RU2594020C1 - Method of obtaining radionuclide lutetium-177 - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to production process of radionuclides for nuclear medicine. Method of obtaining radionuclide ¹⁷⁷Lu includes making target containing lutetium natural isotopic composition or enriched in isotope ¹⁷⁶Lu, irradiating target with neutrons, followed by extraction of target radionuclide ¹⁷⁷Lu, obtained as result of reaction ¹⁷⁶Lu(n, γ)¹⁷⁷Lu . At that, target is composite material consisting of lutetium nano particles or compounds thereof, surrounded by buffer in form of solid substance dissolved in water or other solvents, wherein d is characteristic size of nano particles selected according to condition of λ/d>>1, where λ is length of run in substance nano particles of recoil atoms ¹⁷⁷Lu. After target irradiation nano particles and buffer are separated, buffer is supplied for radiochemical processing for isolation of radionuclide ¹⁷⁷Lu, and nano particles are returned to reactor core in composition of new target.

EFFECT: invention provides efficient production of radionuclide ¹⁷⁷Lu with high specific activity.

7 cl, 1 dwg, 1 ex

Description

Technical field

The invention relates to a technology for producing radionuclides for nuclear medicine, in particular for the treatment of cancer.

In the treatment of cancer, β-emitting radionuclides are widely used. One of the most promising β-emitters for cancer therapy is the radionuclide lutetium-177 ( ¹⁷⁷ Lu), which has optimal nuclear-physical characteristics for use in nuclear medicine. Radiopharmaceuticals (RFPs) based on ¹⁷⁷ Lu are highly effective therapeutic agents in the treatment of cancer of the liver, prostate and skin integument, as well as other diseases, including rheumatoid arthritis and hemophilia.

State of the art

Among the most promising β-emitting radionuclides for cancer therapy, ¹⁷⁷ Lu can be distinguished, which has a convenient half-life (T _1/2 = 6.71 days), acceptable β-particle energy (E _max = 0.497 MeV), and soft associated γ-radiation ( E _γ = 113 keV (6.4%), and 208 keV (11%)). The decay product of ¹⁷⁷ Lu is the stable isotope ¹⁷⁷ Hf. The relatively short path length of the ¹⁷⁷ Lu β-particle in biological tissues (<2 mm) when a significant number of radionuclide atoms are localized in the immediate vicinity of the tumor cell provides selective tumor destruction with minimal damage to surrounding tissues.

Since ¹⁷⁷ Lu simultaneously emits β particles and γ quanta, it is ideal for both diagnosis and treatment of malignant neoplasms.

In its entirety, the advantages of ¹⁷⁷ Lu are revealed by radiotherapy of small tumors, since β-particles of ¹⁷⁷ Lu have a small penetration depth into the tissues.

Currently, intensive research is being conducted in the field of obtaining and using drugs based on ¹⁷⁷ Lu.

One of the key parameters determining the possibility of using ¹⁷⁷ Lu for the synthesis of radiopharmaceuticals (RFP) is its specific activity. To obtain the drug ¹⁷⁷ Lu high specific activity can be used in two ways:

- neutron irradiation of a nuclear reactor starting material containing a stable isotope of lutetium ¹⁷⁶ Lu (the so-called "direct"method);

- irradiation by neutrons of a nuclear reactor of a starting material containing a ytterbium isotope ¹⁷⁶ Yb ("indirect" method).

The prior art method for producing ¹⁷⁷ Lu by reaction of ¹⁷⁶ Yb (n, γ) with the formation of ¹⁷⁷ Yb and its subsequent β-decay in ¹⁷⁷ Lu and the selection of the target radionuclide by the radiochemical method of solid phase extraction (see Ketring, AR Production and Supply of High Specific Activity Radioisotopes for Radiotherapy Applications. Alasbimn Journal 5 (19): January 2003. Article No. AJ19-2). A target weighing several milligrams of ytterbium nitrate, enriched in ¹⁷⁶ Yb to 97.6% in a quartz ampoule, was irradiated with neutrons in a MURR research reactor. After exposure for several hours, the target was dissolved in 500-700 ml of 0.1-0.5 N HCl.

Separation of ytterbium and lutetium was carried out by solid phase extraction using a "Ln spec" resin (50-100 μm), which was a solution of di (2-ethylhexyl) orthophosphoricacid acid (HDEHP) in an inert polymer sorbent Amberchrom ™ CG-71.

The disadvantages of this method include:

- low yield of the target radionuclide ¹⁷⁷ Lu due to the small reaction cross section of ¹⁷⁶ Yb (n, γ) ¹⁷⁷ Yb → ¹⁷⁷ Lu, which for thermal neutrons is about 2 bar,

- a complex technological process for the separation of lutetium and ytterbium, associated with significant losses of the target radionuclide ¹⁷⁷ Lu.

In addition, known method of reaction of ¹⁷⁷ Lu ¹⁷⁶ Yb (n, γ) ¹⁷⁷ Yb (see patent of the Russian Federation RU 2542733 for the invention "Method of radioisotope lutetium-177", authors:. Vereshchagin YI, Semenov, AN ., Chuvilin D.Yu. et al., Published February 27, 2015), which includes irradiating the ytterbium target with neutrons and isolating ¹⁷⁷ Lu from the irradiated target. A stable isotope ¹⁷⁶ Yb is taken as a target, the target is irradiated in the neutron flux of a nuclear reactor, during the irradiation as a result of a nuclear reaction ¹⁷⁶ Yb (n, γ), ¹⁷⁷ Yb is produced in the target, the decay product of which is the target radionuclide ¹⁷⁷ Lu, then it is isolated by chromatographic method on an ion exchange column. A 0.07 N solution of α-isobutyric acid was used as an eluent to flush ¹⁷⁷ Lu from the column. Purification of the product from traces of α-isobutyric acid is carried out on a second ion-exchange column. In this case, the eluate is acidified to pH = 1-2. ¹⁷⁷ Lu is sorbed on a column, the eluate with α-isobutyric acid is sent to waste. The column was then washed with 100 ml of distilled water, after which ¹⁷⁷ Lu was eluted with ten milliliters of 0.5 N HCl. The eluate is evaporated to dryness and the precipitate is washed off with HCl pH = 5.1.

The disadvantages of this method include:

- low yield of ¹⁷⁷ Lu radionuclide due to the small reaction cross section of ¹⁷⁶ Yb (n, γ) ¹⁷⁷ Yb;

- a complex technological process for the separation of lutetium and ytterbium.

As a prototype, the method of obtaining ¹⁷⁷ Lu by reaction ¹⁷⁷ Lu (n, γ) ¹⁷⁷ Lu was selected (see Journal of Radioanalytical and Nuclear Chemistry, V. 277, No. 3, 2008, 663-673). The stable ¹⁷⁶ Lu isotope is irradiated in the reactor and ¹⁷⁷ Lu is produced from the direct reaction of radiative neutron capture of ¹⁷⁶ Lu (n, γ) ¹⁷⁷ Lu. The reaction cross section for thermal neutrons exceeds 2000 bar. As a result, ¹⁷⁷ Lu can be obtained in significant quantities.

However, this method has several disadvantages:

- the target radionuclide ¹⁷⁷ Lu cannot be separated from the carrier - the raw isotope ¹⁷⁶ Lu, which reduces its specific activity and, as a result, significantly reduces the scope of its use in nuclear medicine;

- presence of long-lived radionuclide ^177m Lu with a half life of 160 days.

The possibility of increasing the specific activity of the ¹⁷⁷ Lu radionuclide in the method chosen for the prototype is limited by the fundamental problem of nuclear reactors - the limited heat removal from the reactor core, in which irradiation of targets for producing radionuclides is carried out. As a result, the neutron flux density in the most powerful research reactors does not exceed ≈2 × 10 ¹⁵ cm ^-2 × s ^-1 , and a further increase in this value is almost impossible. Irradiation of ¹⁷⁶ Lu in a flux of 2 × 10 ¹⁵ cm ^-2 s ^-1 (such a flux of thermal neutrons is available only in two reactors in the world: HFIR, USA, Oak Ridge and SM, Russia, Dimitrovgrad) the maximum value of specific activity is achieved in 10 days equal to ~ 70 kCi per g of lutetium. This value is 70% of the theoretical specific activity of ¹⁷⁷ Lu (~ 110 kCi / g) and is currently the limit when implementing the scheme for the reactor production of ¹⁷⁷ Lu from ¹⁷⁶ Lu.

Disclosure of invention

The technical result of the claimed invention is:

- increase in the specific activity of the ¹⁷⁷ Lu radionuclide obtained by the activation method by the radiative capture reaction of ¹⁷⁶ Lu (n, γ) ¹⁷⁷ Lu upon irradiation of a natural isotopic composition or enriched with ¹⁷⁶ Lu isotope in a nuclear reactor;

- simplification of the technological process of obtaining the target radionuclide ¹⁷⁷ Lu without media on standard reactors.

The technical result is achieved by the fact that the method of producing the radionuclide ¹⁷⁷ Lu involves the manufacture of a target containing lutetium of a natural isotopic composition or enriched in the isotope ¹⁷⁶ Lu, irradiation with neutrons of the target, followed by the isolation of the target radionuclide ¹⁷⁷ Lu, obtained as a result of reaction ¹⁷⁶ Lu (n, γ) ¹⁷⁷ Lu, characterized in that the target is a composite material consisting of lutetium nanoparticles or its compounds, surrounded by a buffer in the form of solid, soluble in water or other solvents, with this d - characteristic size of the nanoparticles is selected from the condition λ / d >> 1, where λ - length of the path in the substance recoil atoms nanoparticles ¹⁷⁷ Lu, after irradiation of the target buffer and the nanoparticles are separated, after which the buffer is sent to reprocessing to isolate the desired radionuclide ¹⁷⁷ Lu, and the nanoparticles are returned to the nuclear reactor as part of a new target.

In a preferred embodiment, a metal lutetium of a natural isotopic composition or enriched in the ¹⁷⁶ Lu isotope is used as the material of the nanoparticles. As the material of the buffer using potassium chloride KCl, and the separation of the buffer and nanoparticles is carried out in water. The separation of the buffer and nanoparticles is carried out by centrifugation, or filtration, or other known method. Target irradiation is carried out in the core of a research or energy nuclear reactor with a thermal neutron spectrum. As the material of the nanoparticles, lutetium compounds Lu ₂ O ₃ , or Lu (OH) ₃ , or LuF _{3 are used} . The characteristic size of the nanoparticles is ≈20 nm.

It is known that the ¹⁷⁷ Lu nucleus formed as a result of the radiative capture reaction ¹⁷⁶ Lu (n, γ) at the moment of excitation excitation by emission of γ-quanta acquires a recoil momentum, which, in some cases, is sufficient to overcome chemical bonds with other atoms by the ¹⁷⁷ Lu atom and molecules in the starting material of the target. Such recoil atoms are able to leave the molecules of the compound in which they were originally located, to transfer from solids to the gas phase, etc.

The energy of the ¹⁷⁷ Lu recoil atom, acquired by him as a result of the reaction of ¹⁷⁶ Lu (n, γ) on thermal neutrons, is [see A.N. Nesmeyanov, Radiochemistry, M., 1978]

Where

E _Lu177 - energy recoil atom ¹⁷⁷ Lu;

ε _γ is the energy of the instantaneous γ-quantum;

M is the mass of the recoil atom ¹⁷⁷ Lu;

c is the speed of light.

In the energy spectrum of instantaneous γ-quanta from the reaction ¹⁷⁶ Lu (n, γ) ¹⁷⁷ Lu in the range of 3–9 MeV per one captured neutron, about one γ-quantum is emitted. Assuming that the average energy of instantaneous γ-quanta is 6 MeV, we obtain a recoil energy of ¹⁷⁷ Lu> 300 eV. This energy is enough to run in a solid up to 100 nm.

The specific exit of the recoil atoms from the target will be significant only if the ratio λ / d≈1, where λ is the mean free path of the recoil atom in the target material and d is the characteristic size of the target. If λ / d << 1, then only the surface layer with a thickness of ≈λ will work in the target, and the inner layers will be inaccessible for the release of recoil atoms. The larger the target, the less effective this process.

If lutetium is localized in ≈20 nm nanoparticles, then an energy of 300 eV will be enough to leave a significant fraction of ¹⁷⁷ Lu atoms (up to 30%) beyond the nanoparticle.

Having made the target in the form of a composite material consisting of lutetium nanoparticles or its compounds ≈20 nm in size, surrounded by a binder material (buffer), one can implant ¹⁷⁷ Lu recoil atoms in the buffer in the neutron field during the irradiation of the target, thereby separating them from lutetium nanoparticles.

Implementation example

As an example of the implementation of the claimed method, we consider the following option: a composite target based on lutetium enriched in the ¹⁷⁷ Lu isotope in an IR-8 research reactor.

By the method of electric explosion of a conductor, lutetium nanoparticles are made. The resulting powder is used to prepare a target from a composite material consisting of lutetium nanoparticles of a natural isotopic composition surrounded by a buffer consisting of solid potassium chloride, soluble in water. The target is placed in the neutron field of the IR-8 reactor. ¹⁷⁷ Lu is produced by reaction ¹⁷⁶ Lu (n, γ) ¹⁷⁷ Lu. The characteristic size of the target nanoparticles is selected from the condition λ / d >> 1, where d is the effective diameter of the nanoparticle, λ is the mean free path of the recoil atoms ¹⁷⁷ Lu in lutetium.

The active zone of the IR-8 reactor consists of 16 fuel assemblies (FAs) of the IRT-3M type. The length of the active part of the fuel assembly is 58 cm, the uranium content of ²³⁵ U is 90 grams, and its enrichment is 90%.

The main parameters of the IR-8 reactor are as follows:

- power, MW 8

- the maximum density of the flux of thermal neutrons cm ^-2 × sec ^-1:

in the core 1.5 × 10 ¹⁴

in water filled openings

beryllium reflector blocks 2.5 × 10 ¹⁴

The accumulation rate of ¹⁷⁷ Lu of ¹⁷⁶ Lu for different values of the neutron flux density is shown in figure 1.

Since the neutron flux reaches 1.5 × 10 ¹⁴ cm ^-2 × s ^-1 in the IR-8 reactor, in 15 days of irradiation of the target it is possible to achieve a specific activity of ¹⁷⁷ Lu of about 10 ⁴ Ci / g ¹⁷⁶ Lu.

As a result of irradiation, ¹⁷⁷ Lu recoil atoms are implanted into the potassium chloride buffer. After irradiation, the target is placed in water, the buffer is dissolved and the ¹⁷⁷ Lu radionuclide is converted into a soluble form. The solution is then centrifuged, separating the water-insoluble target nanoparticles from the ¹⁷⁷ Lu radionuclide in the solution. The buffer is sent for radiochemical processing to isolate ¹⁷⁷ Lu, and lutetium nanoparticles are returned to the reactor core as part of a new target.

As the material of the nanoparticles, metal lutetium can be used, as well as lutetium compounds, for example, Lu ₂ O ₃ , Lu (OH) ₃ , LuF ₃ , of a natural isotopic composition or enriched in the ¹⁷⁶ Lu isotope.

A buffer can be potassium chloride KCl or other materials readily soluble in water, having a low neutron absorption cross section and high radiation resistance.

The claimed method of producing a radionuclide ¹⁷⁷ Lu can significantly increase its specific activity compared with the method selected for the prototype, which will expand the use of radionuclide ¹⁷⁷ Lu in nuclear medicine, in particular when implementing the technology of targeted delivery of radionuclide to affected organs or tissues.

Claims (7)

1. A method of producing a radionuclide ¹⁷⁷ Lu, including the manufacture of a target containing lutetium of a natural isotopic composition or enriched in the isotope ¹⁷⁶ Lu, irradiation with neutrons in a nuclear reactor of the target, followed by the selection of the target radionuclide ¹⁷⁷ Lu, obtained by the reaction ¹⁷⁶ Lu (n, γ) ¹⁷⁷ Lu, characterized in that the target is a composite material consisting of lutetium nanoparticles or its compounds, surrounded by a buffer in the form of solid, soluble in water or other solvents, with d - characteristic posted p nanoparticles are selected from the condition λ / d >> 1, where λ - length of the path in the substance recoil atoms nanoparticles ¹⁷⁷ Lu, after irradiation of the target buffer and the nanoparticles are separated, after which the buffer is sent to reprocessing to isolate the desired radionuclide ¹⁷⁷ Lu, nanoparticles and return into a nuclear reactor as part of a new target. 2. The method according to p. 1, characterized in that the material of the nanoparticles use metallic lutetium of a natural isotopic composition or enriched in the isotope ¹⁷⁶ Lu. 3. The method according to p. 1, characterized in that the potassium chloride KCl is used as the buffer material, and the buffer and nanoparticles are separated in water. 4. The method according to p. 1, characterized in that the separation of the buffer and nanoparticles is carried out by centrifugation, or filtration, or other known method. 5. The method according to p. 1, characterized in that the irradiation of the target is carried out in the active zone of a research or energy nuclear reactor with a thermal neutron spectrum. 6. The method according to p. 1, characterized in that as the material of the nanoparticles use compounds of lutetium Lu ₂ O ₃ , or Lu (OH) ₃ , or LuF ₃ . 7. The method according to p. 1, characterized in that the characteristic size of the nanoparticles is ≈20 nm.

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