Radionuclide-labeled boron-containing drugs and their manufacture and use

Abstract

The present invention relates to the field of radioactive drugs, specifically to radionuclide-labeled boron-containing drugs and their preparation methods. The boron-containing drugs are obtained by labeling them with at least one radionuclide, and the boron-containing drugs are obtained by polymerization of dopamine and its derivatives with boron-containing compounds. The radionuclide-labeled boron-containing drugs of the present invention have tumor-targeting properties. A method for labeling a radionuclide to a boron-containing drug via complexation or covalent bonding is also provided.

Description

[Technical Field]

[0001] The present invention relates to the field of radiopharmaceutical technology, and more particularly to radionuclide-labeled boron-containing drugs and their preparation and use. [Background technology]

[0002] Locally targeted internal radiation therapy is an internal radiation therapy that precisely delivers radionuclides to the tumor site via a carrier and provides treatment through radiation emitted from the radionuclides. Due to its remarkable therapeutic effect, it plays an important role in the treatment of diseases such as tumors and is one of the current hot topics of research. Currently, methods, technologies, or drugs that achieve localized, precise internal radiation therapy include microspheres, sealed metal seed sources, small molecules, antibodies, polypeptides, and nanodrugs as radionuclide carriers. The most critical technical challenges in targeted radiopharmaceuticals are (1) designing and developing carriers with good targeting properties, and (2) achieving efficient and stable labeling of radionuclides to carriers with good targeting properties while still ensuring that the carriers labeled with the radionuclides have good targeting properties for the target lesion or tumor cells.

[0003] Currently, most targeted drug carriers in clinical applications, such as small molecules, antibodies, and polypeptides, have difficulty achieving high efficiency, and there are problems with stable labeling of nuclides, poor stability after labeling, and loss of targeting properties after labeling. Due to the high technical difficulties, the development of targeted radioactive drugs has progressed relatively slowly. Summary of the Invention

[0004] The present invention aims to solve the technical problems in the background art by providing a radionuclide-labeled boron-containing drug and its preparation and use, the radioactive drug comprising: 68 Ga, 67 Ga, 64 Cu, 67 Cu, 89 Zr, 89 Sr, 90 Y, 177 Lu, 111In, 165 Dy, 166 Ho, 201 T.I., 213 Bi, 212 Bi, 225 Ac, 223 Ra, 212 Pb, 211 At, 124 I, 123 I, 125 I, 131 I, 18 F, 186 Re, 188 Re, 99m It can be labeled with nuclides such as Tc, enabling integrated medical treatment.

[0005] The first technical solution provided by the present invention is as follows:

[0006] A radionuclide-labeled boron-containing drug can be obtained by labeling a boron-containing drug with at least one radionuclide.

[0007] The boron-containing drug can be obtained by a polymerization reaction between dopamine or its derivatives and a boron-containing compound.

[0008] Preferably, the radionuclide is 68 Ga, 67 Ga, 64 Cu, 67 Cu, 89 Zr, 89 Sr, 90 Y, 177 Lu, 111 In, 165 Dy, 166 Ho, 201 T.I., 213 Bi, 212 Bi, 225 Ac, 223 Ra, 212 Pb, 211 At, 124 I, 123 I, 125 I, 131 I, 18 F, 186 Re, 188 Re, 99mTc.

[0009] Preferably, the particle size of the radionuclide-labeled boron-containing drug is 50 to 1000 nm.

[0010] Preferably, the boron-containing compound includes, but is not limited to, any one or more of boric acid, phenylalanine borate and its derivatives, proline borate, aspartic acid borate, tyrosine borate, cysteine ​​borate, methionine borate, serine borate, 5-amino-2,3-difluorophenylboronic acid, 3-amino-5-cyanophenylboronic acid, 3-amino-4-methylphenylboronic acid, 3-aminophenylborate hydrochloride, and 4-carbamoylphenylboronic acid.

[0011] Preferably, the dopamine and derivatives thereof include any one or more of dopamine, 4-(2-aminopropyl)benzene-1,2-diol, noradrenaline (1-(3,4-dihydroxyphenyl)-2-aminoethanol), L-methyldopa (2-methyl-3-(3,4-dihydroxyphenyl)-L-alanine), droxidopa ((2S,3R)-2-amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropionic acid), and 5-hydroxydopamine.

[0012] Preferably, the dopamine and derivatives thereof are dopamine, L-methyldopa, and 5-hydroxydopamine.

[0013] Preferably, the mass ratio of the dopamine and derivatives thereof to the boron-containing compound is (1-10):1.

[0014] 8. The radionuclide-labeled boron-containing drug according to any one of claims 1 to 7, characterized in that the indications for the radionuclide-labeled boron-containing drug include head and neck tumors, lung cancer, peritoneal cancer, liver cancer, gastric cancer, melanoma, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, and thyroid cancer.

[0015] The second technical solution provided by the present invention is as follows:

[0016] The method for producing a radionuclide-labeled boron-containing drug comprises: Complexation of the radionuclide with the polyhydroxyl or carboxyl groups of the boron-containing drug, followed by precipitation and solidification; or It involves labeling a radionuclide to the benzene ring structure of a boron-containing drug by forming a covalent bond through a chemical reaction.

[0017] The present invention has the following advantageous effects compared to the prior art.

[0018] The radioactive drug of the present invention is 68 Ga, 67 Ga, 64 Cu, 67 Cu, 89 Zr, 89 Sr, 90 Y, 177 Lu, 111 In, 165 Dy, 166 Ho, 201 T.I., 213 Bi, 212 Bi, 225 Ac, 223 Ra, 212 Pb, 211 At, 124 I, 123 I, 125 I, 131 I, 18 F, 186 Re, 188 Re, 99m Highly efficient labeling of nuclides such as Tc is achieved. 68 Ga, 67 Ga, 90 Y, 177 Lu, 165 Dy, 166The labeling rate of multiple nuclides, including Ho, exceeds 98%, and this radioactive drug has good stability in physiological saline, phosphate buffer, and 5% fetal bovine serum. The radioactive drug of the present invention has a particle size of 50-1000 nm, good stability, can enter cells, penetrate the blood-brain barrier, and has tumor targeting properties, making it suitable for simultaneous use in tumor treatment or development. This nuclide-labeled drug can be used in drug distribution studies, screening of potential patients for treatment, and prediction of treatment effects. [Brief explanation of the drawings]

[0019] [Figure 1] FIG. 1 is an SEM image of the boron-containing drug in Example 2 after redissolution; [Figure 2] FIG. 1 is an SEM image of a boron-containing drug labeled with 90Y in Example 4; [Figure 3] FIG. 1 is a DLS diagram of a boron-containing drug labeled with 90Y in Example 4; [Figure 4] FIG. 12 is a SPECT-CT experiment of a mouse using a boron-containing drug labeled with I in Example 12; [Figure 5] 12 shows an experimental image of SPECT-CT of free 131I in a mouse body in Example 12. DETAILED DESCRIPTION OF THE INVENTION

[0020] In order to better understand the technical solution of the present invention, the technical solution of the present invention will be further described below with reference to the drawings and examples. The manner in which the present invention is realized includes, but is not limited to, the following examples, which are for the purpose of illustrating the present invention and do not limit the scope of protection of the present invention. Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art. Unless otherwise specified, the test methods in the following examples are all conventional methods.

[0021] The first embodiment of the present invention provides a radionuclide-labeled boron-containing drug obtained by labeling a boron-containing drug with at least one radionuclide, and the boron-containing drug is obtained by a polymerization reaction between dopamine or its derivatives and a boron-containing compound.

[0022] The boron-containing drug and the radionuclide are complexed or covalently bonded to each other to realize labeling of the boron-containing drug with the radionuclide.

[0023] The boron-containing drug of the present invention contains polyphenols, carboxyl groups, and a benzene ring structure in its molecular structure, possessing good tumor-targeting properties. The boron-containing drug itself possesses good physicochemical stability, enabling it to become a radioactive drug with good targeting properties after being labeled with a radionuclide. The boron-containing drug of the present invention does not possess developmental properties, and the biodistribution and metabolism of the boron-containing drug are difficult research topics in the drug development process. The radionuclide-labeled boron-containing drug provided by the present invention has the property of simultaneously achieving highly efficient and stable labeling of multiple radionuclides, and maintains good physicochemical properties and tumor-targeting properties even after being labeled with a radionuclide, making it potentially suitable for development as a drug for local targeted internal radiation therapy. Furthermore, the nuclide-labeled boron-containing drug contributes to research into the biodistribution and metabolism of the drug itself, facilitating the development of the boron-containing drug.

[0024] The radioactive drug of the present invention does not change the tumor targeting properties of boron-containing drugs, can be metabolized (biodegradable) in the body, and its drug concentration rapidly decreases 48 hours after injection into the body until it is completely metabolized and eliminated.

[0025] In an embodiment of the present invention, the radionuclide used for labeling is 68 Ga, 67 Ga, 64 Cu, 67 Cu, 89 Zr, 89 Sr, 90 Y, 177 Lu, 111 In, 165 Dy, 166Ho, 201 T.I., 213 Bi, 212 Bi, 225 Ac, 223 Ra, 212 Pb, 211 At, 124 I, 123 I, 125 I, 131 I, 18 F, 186 Re, 188 Re, 99m Tc.

[0026] The particle size of the radionuclide-labeled boron-containing drug is usually 50 to 1000 nm, and it has the property of being taken up by cancer cells to achieve tumor targeting.

[0027] In some preferred embodiments, the boron-containing compound includes, but is not limited to, any one or more of boric acid, phenylalanine borate and its derivatives, proline borate, aspartic acid borate, tyrosine borate, cysteine ​​borate, methionine borate, serine borate, 5-amino-2,3-difluorophenylboronic acid, 3-amino-5-cyanophenylboronic acid, 3-amino-4-methylphenylboronic acid, 3-aminophenylborate hydrochloride, and 4-carbamoylphenylboronic acid.

[0028] In some preferred embodiments, the dopamine and derivatives thereof include one or more of dopamine, 4-(2-aminopropyl)benzene-1,2-diol, noradrenaline (1-(3,4-dihydroxyphenyl)-2-aminoethanol), L-methyldopa (2-methyl-3-(3,4-dihydroxyphenyl)-L-alanine), xixidopa ((2S,3R)-2-amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropionic acid), and 5-hydroxydopamine, and more preferably dopamine, L-methyldopa, or 5-hydroxydopamine.

[0029] In some preferred embodiments, the mass ratio of the dopamine and derivatives thereof to the boron-containing compound is (1-10):1.

[0030] Indications for the radionuclide-labeled boron-containing drugs of the present invention include diseases such as head and neck tumors, lung cancer, peritoneal cancer, liver cancer, gastric cancer, melanoma, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, and thyroid cancer.

[0031] The second embodiment of the present invention provides a method for producing a radionuclide-labeled boron-containing drug, which can be realized in the following two forms: (1) Stable labeling is achieved by complexing the metal radionuclide with groups such as polyhydroxyl groups and carboxyl groups in the boron-containing drug and further precipitation and solidification. (2) Stable labeling is achieved by labeling the radionuclide to the benzene ring structure of the boron-containing drug through a covalent bond formed by a chemical reaction. The specific labeling method is not particularly limited as long as it can achieve the above two types of labeling.

[0032] In some specific embodiments, the method for complexing and labeling a radionuclide to a boron-containing drug comprises at least 68 Ga, 67 Ga, 64 Cu, 67 Cu, 89 Zr, 89 Sr, 90 Y, 177 Lu, 111 In, 165 Dy, 166 Ho, 201 T.I., 213 Bi, 212 Bi, 225 Ac, 223 Ra, 212This method is applicable to radionuclides such as Pb. The specific method is as follows: 10-100 mg of boron-containing drug is weighed out, a pH 3.0-7.0 buffer solution is added, and the mixture is uniformly mixed using ultrasound. 0.1-500 mCi of radionuclide solution is added to the sonicated solution, and the mixture is allowed to react for 60 minutes in a water bath at 30-80°C to fully bond the boron-containing drug to the nuclide. The fully bonded mixture is centrifuged to obtain a solid, which is then washed three times with buffer solution. The supernatant and precipitate are collected and their radioactivity is measured, and the labeling rate of the radionuclide-labeled boron-containing drug is calculated. Radionuclide-labeled boron-containing drugs of a certain activity are placed in saline, phosphate buffer, or 5% fetal bovine serum, respectively, and allowed to stand at 37°C for a certain period of time. The supernatant is then sampled and the activity or radioactivity count is measured, and the radionuclide leakage rate of the drug in the different solutions is calculated. Through detection, 68 Ga, 67 Ga, 90 Y, 177 Lu, 165 Dy, 166 The labeling efficiency of several nuclides, including Ho, exceeded 98%, and the leakage rate of the nuclides was less than 5% for 6 days in saline, phosphate buffer, and 5% fetal bovine serum.

[0033] The method for complexing and labeling a radionuclide to a boron-containing drug is as follows: 186 Re, 188 Re, 99m This method is also applicable to radionuclides such as Tc. The specific method is as follows: 5-100 mg of nanoparticles are added to a sodium acetate buffer solution (pH 3.0-6.0) containing 4-500 mg of sodium ascorbate and 100 mg of Na 186 ReO4 / Na 188 ReO4 / Na 99m Add 0.1 to 100 mCi of TcO4 in order, shake and react at 80°C for 15 minutes, then centrifuge to obtain the solid, wash three times with buffer solution, collect the supernatant and precipitate, measure their radioactivity, and calculate the labeling rate of the radionuclide-labeled boron-containing drug. 186 Re, 188 Re, 99m The Tc labeling rate is over 85%, and the radiopharmaceutical of the present invention can be used to treat tumors.

[0034] In some other specific embodiments, the method for labeling a boron-containing drug with a radionuclide by a covalent bonding reaction comprises at least 211 At, 124 I, 123 I, 125 I, 131 It is applicable to radionuclides such as I, and the specific method is as follows: Chloramine T is dissolved in an organic solvent, applied to the bottom of a tube, and allowed to dry; 5-10 mg of a boron-containing drug and a pH 7.0-8.0 buffer solution are placed in a reaction tube, and the radionuclide is added and allowed to react for 5-30 minutes in an ice bath; the reaction mixture is centrifuged after the reaction is complete, and the precipitate is washed multiple times. The total radioactivity in the supernatant and precipitate is measured, and the labeling rate of the radionuclide-labeled boron-containing drug is calculated. Drugs of a certain activity are placed in saline, phosphate buffer, and 5% fetal bovine serum, respectively, and allowed to stand at 37°C for a certain period of time. The activity or radioactivity count of the supernatant is measured, and the radionuclide leakage rate of the drug in different solutions is calculated. Through detection, 131 I and 123 The I labeling rate was over 85%, the labeling dose was over 10 mCi / mg, the labeling was stable, the nuclide was not significantly lost in the body, and the therapeutic effect on tumors was remarkable. After 48 hours of storage in saline, phosphate buffer, and 5% fetal bovine serum, the nuclide leakage rate was less than 1% in all cases.

[0035] The method of labeling a boron-containing drug with a radionuclide by covalent bonding reaction is as follows: 18 This method can also be applied to radionuclides such as F. The specific method is as follows: A boron-containing drug is uniformly dispersed in a trifluoroacetic acid solution, and then the mixture is mixed with the boron-containing drug. 18 The reaction is carried out by bubbling F2 gas into the solution. After half an hour of reaction, the precipitate is collected and its radioactivity is measured to calculate the labeling rate of the boron-containing drug. 18 The F labeling rate exceeds 70%, making it suitable for biodistribution studies of boron-containing drugs.

[0036] The method for producing a boron-containing drug includes mixing an aqueous solution of dopamine and its derivatives with an aqueous solution of a boron-containing compound to cause a reaction, separating the solution into solid and liquid to obtain a solid, washing the solid, and freeze-drying the solid.

[0037] In some preferred embodiments, the pH of the mixing reaction is 6 to 14, the mixing reaction time is 0.5 to 48 hours, and the stirring speed during the reaction is 200 rpm or more.

[0038] A third embodiment of the present invention provides the use of a radionuclide-labeled boron-containing drug in the manufacture of a drug for tumor treatment and / or tumor imaging diagnosis. That is, the drug can not only achieve tumor treatment or tumor development, but also realize a drug integrated into tumor diagnosis and treatment. The radionuclide-labeled drug of the present invention can be used in drug distribution studies and for screening potential patients or predicting treatment effects.

[0039] Based on the composition and structural design of the boron-containing drug, the present invention makes the boron-containing drug an effective radionuclide carrier, and realizes radionuclide labeling by a simple nuclide labeling method. After labeling with the developed and / or treated radionuclide, the boron-containing drug can be used in the treatment of tumor patients.

[0040] The present invention provides 211 At, 124 I, 123 I, 125 I, 131 I and 18 Radionuclide-labeled boron-containing drugs, such as F, can be developed by SPECT-CT, which can be used to study the distribution of boron-containing drugs in the body, helping to understand the dynamic distribution information of boron-containing drugs in the patient's body. 211 At, 124 I, 123 I, 125 I, 131 I and 18 Radionuclide-labeled boron-containing drugs such as F can be used for pre-treatment screening and treatment effect prediction for patients, and are expected to realize accurate medical treatment.131 The I-labeled drug is expected to be useful in the integrated treatment of tumors.

[0041] 131 After intravenous injection of I-labeled boron-containing drugs, SPECT-CT imaging showed that the drugs were highly concentrated in the tumors within approximately 24 hours. The nuclide labeling did not alter the tumor targeting of the boron-containing drugs, and no significant changes were observed in the thyroid glands of the animals. 131 There was no concentration of I, 131 It was demonstrated that the I-labeled drug does not concentrate in the thyroid gland, and that the drug is labeled 131 No obvious dropouts occurred in I.

[0042] In order to make the technical solution of the present invention clearer, several specific examples are given below to illustrate the radionuclide-labeled boron-containing drug, its preparation method and use. [Example]

[0043] Example 1 Preparation of a boron-containing drug 80 mg of dopamine hydrochloride was weighed into a reaction flask, 34 ml of 30% ethanol solution was added, and the mixture was stirred to dissolve. 20 mg of 4-boronodecanoic acid-L-phenylalanine (BPA) was weighed into a centrifuge tube, 3 ml of water was added, and 0.2 ml of 2.5 mol / L NaOH solution was added to completely dissolve the BPA. The solution was mixed, and the pH was adjusted to about 10 with NaOH. The mixture was stirred at 300 rpm for 24 hours, centrifuged at 10,000 rpm, and washed three times with pure water. The product was suspended in water and freeze-dried to obtain the boron-containing drug.

[0044] Example 2 Redissolution experiment of boron-containing drug after freeze-drying 5 mg of the boron-containing drug in Example 1 was taken, and 5 mL of solvent was added. The solvent included, but was not limited to, sterile water for injection, sodium chloride injection, glucose injection, and PBS buffer solution. Water was used as a dispersant. After manual mixing, SEM detection was performed. The morphology characteristics are shown in Figure 1.

[0045] Example 3 Preparation of radiopharmaceuticals In this embodiment, 68 The Ga labeling process is as follows: 5 mg of the boron-containing drug in Example 1 is weighed, and 2 ml of sodium acetate buffer solution with a pH of 5.5 is added and mixed uniformly by ultrasonication. 68 GaCl3 solution was added and the mixture was shaken in a water bath at 50°C for 50 minutes. The mixture was centrifuged and washed three times with sodium acetate (pH 5.5) to obtain the supernatant and precipitate. Their radioactivity was measured, and the nuclide labeling rate of the boron-containing drug was calculated to be greater than 99%. The precipitate was placed in saline, phosphate buffer, or 5% fetal bovine serum and allowed to stand at 37°C for 24 hours. The supernatant and precipitate were centrifuged and washed three times with sodium acetate (pH 5.5). The supernatant and precipitate were collected and their radioactivity was measured, and the leakage rate of the boron-containing drug was calculated to be less than 1%.

[0046] Example 4 Preparation of radiopharmaceuticals In this embodiment, 90 The labeling process of Y is as follows: 5 mg of the boron-containing drug in Example 1 is weighed, and 2 ml of sodium acetate buffer solution with a pH of 5.5 is added and mixed uniformly by ultrasonication. 90 Add YCI3 standard solution and shake for 50 minutes in a 50°C water bath. Centrifuge and wash three times with pH 5.5 sodium acetate buffer. The resulting supernatant and precipitate were collected and their radioactivity was measured. The labeling rate of the boron-containing drug was calculated to be over 98%. The precipitate was placed in saline, phosphate buffer, or 5% fetal bovine serum and left at 37°C for 6 days. The supernatant and precipitate were centrifuged and washed three times with pH 5.5 sodium acetate buffer. The resulting supernatant and precipitate were collected and their radioactivity was measured. The leakage rate of the boron-containing drug was calculated to be less than 1%.

[0047] In this embodiment 90The SEM image of the Y-labeled boron-containing drug is shown in Figure 2, and the DLS image is shown in Figure 3.

[0048] Example 5 Preparation of radiopharmaceuticals In this embodiment, 177 The labeling process of Lu is as follows: 5 mg of the boron-containing drug in Example 1 is weighed, and 2.5 ml of sodium acetate buffer solution with a pH of 5.5 is added and mixed uniformly by ultrasonication. 177 LuCI3 standard solution was added and the mixture was shaken in a water bath at 50°C for 50 minutes. The supernatant and precipitate were centrifuged and washed three times with sodium acetate (pH 5.5). The resulting supernatant and precipitate were collected and their radioactivity was measured. The labeling rate of the boron-containing drug was calculated to be over 99%. The precipitate was placed in saline, phosphate buffer, or 5% fetal bovine serum and left at 37°C for 6 days. The supernatant and precipitate were centrifuged and washed three times with sodium acetate (pH 5.5). The resulting supernatant and precipitate were collected and their radioactivity was measured. The leakage rate of the boron-containing drug was calculated to be less than 1%.

[0049] Example 6 Preparation of radiopharmaceuticals In this embodiment, 64 Cu, 67 Cu, 89 Zr, 89 Sr, 111 In, 165 Dy, 166 Ho, 201 T.I., 213 Bi, 212 Bi, 225 Ac, 223 Ra, 212 The labeling effect of Pb is explained. The labeling process is shown in Example 4, and the labeling rate and leakage rate are shown in Table 1.

[0050] [Table 1]

[0051] Example 7 Preparation of radiopharmaceuticals In this embodiment, 131 The labeling process of I is explained as follows: Chloramine T is dissolved in an organic solvent, applied to the bottom of the tube, and allowed to dry. 25 mg of the boron-containing drug of Example 1 is uniformly dispersed in 10 ml of PBS buffer solution and placed in a reaction tube, which is then placed in an ice bath. 131 Add 5mCi of I solution and let it react for 10 minutes. After ultrafiltration, measure the total activity in the ultrafiltration tube, and the labeling rate is over 95%. Place the precipitate in saline, phosphate buffer, or 5% fetal bovine serum, respectively, and let it stand at 37°C for 48 hours. Centrifuge the supernatant and precipitate, then wash three times with sodium acetate (pH 5.5) buffer. Collect the resulting supernatant and precipitate, and measure their radioactivity. Calculate the leakage rate of the boron-containing drug to be less than 1% in both cases.

[0052] Example 8 Preparation of radiopharmaceuticals In this embodiment, 123 The labeling process of I is explained as follows: Chloramine T is dissolved in an organic solvent, applied to the bottom of the tube, and allowed to dry. 5 mg of the boron-containing drug of Example 1 is uniformly dispersed in 2 ml of PBS buffer solution and placed in a reaction tube, which is then placed in an ice bath. 123 Add 1 mCi of I solution and let it react for 10 minutes. After ultrafiltration, measure the total activity in the ultrafiltration tube, and the labeling rate is 86%.

[0053] Example 9 Preparation of radiopharmaceuticals In this embodiment, 18 The F labeling process is explained as follows: 2.5 mg of a boron-containing drug is dissolved in a mixture of 0.6 ml of trifluoroacetic acid and 0.9 ml of trichlorofluoromethane. 18 F]F2 gas was injected together with neon gas, and trifluoroacetic acid and 0.9 ml of trichlorofluoromethane were evaporated under a neon gas atmosphere. The remaining nanoparticles were collected and their radioactivity was measured to calculate the labeling rate, which was 71%.

[0054] Example 10 Preparation of radiopharmaceuticals In this embodiment, 99m The Tc labeling process is described as follows: 5 mg of nanoparticles are added to 5 ml of sodium acetate buffer solution (pH 4.0) containing 4 mg of sodium ascorbate, 100 mg of NaCl, and 100 mg of NaCl. 99m TcO4 1mCi was added in sequence, and the mixture was shaken at 80°C for 15 minutes to achieve the target nuclide labeling, with a labeling rate of 85%.

[0055] Example 11: Biodistribution experiment of boron-containing drugs in a mouse subcutaneous brain glioma model The boron-containing drug from Example 1 was collected and injected into tumor-bearing mice via the tail vein at a dose of 150 mg / kg. 12, 24, and 36 hours after administration, the mouse's heart, liver, spleen, lungs, kidneys, blood, brain, tumor, and normal tissue from the tumor edge were collected. Each tissue was weighed and digested, and the boron concentration in each organ was measured using ICP-MS. 24 hours later, the boron concentration in the tumor reached 74 μg / g, with a T / N ratio of 70:1. The distribution of boron in the mice at 12, 24, and 36 hours after administration is shown in Table 2.

[0056] [Table 2]

[0057] This example investigated the distribution of subcutaneous brain glioma model animals, and found that the boron-containing drug was significantly taken up into the tumor site.

[0058] Example 12 SPECT-CT Experiment About 0.2 mCi of Example 7 131 A boron-containing drug labeled with I was injected into the tumor-bearing mice via the tail vein. SPECT-CT image data were statically collected for 10 min at 9, 18, 24, and 48 hours after the injection. The results are shown in Figure 4. 131Figure 5 shows SPECT-CT image data obtained by statically collecting I for 10 minutes after injection into tumor-bearing mice via the tail vein. I was mainly metabolized by the kidney and bladder. Except for the major metabolic organs such as the gallbladder, kidney, and bladder, there was no significant uptake by the remaining normal tissues, and there was significant uptake at the tumor site, indicating that nuclide labeling does not affect the uptake of boron-containing drugs at the tumor site.

[0059] Example 13 131 Treatment of mouse subcutaneous brain gliomas with I-labeled boron-containing drugs Saline and approximately 2 mCi of Example 7 131 The I-labeled boron-containing drugs were injected into tumor-bearing mice via the tail vein, and the volume of the subcutaneous brain gliomas in the mice was measured on days 3, 5, and 10. The specific results are shown in Table 3. 131 I-labeled boron-containing drugs can significantly inhibit tumor growth.

[0060] [Table 3]

[0061] Finally, it should be noted that the above embodiments are only for explaining the technical solutions of the present invention, and are not intended to limit the same. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art can still modify the technical solutions described in the above embodiments or make equivalent substitutions for some or all of the technical features therein, and these modifications or substitutions should not cause the essence of the corresponding technical solutions to depart from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. obtained by labeling a boron-containing drug with at least one radionuclide, A radionuclide-labeled boron-containing drug, characterized in that the boron-containing drug is obtained by a polymerization reaction between dopamine or a derivative thereof and a boron-containing compound.

2. The radionuclide is ６８ Ga, ６７ Ga, ６４ Cu, ６７ Cu, ８９ Zr, ８９ Sr, ９０ Y. １７７ Lu, １１１ In, １６５ Dy, １６６ Ho, ２０１ T.I., ２１３ Bi, ２１２ Bi, ２２５ Ac, ２２３ Ra, ２１２ Pb, ２１１ At, １２４ I, １２３ I, １２５ I, １３１ I, １８ F. １８６ Re, １８８ Re, ９９ｍ 2. The radionuclide-labeled boron-containing drug of claim 1, comprising any one or more of Tc.

3. 2. The radionuclide-labeled boron-containing drug according to claim 1, wherein the particle size of the radionuclide-labeled boron-containing drug is 50 to 1000 nm.

4. 2. The radionuclide-labeled boron-containing drug according to claim 1, wherein the boron-containing compound comprises one or more of boric acid, phenylalanine borate and derivatives thereof, proline borate, aspartic acid borate, tyrosine borate, cysteine ​​borate, methionine borate, serine borate, 5-amino-2,3-difluorophenylboronic acid, 3-amino-5-cyanophenylboronic acid, 3-amino-4-methylphenylboronic acid, 3-aminophenylborate hydrochloride, and 4-carbamoylphenylboronic acid.

5. The radionuclide-labeled boron-containing drug according to claim 1, wherein the dopamine and its derivatives include one or more of dopamine, 4-(2-aminopropyl)benzene-1,2-diol, noradrenaline, L-methyldopa, droxidopa, and 5-hydroxydopamine.

6. The radionuclide-labeled boron-containing drug according to claim 5, wherein the dopamine and its derivatives are dopamine, L-methyldopa, or 5-hydroxydopamine.

7. 2. The radionuclide-labeled boron-containing drug according to claim 1, wherein the mass ratio of the dopamine and its derivatives to the boron-containing compound is (1-10):

1.

8. 8. The radionuclide-labeled boron-containing drug according to any one of claims 1 to 7, characterized in that the indications for the radionuclide-labeled boron-containing drug include head and neck tumors, lung cancer, peritoneal cancer, liver cancer, gastric cancer, melanoma, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, and thyroid cancer.

9. Complexation of the radionuclide with the polyhydroxyl or carboxyl groups of the boron-containing drug, followed by precipitation and solidification; or Labeling of a radionuclide to the benzene ring structure of a boron-containing drug by forming a covalent bond through a chemical reaction 9. A method for producing a radionuclide-labeled boron-containing drug according to any one of claims 1 to 8, comprising:

10. 10. Use of a radionuclide-labelled boron-containing drug according to any one of claims 1 to 8 in the manufacture of a drug for the treatment of tumours and / or for the diagnostic imaging of tumours.

Images