Method for rapidly measuring purity of Ac-225 nuclide

Abstract

The invention belongs to the technical field of radioactive nuclear purity analysis and nuclear medicine, and particularly relates to a method for rapidly measuring the liquid nuclear purity of an Ac-225 nuclide product, which comprises the following steps: (1) preparing an Ac-225 nuclide solution into a to-be-measured sample; (2) measuring the actual activity of radionuclide in the to-be-tested sample by adopting a high-purity germanium gamma energy disperse spectroscopy; and (3) calculating the ratio of the activity of the Ac-225 nuclide to the total radionuclide to obtain the purity of the Ac-225 nuclide. According to the method, the Ac-225 and radioactive impurity nuclides of the Ac-225 nuclide product liquid are rapidly analyzed at the same time by using the high-purity germanium gamma spectrometer, the operation is convenient, the analysis and detection period is short, the detection efficiency is greatly improved, and the method can be widely popularized and applied to quality control of various radionuclide products.

Description

Technical Field

[0001] The invention belongs to the technical field of radioactive nuclear purity analysis and nuclear medicine, and in particular relates to a method for rapidly measuring the purity of Ac-225 nuclides. Background Art

[0002] Radioactive medical isotope drugs are a special type of drugs containing radioactive isotopes for medical diagnosis and treatment, which can achieve early screening, diagnosis, precision treatment and pain relief of malignant tumors. α-targeted therapy has two obvious advantages over conventional therapy: (1) In terms of safety: α radiation has a short range in human tissue (<0.1mm), which can selectively kill targeted cancer cells without affecting surrounding healthy tissues; (2) In terms of tumor killing effect: high-energy α radiation of several MeV has a very high linear energy density, which can achieve efficient cell killing by acting on DNA double-strand and DNA cluster breaks. This damage is independent of the cell cycle and has nothing to do with its oxygenation state.

[0003] Ac-225 is a 100% alpha decay radionuclide with a half-life of t 1 / 2 The biological effect of the parent nuclide is 9.96 days, and it undergoes 4 alpha decays and 2 beta decays in the process of decaying to the stable nuclide Bi-209 (approximately stable), releasing alpha particles with a total energy of 27.5MeV. This makes the radiation dose of the parent nuclide to the target site large and has significant biological effects. It is considered to be the most suitable alpha targeted therapeutic nuclide for tumor treatment, especially for the treatment of tumors that have failed to be treated by other methods, especially in the late stage with multiple metastatic tumors.

[0004] In the prior art, Ac-225 is often produced by proton irradiation of Th-232, but in the process of bombarding the metal thorium target (Th-232) with a 120MeV high-energy proton accelerator, a large number of radioactive nuclides are co-produced, such as Th-227, Th-226, Ac-229, Ac-226, Ac-224, Ra-224, Ra-223, etc. The short half-life nuclides in these impurity nuclides will decrease with the increase of cooling time, and the radioactive nuclides of thorium and radium can be removed by separation and purification process. In quality control-radioactive nuclear purity testing, the focus is often on the long half-life nuclides Ac-227 (T1 / 2 = 21.8y) and the nuclides Ac-226 (T1 / 2 = 1.22d) with a large EOI, especially the Ac-227 nuclides, which have a long half-life and similar chemical properties to Ac-225, making it difficult to separate. Therefore, the production ratio of Ac-227 and Ac-225 should be strictly controlled during the target shooting stage.

[0005] The existing domestic and foreign pharmacopoeias do not directly mention the quality control methods and principles of alpha-nuclides radioactive drugs in the quality control guidelines for radioactive drugs. The methods for nuclide identification and radioactive purity test in the General Chapter 1401 of the Chinese Pharmacopoeia "Radioactive Drugs" are all gamma spectrometer methods, but they are not suitable for direct measurement of alpha decay radioactive nuclide Ac-225 nuclide products. The European Pharmacopoeia introduces the use of alpha spectrometers to identify alpha nuclides and the use of liquid scintillation counters to measure the activity of alpha nuclides. However, many by-product nuclides in Ac-225 nuclide products are gamma nuclides. Alpha spectrometers or liquid scintillation counters can only identify or measure alpha nuclides, and cannot directly analyze their radioactive purity.

[0006] In addition, the Chinese Pharmacopoeia and standards have not yet set quality standards for Ac-225 radiopharmaceuticals. The European Pharmacopoeia stipulates that the nuclear purity of Ac-225 radiopharmaceuticals is: Ac-225 content ≥ 99.9%, and other γ impurity nuclides total ≤ 0.1%. Radionuclear purity refers to the ratio (%) of the radioactivity of a specified radionuclide to the total radioactivity of the test sample. Rapid analysis of the radionuclear purity of the obtained Ac-225 nuclide products and quality control are of great significance in terms of drug safety and effectiveness. Summary of the invention

[0007] The purpose of the present invention is to provide a method for rapidly measuring the purity of Ac-225 nuclides, thereby overcoming the deficiencies of the prior art and establishing a method for rapidly measuring the purity of Ac-225 nuclides according to the equilibrium relationship between Ac-225, Ac-227 nuclides and their decay daughter nuclei, which has good practical value and prospects for promotion and application.

[0008] In order to achieve the above object, the technical solution of the present invention is:

[0009] In a first aspect, the present invention provides a method for rapidly measuring the nuclide purity of Ac-225, comprising the following steps:

[0010] (1) Prepare the Ac-225 nuclide solution into a sample to be tested;

[0011] (2) Use a high-purity germanium gamma spectrometer to measure the actual activity of the radioactive nuclides in the sample to be tested;

[0012] (3) The purity of Ac-225 nuclide is calculated by calculating the ratio of Ac-225 nuclide activity to total radionuclides.

[0013] In some other embodiments, step (2) further includes establishing a nuclide library, wherein the nuclide library includes nuclides Fr-221, Fr-223, Th-227, Ac-226, Th-229, Ra-225 and Ra-224;

[0014] The actual activity of the radionuclide is obtained by performing branching ratio correction on the activity of the radionuclide measured by the high-purity germanium gamma spectrometer and the number of nuclei in the nuclide library.

[0015] In some other embodiments, in step (1), the preparation method of the Ac-225 nuclide solution is: dissolving the irradiated thorium target, and separating and purifying it by four-stage series connection of a cation exchange resin column, a UTEVA or TK200 resin extraction column, a DGA resin extraction column and an 1N resin extraction column.

[0016] In some other embodiments, the conditions for irradiating the thorium target are: using a 100-120 MeV high energy proton accelerator to irradiate the metal thorium target, the irradiation flux is 80-100 μA, the irradiation time is 10-15 days, and the cooling time should be 3-10 days;

[0017] Preferably, a 120 MeV high energy proton accelerator is used to irradiate the metal thorium target, the irradiation flux is 100 μA, the irradiation time is 10 days, and the cooling time is 7 days.

[0018] In some other embodiments, in step (1), the method for preparing the test sample is: dropping 1-5 μL of Ac-225 nuclide solution on chromatographic paper and sealing; preferably, the volume of the Ac-225 nuclide solution is 2 μL.

[0019] In some other embodiments, in step (2), the conditions for measuring with the high-purity germanium gamma spectrometer are: the measuring time is 1200-1500 s, and the distance between the sample to be tested and the probe of the high-purity germanium gamma spectrometer is 20 cm;

[0020] Preferably, the measurement time is 1200 s.

[0021] In some other embodiments, in step (2), the measurement process of the high-purity germanium gamma spectrometer is: first, the efficiency and energy calibration of the high-purity germanium gamma spectrometer is performed using a standard source, then a blank sample test is performed, and then the test sample is allowed to stand for 30-60 minutes before testing; preferably, it is allowed to stand for 49 minutes.

[0022] In some other embodiments, in step (2), the radionuclide is Ac-225 and its daughter nuclides, Ac-227 and its daughter nuclides, Ac-226, Th-229, Ra-225 and Ra-224;

[0023] Preferably, the radioactive nuclides are Fr-221, Fr-223, Th-227, Ac-226, Th-229, Ra-225 and Ra-224.

[0024] In some other embodiments, in step (2), the activity of Fr-221 is equal to the activity of Ac-225;

[0025] Or, the relationship between the activity of Fr-223 and the activity of Ac-227 is:

[0026] A(Ac-227)=47959247.78A(Fr-223);

[0027] Or, the relationship between the activity of Th-227 and the activity of Ac-227 is:

[0028] A(Ac-227)=342082.8595A(Th-227).

[0029] In a second aspect, the present invention provides a method for detecting the quality of an Ac-225 nuclide product, which comprises using the method for rapidly measuring the purity of the Ac-225 nuclide described in the first aspect to detect the activity of Ac-225 and its daughter nuclides, Ac-227 and its daughter nuclides, Ac-226, Th-229, Ra-225 or Ra-224 in the Ac-225 nuclide product.

[0030] Compared with the prior art, the beneficial effects of the present invention are:

[0031] (1) Small loss of Ac-225 nuclide product: The high-purity germanium gamma spectrometer measures the radioactive nuclear purity with a small sampling volume of only 2ul. After the radioactive nuclear purity is measured, the sample can be directly used for radioactive nuclide identification testing, resulting in small product loss.

[0032] (2) High sensitivity and high precision: The activity of the daughter Fr-221 is accurately measured based on the decay balance of Ac-225, thereby inferring the activity of Ac-225. The activity of daughter nuclides Ac-225 and Ac-227, as well as other radionuclides Ac-226, Th-229, Ra-225, and Ra-224 are simultaneously measured using a high-purity germanium gamma spectrometer. The results are accurate and reliable, the operation is simple and convenient, and it has good practical value and prospects for promotion and application. It can provide a basis for the formulation of quality standards for Ac-225 radiopharmaceuticals in my country. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0034] Figure 1 In the embodiment of the present invention Figure 1 It is the decay chain diagram of radionuclides Ac-225, Ac-226, and Ac-227;

[0035] Figure 2 is the gamma spectrum of the Ac-225 product solution in Example 1 of the present invention;

[0036] Figure 3 It is the liquid scintillation spectrum of the Ac-225 product liquid in Comparative Example 1 of the present invention. DETAILED DESCRIPTION

[0037] The present invention provides a method for rapidly measuring the purity of Ac-225 nuclides, and the overall inventive concept adopted is:

[0038] Ac-225 products are produced by optimizing the conditions of high-energy proton accelerator irradiation of metal thorium targets (Th-232). Figure 1 This is the decay chain diagram of the radioactive nuclides Ac-225, Ac-226, and Ac-227. Figure 1 It can be seen that since the half-life of Ac-226 is 1.22d, the decay rate is greater than that of Ac-225. With the increase of cooling time, Ac-226 and other short half-life nuclides decay, the radioisotope purity of Ac-225 increases, but the activity of Ac-225 also decreases accordingly. Under the condition of ensuring sufficient radioactive nuclear purity, try to retain Ac-225 with a larger activity. The cooling time should be 3-10 days. Here, the cooling time is set to 7 days. After 7 days, the decay rate of Ac-226 is about 99.3%. At this time, the separation and purification process can obtain a relatively pure Ac-225 nuclide product liquid.

[0039] The Ac-225 nuclide product liquid is sampled. To reduce the self-absorption effect during the sample measurement, the sample volume is kept as small as possible. The specific sampling method is: drop the Ac-225 nuclide product liquid on the center of the chromatographic paper, and put the chromatographic paper into a sealed bag to prevent contamination of the instrument probe, thus preparing the sample to be tested.

[0040] Ac-225 decays into Fr-221 through α decay. The half-life of Fr-221 is 4.9 minutes. During decay, it emits γ rays with energies of 218, 100.2, and 410.4 KeV. The activity of Fr-221 in the sample to be tested depends on the decay of Ac-225. After a period of time 10 times the half-life of Fr-221 (49 minutes), Ac-225 and Fr-221 reach radioactive equilibrium, at which point the activity of Ac-225 is equal to that of Fr-221. A high-purity germanium γ spectrometer is used to measure the γ rays emitted by Fr-221 to calculate the activity of the nuclide Ac-225.

[0041] When the Ac-227 nuclide decays, the gamma ray branching ratio is less than 1%. Directly measuring the Ac-227 nuclide at low activity can easily lead to large errors in the results. The Ac-227 nuclide undergoes α decay (1.38%) to become Fr-223 and β decay (98.62%) to become Th-227. The half-life of Fr-223 is 22 minutes, and it emits gamma rays with an energy of 50.094KeV (34%) when it decays. The half-life of Th-227 is 18.68 days, and it emits gamma rays with an energy of 235.96KeV (12.9%) when it decays. According to the formula of the law of sequential decay:

[0042]

[0043]

[0044] Where, t: decay time, s; A1: parent nuclide activity, Bq; λ1: parent nuclide decay constant, S -1 ; A2: activity of parent nuclide, Bq; λ2: decay constant of parent nuclide, S -1 .

[0045] The decay constant of the parent nuclide Ac-227 is 1.00886E-9S -1 ; The decay constant of the daughter nuclide Fr-223 is 5.251E-4S -1 ; When the decay time is 49 minutes, the relationship between the nuclide activities of Ac-227 and Fr-223 is:

[0046] A (Ac -227)=47959247.78A (Fr -223)

[0047] The decay constant of the daughter nuclide Th-227 is 4.2908E-7S -1 ; When the decay time is 49 minutes, the relationship between the nuclide activities of Ac-227 and Th-227 is:

[0048] A (Ac -227)=342082.8595A (Th -227)

[0049] The half-life of Ac-226 nuclide is 29.37h, and the γ-ray branching ratio during decay is 230KeV (26.9%), 158.05KeV (17.5%), and 72.23KeV (0.56%).

[0050] A nuclide library is established on the software connected to the high-purity germanium gamma spectrometer, including Fr-221, Fr-223, Th-227, Ac-226, Th-229, Ra-225, and Ra-224. A sample measurement method is established, and the measurement time is 1200 seconds. The sample is placed 20 cm away from the high-purity germanium gamma spectrometer probe and the sample activity is measured.

[0051] The measured activity of the radionuclide is corrected for the branching ratio to obtain the actual activity of the radionuclide. The data processing system connected to the instrument can generally directly give the activity after branching ratio correction. If not, it is calculated manually. The manual calculation formula is: the actual activity of the radionuclide is equal to the measured activity of the radionuclide divided by the branching ratio of the gamma energy spectrum of the nuclide. The ratio (%) of the Ac-225 activity in the sample to the total activity of all radionuclides is the radionuclides purity of the Ac-225 product liquid.

[0052] The present invention is further described below in conjunction with specific embodiments.

[0053] Example 1

[0054] 1. Main instruments and reagents used

[0055] p-type wide energy high purity germanium gamma spectrometer (ORTEC GEM-C30, AMETEK); carolina chromatography paper (15×2 cm, Shanghai Qifa Experimental Reagent Co., Ltd.).

[0056] 2. Preparation of test samples

[0057] A 120MeV high-energy proton accelerator was used to irradiate 60g of a metal thorium target (Th-232), with a flux of 100μA, irradiation for 10 days, and cooling for 7 days. After the irradiated thorium target was cut into small pieces, nitric acid and a catalyst were added for dissolution, and a four-stage series separation and purification process of a cation exchange resin column, a UTEVA or TK200 resin extraction column, a DGA resin extraction column, and an lN resin extraction column was used to obtain the Ac-225 nuclide product solution. For the specific preparation process, please refer to the preparation process of the actinium product solution in the application number 202311390371.0 A method for separating actinium from an irradiated thorium target.

[0058] Take 2ul of the separated and purified Ac-225 nuclide product liquid and drop it on the center of the chromatographic paper, put it into a sealed bag, and prepare the test sample.

[0059] 3. Radioactivity measurement

[0060] Standard nuclide material 210 Pb, 241 Am, 109 Cd, 57 Co. 141 Ce,51 Cr, 137 Cs, 54 Mn, 22 Na, 88 Y. 152 Eu and other standard sources are used to calibrate the efficiency and energy of the high purity germanium gamma spectrometer.

[0061] After the instrument is fully preheated, select the established nuclide library (including nuclides Fr-221, Fr-223, Th-227, Ac-226, Th-229, Ra-225, Ra-224), the test time is 1200 seconds, the sampling volume is 2ul, and the output nuclide results are automatically corrected for branching ratios. Do not put in samples first, and measure the background of the instrument and the environment.

[0062] After the prepared test sample was placed for 49 minutes, it was placed 20 cm away from the probe of the high-purity germanium γ spectrometer and the test began. The obtained γ energy spectrum is shown in Figure 2 , the activity test results are shown in Table 1.

[0063] Table 1 Test results of activity of nuclides to be tested in the nuclide library

[0064]

[0065]

[0066] 4. Calculation of radioactive nucleus purity

[0067] The radioactivity of Fr-221 measured in this example is 7.415E+005Bq. Since Ac-225 and Fr-221 reach radioactivity equilibrium at this time, the activity of Ac-225 in the sample is also 7.415E+005Bq. The activities of Th-227 and Fr-213, daughter nuclides of Ac-227 measured in this example are both lower than the lower limit of measurement of this nuclide and can be considered as absent. The total activity of all nuclides measured in this example is 7.421E+005Bq.

[0068] The nuclear purity of Ac-225 in the sample is the percentage of Ac-225 activity to the total radioactive activity of all nuclides in the sample, which is 99.92%, meeting the quality control requirements of the European Pharmacopoeia for Ac-225 nuclide product liquid.

[0069] Comparative Example 1

[0070] When Ac-225 decays, the energy of the alpha particles released is 5.83MeV (branching ratio 50.7%), 5.792MeV (branching ratio 18.1%), and 5.791MeV (branching ratio 8.6%); when Ac-227 decays, the energy of the alpha particles released is 4.953MeV (branching ratio 0.625%), and the energy of the beta particles is 37.9KeV (branching ratio 54%).

[0071] To verify the accuracy of the data measured by the method described in Example 1, 2 ul of the Ac-225 nuclide product solution prepared in Example 1 was placed in a liquid scintillation sample bottle, 3 mL of scintillation liquid was added, and the sample was shaken to prepare a test sample. After standing for 49 minutes, the radioactivity of Ac-225 and Ac-227 in the sample was analyzed using a liquid scintillation spectrometer.

[0072] The liquid scintillation spectrometer used is a Quantulus-1220 ultra-low background high-sensitivity liquid scintillation spectrometer, the measurement mode is cpm (normal counting mode), the counting range is 20KeV to 6000KeV, and the measurement time is 1200 seconds.

[0073] The obtained liquid scintillation spectrum is shown in Figure 3 , the activity of Ac-225 is 7.415E+005Bq, and the activity of Ac-227 is not measured. This activity result is consistent with the radioactive nuclide activity of Ac-225 and Ac-227 in the Ac-225 nuclide product liquid measured by the high-purity germanium gamma spectrometer in Example 1. However, many byproduct nuclides in the Ac-225 nuclide product are gamma nuclides, and the alpha spectrometer or liquid scintillation counter can only identify or measure the alpha nuclides, and cannot directly analyze their radioactive purity. It can be proved that the present invention uses a high-purity germanium gamma spectrometer to analyze the radioactive nuclide activities of Ac-225 and Ac-227 in the Ac-225 nuclide product liquid, and then calculates the result of the purity of the Ac-225 nuclide accurately and reliably.

[0074] In summary, the present invention discloses a method for rapidly measuring the nuclear purity of an Ac-225 nuclide product liquid, and specifically relates to the field of radioactive nuclear purity analysis and nuclear medicine technology. The present invention uses a high-purity germanium gamma spectrometer to simultaneously and rapidly analyze Ac-225 and radioactive impurity nuclides in an Ac-225 nuclide product liquid, which is convenient to operate, has a short analysis and detection cycle, greatly improves the detection efficiency, and can be widely promoted and applied to the quality control of various radioactive nuclide products.

[0075] Although the present invention has been described in detail above using general instructions and specific implementation schemes, some modifications or improvements can be made on the basis of the present invention. These modifications or improvements made without departing from the spirit of the present invention are all within the scope of protection required by the present invention.

Claims

1. A method for rapidly measuring the nuclide purity of Ac-225, characterized in that: The following steps are involved: (1) Prepare the Ac-225 nuclide solution into a sample to be tested; (2) Use a high-purity germanium gamma spectrometer to measure the actual activity of the radioactive nuclides in the sample to be tested; (3) The purity of Ac-225 nuclide is calculated by calculating the ratio of Ac-225 nuclide activity to total radionuclides.

2. The method for rapidly measuring the purity of Ac-225 nuclides according to claim 1, characterized in that: Step (2) further includes establishing a nuclide library, wherein the nuclide library includes nuclides Fr-221, Fr-223, Th-227, Ac-226, Th-229, Ra-225 and Ra-224; The actual activity of the radionuclide is obtained by performing branching ratio correction on the activity of the radionuclide measured by the high-purity germanium gamma spectrometer and the number of nuclei in the nuclide library.

3. The method for rapidly measuring the purity of Ac-225 nuclides according to claim 1, characterized in that: In step (1), the preparation method of the Ac-225 nuclide solution is: dissolving the irradiated thorium target, and separating and purifying it by connecting a cation exchange resin column, a UTEVA or TK200 resin extraction column, a DGA resin extraction column and an 1N resin extraction column in four stages in series.

4. The method for rapidly measuring the purity of Ac-225 nuclides according to claim 3, characterized in that: The conditions for irradiating the thorium target are: using a 100-120 MeV high energy proton accelerator to irradiate the metal thorium target, the irradiation flux is 80-100 μA, the irradiation time is 10-15 days, and the cooling time should be 3-10 days; Preferably, a 120 MeV high energy proton accelerator is used to irradiate the metal thorium target, the irradiation flux is 100 μA, the irradiation time is 10 days, and the cooling time is 7 days.

5. The method for rapidly measuring the purity of Ac-225 nuclides according to claim 1, characterized in that: In step (1), the preparation method of the test sample is: drop 1-5 μL of Ac-225 nuclide solution on the chromatographic paper and seal it; preferably, the volume of the Ac-225 nuclide solution is 2 μL.

6. The method for rapidly measuring the nuclide purity of Ac-225 according to claim 1, characterized in that: In step (2), the conditions for the measurement of the high-purity germanium gamma spectrometer are: the measurement time is 1200-1500s, and the distance between the sample to be tested and the probe of the high-purity germanium gamma spectrometer is 20cm; Preferably, the measurement time is 1200 s.

7. The method for rapidly measuring the purity of Ac-225 nuclides according to claim 1, characterized in that: In step (2), the process of measuring with the high-purity germanium gamma spectrometer is as follows: first, the efficiency and energy of the high-purity germanium gamma spectrometer are calibrated using a standard source, then a blank sample is tested, and then the sample to be tested is allowed to stand for 30-60 minutes before being tested; preferably, the sample is allowed to stand for 49 minutes.

8. The method for rapidly measuring the purity of Ac-225 nuclides according to claim 1, characterized in that: In step (2), the radioactive nuclides are Ac-225 and its daughter nuclides, Ac-227 and its daughter nuclides, Ac-226, Th-229, Ra-225 and Ra-224; Preferably, the radioactive nuclides are Fr-221, Fr-223, Th-227, Ac-226, Th-229, Ra-225 and Ra-224.

9. The method for rapidly measuring the nuclide purity of Ac-225 according to claim 8, characterized in that: In step (2), the activity of Fr-221 is equal to the activity of Ac-225; Or, the relationship between the activity of Fr-223 and the activity of Ac-227 is: A(Ac-227)=47959247.78A(Fr-223); Or, the relationship between the activity of Th-227 and the activity of Ac-227 is: A(Ac-227)=342082.8595A(Th-227).

10. A method for detecting the quality of an Ac-225 nuclide product, comprising detecting the activity of Ac-225 and its daughter nuclides, Ac-227 and its daughter nuclides, Ac-226, Th-229, Ra-225 or Ra-224 in the Ac-225 nuclide product by using the method for rapidly measuring the purity of Ac-225 nuclides as described in any one of claims 1 to 9.

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