Radioactive nuclide-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 belongs to the technical field of radiopharmaceuticals, and specifically relates to radionuclide-labeled boron-containing drugs, and the preparation and use thereof.

Background Art

[0002] Local targeted internal irradiation therapy is an internal irradiation therapy that accurately delivers radionuclides to the local tumor site via a carrier and achieves treatment through radiation emitted from the radionuclide. Due to its remarkable therapeutic effect, it plays an important role in the treatment of diseases such as tumors and is currently one of the hot research directions. At present, as radionuclide carriers, there are methods, technologies or drugs that achieve accurate local internal irradiation therapy using microspheres, sealed metal seed sources, small molecules, antibodies, polypeptides, nano-drugs, etc. The core technical difficulties of targeted radiopharmaceuticals are: (1) designing and developing carriers with good targeting properties; (2) achieving efficient and stable labeling of radionuclides on carriers with good targeting properties, and ensuring that the radionuclide-labeled carrier still retains good targeting properties for target lesions or tumor cells.

[0003] At present, most targeted drug carriers such as small molecules, antibodies and polypeptides used in clinical applications have problems such as difficulty in achieving high-efficiency stable radionuclide labeling, poor stability after radionuclide labeling, and loss of targeting properties after radionuclide labeling. Due to the high technical difficulty, the development progress of targeted radiopharmaceuticals is relatively slow and delayed.

Summary of the Invention

[0004] In order to solve the technical problems in the background art, an object of the present invention is to provide a radionuclide-labeled boron-containing drug, and the preparation and use thereof. The radiopharmaceutical is 68 Ga, 67 Ga, 64 Cu, 67 Cu, 89 Zr, 89 Sr, 90 Y, 177 Lu, 111In, 165 Dy, 166 Ho, 201 TI, 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 radionuclides 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 is obtained by labeling the boron-containing drug with at least one radionuclide.

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

[0008] Preferably, the radioactive nuclide is 68 Ga, 67 Ga, 64 Cu, 67 Cu, 89 Zr, 89 Sr, 90 Y, 177 Lu, 111 In, 165 Dy, 166 Ho, 201 TI, 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, 99mIncludes one or more of the following Tc types.

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

[0010] Preferably, the boron-containing compound is boric acid, Borono Phenylalanine and its derivatives, Borono Proline, Borono Aspartic acid, Borono Tyrosine, Borono Cysteine, Borono Methionine, Borono Serine, 5-amino-2,3-difluorophenyl boron Acid, 3-amino-5-cyanophenyl Boronic acid , 3-amino-4-methylphenyl Boronic acid , 3-aminophenyl Boronic acid Hydrochloride, 4-carbamoylphenyl Boronic acid This includes, but is not limited to, one or more of the following:

[0011] Preferably, the dopamine and its derivatives include one or more of the following: dopamine, 4-(2-aminopropyl)benzene-1,2-diol, norepinephrine (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 its derivatives are dopamine, L-methyldopa, and 5-hydroxydopamine.

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

[0014] 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 radioactive nuclide-labeled boron-containing drug is as follows: Complexation of a polyhydroxy group or carboxyl group in a boron-containing drug with a radionuclide, as well as precipitation and solidification, or This method involves forming a covalent bond through a chemical reaction and labeling the benzene ring structure of a boron-containing drug with a radionuclide.

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

[0018] The radiopharmaceutical 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 TI, 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 This enables highly efficient labeling of radionuclides such as Tc, 68 Ga, 67 Ga, 90 Y,177 Lu, 165 Dy, 166 The labeling efficiency of multiple radionuclides, including Ho, exceeds 98%, and this radiopharmaceutical exhibits good stability in physiological saline, phosphate buffer, and 5% fetal bovine serum. The radiopharmaceutical of the present invention has a particle size of 50-1000 nm, good stability, enters cells, crosses the blood-brain barrier, and possesses tumor-targeting properties, allowing it to be used simultaneously for tumor treatment or development. This radiopharmaceutical, labeled with radionuclides, can be used for drug distribution studies, screening of potential patients for treatment, or prediction of therapeutic effects. [Brief explanation of the drawing]

[0019] [Figure 1] This is an SEM image of the boron-containing drug after redissolution in Example 2. [Figure 2] This is an SEM image of the boron-containing drug labeled with 90Y in Example 4. [Figure 3] This is a DLS diagram of the boron-containing drug labeled with 90Y in Example 4. [Figure 4] This is a SPECT-CT image of a mouse body containing a boron-containing drug labeled with 131I in Example 12. [Figure 5] This is a SPECT-CT image of a free 131I mouse in Example 12. [Modes for carrying out the invention]

[0020] To better understand the technical concept of the present invention, the technical concept of the present invention will be further described below with reference to the drawings and examples. The methods for realizing the present invention include, but are not limited to, the following examples, and are for illustrative purposes only and do not limit the scope of protection of the present invention. Unless otherwise specified, the technical means used in the examples are common 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 provided by the present invention is a radionuclide-labeled boron-containing drug obtained by labeling a boron-containing drug with at least one radionuclide, wherein the boron-containing drug is obtained by a polymerization reaction of dopamine or a derivative thereof and a boron-containing compound.

[0022] Between the boron-containing drug and the radionuclide, labeling of the radionuclide to the boron-containing drug is achieved in the form of complexation or covalent bonding.

[0023] The boron-containing drug of the present invention contains polyphenol, carboxyl group and benzene ring structure in its molecular structure, has good tumor targeting properties, and the boron-containing drug itself has good physicochemical stability properties, and can become a radiopharmaceutical with good targeting properties after being labeled with a radionuclide. The boron-containing drug of the present invention itself does not have development properties, and the in vivo distribution and metabolism of the boron-containing drug is a difficult point in research during the drug development process. The radionuclide-labeled boron-containing drug provided by the present invention has the property of simultaneously achieving efficient and stable labeling of multiple radionuclides, and still has good physicochemical properties and tumor targeting properties after being labeled with a radionuclide, and has the potential to be developed as an integrated local targeted internal irradiation diagnosis and treatment drug. In addition, the radionuclide-labeled boron-containing drug contributes to the research on the in vivo distribution and metabolism of the drug itself, and assists in the development of the boron-containing drug.

[0024] The radiopharmaceutical of the present invention does not change the tumor targeting property of the boron-containing drug, can be metabolized (biodegraded) in the body, and 48 hours after being injected into the body, the drug concentration decreases rapidly until it is completely metabolized and eliminated.

[0025] The radionuclide used for labeling in the embodiment 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, 166Ho, 201 TI, 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 comprises any one or more of Tc.

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

[0027] In some preferred embodiments, the boron-containing compound is boric acid, Borono phenylalanine and derivatives thereof, Borono proline, Borono aspartic acid, Borono tyrosine, Borono cysteine, Borono methionine, Borono serine, 5-amino-2,3-difluorophenyl boron acid, 3-amino-5-cyanophenyl Boronic acid , 3-amino-4-methylphenyl Boronic acid , 3-aminophenyl Boronic acid hydrochloride, 4-carbamoylphenyl Boronic acid includes, but is not limited to, any one or more of the above.

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

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

[0030] The indications for the radionuclide-labeled boron-containing drug 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] A second embodiment of the present invention provides a method for producing a boron-containing drug labeled with a radionuclide, the method of which can be implemented in the following two forms: (1) Stable labeling is achieved by complexing and further precipitation solidification of a metallic radionuclide with groups such as polyhydroxy groups and carboxyl groups in the boron-containing drug. (2) Stable labeling is achieved by labeling the radionuclide to the benzene ring structure of the boron-containing drug by forming a covalent bond through a chemical reaction. The specific labeling method is not particularly limited, as long as it can achieve the above two types of labeling.

[0032] As some specific embodiments, a method for complexing and labeling a radionuclide with a boron-containing drug is 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 TI, 213 Bi, 212 Bi, 225 Ac, 223 Ra, 212 This method is applied to radionuclides such as Pb, and the specific method is as follows: 10-100 mg of boron-containing drug is weighed, a buffer solution with a pH of 3.0-7.0 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 reacted for 60 minutes under water bath conditions at 30-80°C to allow sufficient binding of the boron-containing drug and the radionuclide; the well-bound mixed solution is centrifuged to obtain a solid, washed three times with buffer solution, and the supernatant and precipitate are collected. The radioactivity of each is measured, and the labeling rate of the radionuclide-labeled boron-containing drug is calculated. Radionuclide-labeled boron-containing drugs with a certain level of activity are placed in physiological saline, phosphate buffer, and 5% fetal bovine serum, respectively, and allowed to stand at 37°C for a certain period of time. The supernatant is taken, and the activity or radioactivity is measured to calculate the radionuclide leakage rate of the drug in different solutions. 68 Ga, 67 Ga, 90 Y, 177 Lu, 165 Dy, 166 The labeling efficacy of multiple radionuclides, including Ho, exceeded 98%, and the radionuclide leakage rate was less than 5% over 6 days in physiological saline, phosphate buffer, and 5% fetal bovine serum.

[0033] A method for complexing and labeling radionuclides with boron-containing drugs is: 186 Re, 188 Re, 99m This method is also applicable to radionuclides such as Tc, and the specific method is as follows: Add 4-500 mg of sodium ascorbate to a sodium acetate buffer solution (pH 3.0-6.0) containing 5-100 mg of nanoparticles, and Na 186 ReO4 / Na 188 ReO4 / Na 99mTcO40.1 to 100 mCi are added sequentially, and the reaction is carried out with shaking at 80°C for 15 minutes. The solid is obtained by centrifugation, washed three times with buffer solution, and the supernatant and precipitate are collected. The radioactivity of each is measured, and the labeling fraction of the radionuclide-labeled boron-containing drug is calculated. Upon detection, 186 Re, 188 Re, 99m The labeling efficiency of Tc exceeds 85%, and the radiopharmaceutical of the present invention can be used for the treatment of tumors.

[0034] As some other specific embodiments, a method for labeling a boron-containing drug with a radionuclide by a covalent reaction is at least 211 At, 124 I, 123 I, 125 I, 131 Applicable to radionuclides such as I, the specific method is as follows: Dissolve chloramine T in an organic solvent, coat the bottom of the tube, and dry it; place 5-10 mg of boron-containing drug and a buffer solution with a pH of 7.0-8.0 in a reaction tube, add the radionuclide in an ice bath, and react for 5-30 minutes; centrifuge the mixed solution after the reaction is complete, wash the precipitate multiple times, measure the total radioactivity in the supernatant and precipitate, and calculate the labeling fraction of the radionuclide-labeled boron-containing drug. Place drugs with a certain level of activity in physiological saline, phosphate buffer, and 5% fetal bovine serum, stand at 37°C for a certain period of time, take the supernatant, measure the activity or radioactivity count, and calculate the radionuclide leakage rate of the drug in different solutions. 131 I and 123 The labeling efficacy of I exceeded 85%, the labeling amount exceeded 10 mCi / mg, the labeling was stable, the radionuclide did not clearly detach in the body, and the therapeutic effect against tumors was remarkable. When incubated in physiological saline, phosphate buffer, and 5% fetal bovine serum for 48 hours, the leakage rate of the radionuclide was less than 1% in all cases.

[0035] A method for labeling a boron-containing drug with a radionuclide via a covalent bond reaction is: 18 This method is also applicable to radioactive nuclides such as F, and the specific method is as follows: Disperse the boron-containing drug uniformly in a trifluoroacetic acid solution. 18The reaction is carried out by introducing the F2 gas into the solution using gas bubbling. After half an hour, the precipitate is collected, its radioactivity is measured, and the labeling efficiency of the boron-containing drug is calculated. 18 The labeling efficiency of F exceeds 70%, making it suitable for studies on the in vivo distribution of boron-containing drugs.

[0036] A 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, reacting the mixture, obtaining a solid by solid-liquid separation, washing the solid, and freeze-drying it.

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

[0038] A third embodiment of the present invention provides the use of a radionuclide-labeled boron-containing drug in the manufacture of drugs for the treatment and / or imaging of tumors. That is, the drug can not only achieve the treatment or development of tumors, but also enable the creation of an integrated drug for tumor treatment. The developed radionuclide-labeled drug of the present invention can be used for drug distribution studies and screening of potential patients for treatment or prediction of treatment efficacy.

[0039] This invention, based on the composition and structural design of a boron-containing drug, makes the boron-containing drug a good radionuclide carrier and enables labeling of radionuclides by a simple radionuclide labeling method. After labeling the developed and / or treated radionuclide, the boron-containing drug can be used in the treatment of cancer patients.

[0040] The present invention 211 At, 124 I, 123 I, 125 I, 131 I and 18Radioactively labeled boron-containing drugs such as fluorine can be used to develop boron-containing drugs using SPECT-CT, and are used in studies of the in-vivo distribution of boron-containing drugs, helping to understand the dynamic distribution information of boron-containing drugs within patients. 211 At, 124 I, 123 I, 125 I, 131 I and 18 Radioactively labeled boron-containing drugs such as F can be used for pre-treatment screening and prediction of treatment effectiveness in patients, and are expected to enable accurate medical treatment. 131 The drug labeled with I is expected to be useful in the integrated treatment of tumors.

[0041] 131 After intravenous injection of a boron-containing drug labeled with I, SPECT-CT development showed that the drug was highly concentrated in the tumor at approximately 24 hours, and that radionuclide labeling did not alter the tumor targeting properties of the boron-containing drug, which were clearly evident in the animal thyroid gland. 131 I did not show any concentration. 131 It is proven that the drug labeled with I does not concentrate in the thyroid gland, and that the label on the drug 131 No clear dropouts occurred in group I.

[0042] To further clarify the technical concept of the present invention, the radionuclide-labeled boron-containing drug, its manufacturing method, and its use will be described below with reference to several specific examples. [Examples]

[0043] Example 1: Production of a boron-containing drug Weigh 80 mg of dopamine hydrochloride into a reaction flask, add 34 ml of 30% ethanol solution, and stir to dissolve. 4-Borono ( 10 B)-L-phenylalanineWeigh 20 mg of (BPA) into a centrifuge tube, add 3 ml of water, and then add 0.2 ml of 2.5 mol / L NaOH solution to completely dissolve the BPA; mix the solutions, adjust the pH to about 10 with NaOH, stir at 300 rpm for 24 hours, centrifuge at 10000 rpm, and wash three times with pure water; suspend the product in water and freeze-dry to obtain a boron-containing drug.

[0044] Example 2: Redissolution experiment of boron-containing drugs after freeze-drying. 5 mg of the boron-containing drug from 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, with water being one of the dispersants. After uniform mixing by hand, SEM detection was performed, and the morphological characteristics are shown in Figure 1.

[0045] Example 3: Production of radioactive drugs This embodiment is, 68 This is to explain the Ga labeling process, which is as follows: 5 mg of the boron-containing drug in Example 1 is weighed, 2 ml of sodium acetate buffer solution with pH=5.5 is added, and it is mixed uniformly using ultrasound. 500 μCi 68 A GaCl3 solution is added, and the mixture is shaken for 50 minutes under 50°C water bath conditions. The mixture is centrifuged, and the solution is washed three times with sodium acetate at pH=5.5. The supernatant and precipitate are collected, and their radioactivity is measured. It is calculated that the nuclide labeling rate of the boron-containing drug exceeds 99%. The precipitates are placed in physiological saline, phosphate buffer, and 5% fetal bovine serum, respectively, and allowed to stand at 37°C for 24 hours. The supernatant and precipitate are centrifuged, and the solution is washed three times with sodium acetate at pH=5.5. The supernatant and precipitate are collected, and their radioactivity is measured. It is calculated that the leakage rate of the boron-containing drug is less than 1% in all cases.

[0046] Example 4: Production of radioactive drugs This embodiment is, 90This is to explain the labeling process for Y, and is as follows: 5 mg of the boron-containing drug in Example 1 is weighed, 2 ml of sodium acetate buffer solution with pH=5.5 is added, and it is mixed uniformly using ultrasound. 500 μCi 90 YCI3 standard solution is added, and the mixture is shaken for 50 minutes under 50°C water bath conditions. The mixture is centrifuged, and the solution is washed three times with sodium acetate at pH=5.5. The supernatant and precipitate are collected, and their radioactivity is measured. It is calculated that the labeling efficiency of the boron-containing drug exceeds 98%. The precipitates are placed in physiological saline, phosphate buffer, and 5% fetal bovine serum, respectively, and allowed to stand at 37°C for 6 days. The supernatant and precipitate are centrifuged, and the solution is washed three times with sodium acetate at pH=5.5. The supernatant and precipitate are collected, and their radioactivity is measured. It is calculated that the leakage rate of the boron-containing drug is less than 1% in all cases.

[0047] In this embodiment 90 SEM images of boron-containing drugs labeled with Y are shown in Figure 2, and DLS images are shown in Figure 3.

[0048] Example 5: Production of radioactive drugs This embodiment is, 177 This is to explain the labeling process for Lu, and is as follows: 5 mg of the boron-containing drug in Example 1 is weighed, 2.5 ml of sodium acetate buffer solution with pH=5.5 is added, and it is mixed uniformly with ultrasound. 500 μCi 177 LuCl3 standard solution is added, and the mixture is shaken for 50 minutes under 50°C water bath conditions. The supernatant and precipitate are centrifuged, and the mixture is washed three times with sodium acetate at pH=5.5. The obtained supernatant and precipitate are collected, and their radioactivity is measured. It is calculated that the labeling efficiency of the boron-containing drug exceeds 99%. The precipitates are placed in physiological saline, phosphate buffer, and 5% fetal bovine serum, respectively, and allowed to stand at 37°C for 6 days. The supernatant and precipitate are centrifuged, and the mixture is washed three times with sodium acetate at pH=5.5. The obtained supernatant and precipitate are collected, and their radioactivity is measured. It is calculated that the leakage rate of the boron-containing drug is less than 1% in all cases.

[0049] Example 6: Production of radioactive drugs This embodiment is, 64 Cu, 67 Cu, 89 Zr, 89 Sr, 111 In, 165 Dy, 166 Ho, 201 TI, 213 Bi, 212 Bi, 225 Ac, 223 Ra, 212 This explains the labeling effect of Pb. The labeling process is described in Example 4, and the labeling rate and leakage rate are shown in Table 1.

[0050] [Table 1]

[0051] Example 7: Production of radioactive drugs This example is 131 This is to explain the labeling process of I, and is as follows: Dissolve chloramine T in an organic solvent, coat the bottom of the tube with the solution, and let it dry. Disperse 25 mg of the boron-containing drug from Example 1 uniformly in 10 ml of PBS buffer solution and place it in a reaction tube, then place the reaction tube in an ice bath, 131 Add 5 mCi of solution I and allow to react for 10 minutes. Ultrafiltration is performed and the overall activity in the ultrafiltration tube is measured, with a labeling efficiency exceeding 95%. The precipitates are placed in physiological saline, phosphate buffer, and 5% fetal bovine serum, respectively, and allowed to stand at 37°C for 48 hours. The supernatant and precipitate are centrifuged, and washed three times with sodium acetate at pH=5.5. The obtained supernatant and precipitate are collected, and their radioactivity is measured, resulting in a leakage rate of less than 1% for the boron-containing drug in each case.

[0052] Example 8: Production of radioactive drugs This example is 123This is to explain the labeling process of I, and is as follows: Dissolve chloramine T in an organic solvent, coat the bottom of the tube with the solution, and let it dry. Disperse 5 mg of the boron-containing drug from Example 1 uniformly in 2 ml of PBS buffer solution and place it in a reaction tube, then place the reaction tube in an ice bath, 123 Add 1 mCi of solution I and allow to react for 10 minutes. Ultrafiltration is performed and the overall activity in the ultrafiltration tube is measured; the labeling efficiency is 86%.

[0053] Example 9: Production of radioactive drugs This embodiment is, 18 This is to explain the labeling process of F, and is as follows: 2.5 mg of boron-containing drug is dissolved in a mixed solution of 0.6 ml of trifluoroacetic acid and 0.9 ml of trichlorofluoromethane. A certain activity level is added to this solution [ 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 efficiency, which was found to be 71%.

[0054] Example 10: Production of a radioactive drug This embodiment is, 99m This is to explain the labeling process for Tc, and is as follows: 5 ml of sodium acetate buffer solution (pH 4.0) containing 5 mg of nanoparticles, then 4 mg of sodium ascorbate and Na 99m TcO41mCi was added sequentially, and the reaction was carried out at 80°C for 15 minutes with shaking to achieve labeling of the target nuclide, with a labeling efficiency of 85%.

[0055] Example 11: Experiment on the in vivo distribution of boron-containing drugs in a mouse subcutaneous 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. At 12, 24, and 36 hours after administration, normal tissue samples were collected from the heart, liver, spleen, lungs, kidneys, blood, brain, tumor, and tumor edge of the mice. Each tissue sample was weighed, decomposed, and the boron concentration in each organ was measured by ICP-MS. At 24 hours, the boron concentration in the tumor site reached 74 μg / g, and the T / N ratio reached 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 studied the distribution of boron-containing drugs in subcutaneous glioma model animals, and found that the boron-containing drug was significantly absorbed at the tumor site.

[0058] Example 12: SPECT-CT experiment In Example 7, approximately 0.2 mCi 131 Boron-containing drugs labeled with I were injected into the bodies of tumor-bearing mice via the tail vein. After injection, static samples were collected for 10 minutes at 9h, 18h, 24h, and 48h, respectively, and SPECT-CT image data was acquired. The results are shown in Figure 4. 131 SPECT-CT image data obtained by injecting I into tumor-bearing mice via the tail vein and statically collecting for 10 minutes is shown in Figure 5. It is mainly metabolized by the kidney and bladder, and except for major metabolic organs such as the gallbladder, kidney, and bladder, it is not significantly taken up by any of the remaining normal tissues, while uptake is significant at the tumor site, indicating that radionuclide labeling does not affect the uptake of boron-containing drugs at the tumor site.

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

[0060] [Table 3]

[0061] Finally, it should be noted that the above embodiments are merely for illustrating the technical concepts of the present invention and do not limit them. While the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical concepts described in the above embodiments or make equivalent substitutions for some or all of the technical features therein, and that such modifications or substitutions will not cause the essence of the corresponding technical concepts to deviate from the scope of the technical concepts of the embodiments of the present invention.

Claims

1. Obtained by labeling a boron-containing drug with at least one radionuclide, The boron-containing drug is obtained by a polymerization reaction between dopamine and its derivatives and a boron-containing compound. The boron-containing compound comprises one or more of the following: boric acid, 4-borono(10B)-L-phenylalanine (BPA), boronoproline, boronospartic acid, boronotyrosine, boronocysteine, boronomethionine, boronoserine, 5-amino-2,3-difluorophenylboronic acid, 3-amino-5-cyanophenylboronic acid, 3-amino-4-methylphenylboronic acid, 3-aminophenylboronic acid salt, and 4-carbamoylphenylboronic acid. The dopamine and its derivatives include one or more of the following: dopamine, 4-(2-aminopropyl)benzene-1,2-diol, norepinephrine, L-methyldopa, droxidopa, and 5-hydroxydopamine. A radionuclide-labeled boron-containing drug characterized in that the radionuclide includes one or more of the following: 68 Ga, 67 Ga, 64 Cu, 67 Cu, 89 Zr, 89 Sr, 90 Y, 177 Lu, 111 In, 165 Dy, 166 Ho, 201 Ti, 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, and 99 mTc.

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

3. The radionuclide-labeled boron-containing drug according to claim 1, characterized in that the dopamine and its derivatives are dopamine, L-methyldopa, or 5-hydroxydopamine.

4. The radionuclide-labeled boron-containing drug according to claim 1, characterized in that the mass ratio of dopamine and its derivatives to the boron-containing compound is (1 to 10):

1.

5. Complexation of a polyhydroxy group or carboxyl group in a boron-containing drug with a radionuclide, as well as precipitation and solidification, or To label the benzene ring structure of a boron-containing drug with a radionuclide by forming a covalent bond through a chemical reaction. A method for producing a radionuclide-labeled boron-containing drug according to any one of claims 1 to 4, characterized by including the following:

6. Use of a radionuclide-labeled boron-containing drug according to any one of claims 1 to 4 in the manufacture of a drug for the treatment of tumors and / or for imaging diagnostics of tumors.

7. The use according to claim 6, characterized in that the tumor includes head and neck tumors, lung cancer, peritoneal cancer, liver cancer, stomach 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.

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