to dilute or hydrate, and adjusting the pH to 2-8 to obtain the boron-containing preparation; the polymer compound containing a polyoxyethylene chain segment comprises one or more of polyethylene glycol, Tween, poloxamer, fatty alcohol polyoxyethylene ether, polyoxyethylene hydrogenated castor oil, and polyoxyethylene alkyl ether; The weight average molecular weight of the polymer compound is 300 to 100,000 g / mol; The phenylboronic acid derivative is 4-boron-L-phenylalanine.

5. The preparation method according to claim 4, characterized in that The mass percentage of the phenylboronic acid derivative in the boron-containing preparation is 0.1% to 25%.

6. The preparation method according to claim 4, characterized in that The mass ratio of the phenylboronic acid derivative to the polymer compound containing a polyoxyethylene chain segment is 1:2-100.

7. The preparation method according to claim 4, characterized in that Adjust pH to 2-6.

8. A method for preparing a boron-containing preparation capable of increasing boron accumulation in tumors, characterized in that: A phenylboronic acid derivative and a polymer compound containing a polyoxyethylene chain segment are dissolved in an organic solvent, the resulting mixture is transferred to a dialysis bag, and dialyzed using an aqueous solution with a pH of 2 to 7 as a medium, the organic solvent is removed, and the liquid in the dialysis bag is collected and diluted with ultrapure water, and the pH is adjusted to 2 to 8 to obtain the boron-containing preparation; the polymer compound containing a polyoxyethylene chain segment comprises one or more of polyethylene glycol, Tween, poloxamer, fatty alcohol polyoxyethylene ether, polyoxyethylene hydrogenated castor oil, and polyoxyethylene alkyl ether; The weight average molecular weight of the polymer compound is 300 to 100,000 g / mol; The phenylboronic acid derivative is 4-boron-L-phenylalanine.

9. The preparation method according to claim 8, characterized in that The mass percentage of the phenylboronic acid derivative in the boron-containing preparation is 0.1% to 25%.

10. The preparation method according to claim 8, characterized in that The mass ratio of the phenylboronic acid derivative to the polymer compound containing a polyoxyethylene chain segment is 1:2-100.

11. The preparation method according to claim 8, characterized in that Adjust pH to 2~5.

12. Use of the boron-containing preparation prepared by the preparation method according to any one of claims 1 to 11 in the preparation of boron neutron capture therapy drugs.

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