RU2212260C2 - Method for planning neutron capture therapy - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: method involves administering tumorothropic gammaradiation-labeled preparation possessing high cross- section of heat neutron capture. Preparation accumulation and removal dynamics is studied by means of gamma-tomograph device. Time interval is selected for administering neutron capture therapy under condition of

where C_tumor(t) and C_tisue(t) - is the high heat neutron capture cross-section chemical element concentration in tumor and surrounding tissues, ^minC_tumor(t) is the minimum high heat neutron capture cross-section chemical element concentration in tumor enabling heat neutron irradiation results in effective absorption dose. Radiation dose power due to neutron capture reaction taking place is calculated. Labeled substance accumulation dynamics is studied from the moment of its administration within 48 h. Dose power is determined from P = Φ•(C_tumor•N_A/M)•σ•E•K, where P is the dose power, cGr/s, Φ is the heat neutron flux density, n/sq.cm, N_A is the Avogadro number, M is molecular mass of the chemical element having high cross-section of heat neutron capture, σ is the heat neutron capture cross-section in sq.cm, E is the reaction product energy in MeV, K is the dimension coordination coefficient equal to 1,6•10^-8 cGrg/MeV. EFFECT: enhanced effectiveness of treatment planning in the cases of complex malignant tumor forms. 3 cl, 3 dwg, 1 tbl

Description

 The invention relates to the field of radiation therapy, in particular neutron capture therapy (NRT), using preparations containing chemical elements with a large capture cross section of thermal neutrons.

 A known method of planning neutron capture therapy (NRT) based on the determination of boron concentration in tissue samples by atomic emission spectroscopy with inductively coupled plasma [1]. The essence of the method is that many chemical elements upon excitation emit radiation with characteristic wavelengths. The determination of the amount of boron is based on an empirical relationship between the intensity of the emitted radiation at specific wavelengths and the number of elements in the tissue sample. This method includes: 1) taking samples of the tumor and tissues; 2) preparation of homogeneous solutions; 3) injection of samples into the plasma (T = 8000 K), formed by transferring the energy of a high-frequency alternating field to a gas (argon) by means of magnetic induction; 4) recording on the spectrograph of boron radiation at a wavelength of 249.678 nm; 5) determination of the concentration of boron in the tumor at the time of irradiation with thermal neutrons by the level of boron in the blood and the previously established ratio (boron in the tumor) / (boron in the blood).

The disadvantages of the method are:
1) significant time spent on sample preparation and a lot of labor when conducting analytical studies;
2) analysis only in selected biomedical samples (in vitro);
3) one-time selection of tissue samples for analysis (during a surgical operation) and, as a result, the impossibility of directly determining the concentration of boron at different times after administration of a boron-containing preparation.

A known method of planning NRT based on determining the amount of boron by the method of neutron activation radiography [2, 3]. In this case, solid-state track detectors (different types of polymer films) are used to assess the distribution and quantitative content of ¹⁰ V in tissues, which has a large capture cross section in the ¹⁰ V (n, α, γ) ⁷ Li reaction. The resulting α particles cause damage to the detector and the appearance of ultramicro-holes on its surface - tracks that are analyzed using an optical microscope. The number of tracks is proportional to the concentration of boron in the sample. This method includes: 1) sampling of a tumor, tissue, blood; 2) preparation of dried, compressed tablets from samples; 3) fastening to the surface of the tablets of the detectors; 4) neutron irradiation; 5) analysis of the resulting tracks on an optical microscope; 6) determination of boron concentration in the tumor at the time of NRT by the level of boron in the blood and the previously established ratio (boron in the tumor) / (boron in the blood). The disadvantages of the method are:
1) the duration (6-7 days) and the complexity of the analysis;
2) the need to use a source of thermal neutrons to determine the concentration of boron;
3) analysis only in vitro;
4) one-time selection of tissue samples for analysis (during a surgical operation and, as a result, the impossibility of directly determining the concentration of boron at different times after administration of the boron-containing preparation.

A known method of planning NRT using the quantitative determination of boron by spectrometry of instant gamma radiation [4, 5]. The concentration is determined in small biomedical samples and in the whole organism. The method is based on determining boron concentration directly in the process of irradiation of samples with thermal neutrons (n _t ) by detecting instant gamma radiation from the reaction n _t + ¹⁰ V -> ⁷ Li + ⁴ He + γ. The intensity of the emitted gamma radiation is proportional to the concentration of boron in the sample. This method includes: 1) introducing a boron-containing preparation into the body; 2) selection and preparation of samples of biological tissues (in the case of in vitro); 3) irradiation of tissue or living organism samples with a beam of thermal neutrons from the reactor; 4) registration of gamma radiation. The obtained data on the concentration of boron in the tumor allow you to adjust the dose rate of thermal neutrons during NRT. The disadvantages of the method are:
1) the need to use a source of thermal neutrons to determine the concentration of boron;
2) repeated radiation load on the body (radiation at the reactor) when studying the dynamics of accumulation of boron-containing preparation;
3) the high cost of implementing the method.

The prototype of the proposed technical solution is the method of planning NRT based on the quantitative determination of boron in the body using positron emission tomography [6]. This method is based on the use of positron-emitting ultrashort-lived isotopes as a radioactive label, which, in combination with boron-containing compounds, are introduced into the body. The positron annihilates with the electron, which is accompanied by the release of two photons recorded using a system of detectors. Computer processing of the obtained data allows us to present a picture of the volume distribution of boron in a living organism and calculate its concentration in the tumor and surrounding tissues. This method includes: 1) synthesis of a labeled positron-emitting isotope ( ¹⁸ F) with a boron-containing compound for which the maximum accumulation of boron in the tumor occurs in the first hours after administration (for example, borphenylalanine (BPA)); 2) the introduction of a labeled compound into the body; 3) the study of the accumulation of boron in the tumor on a positron emission tomograph; 4) computer analysis, which allows to determine the concentration of boron in the tumor and the ratio (boron in the tumor) / (boron in the surrounding tissues) during the first hours (0-6 hours) from the moment of administration of the labeled drug.

The disadvantages of the method are:
1) the rapid decay of positron-emitting isotopes, which excludes the possibility of synchronizing the process of physical decay of isotopes with the kinetics of drug accumulation, in which the maximum accumulation of boron in the tumor occurs at a later date;
2) the need to attract specialists of various profiles;
3) the need to combine in one scientific center a cyclotron, a laboratory for the synthesis of labeled boron-containing compounds and a positron emission tomograph;
4) the high cost of implementing the method.

 The aim of the invention is to eliminate the disadvantages of the prototype and to enable the determination of the optimal ratio between the boron content in the tumor and surrounding tissues for a long time from the moment of administration of the boron-containing compound into the body.

 To achieve this goal, in a method involving the administration of a tumorotropic boron-containing preparation into the body, measuring the dynamics of boron accumulation in the tumor and surrounding tissues, a gamma emitter, for example, an iodine isotope, is used as a label for the boron-containing preparation. The magnitude of its radioactivity using a gamma tomograph measures the dynamics of the accumulation of boron over several days. Moreover, after reaching the maximum accumulation of radioiodine in the tumor and the ratio of boron concentration in the tumor and surrounding tissues, the optimal regime of neutron capture therapy is set.

List of figures:
FIG. 1. Kinetics of the distribution of labeled boron compounds in the tumor:
1 - tumorotropic compound labeled with iodine isotope ( ¹³¹ I-BSH);
2 - a tumor -otropic compound labeled with a positron - a radiating isotope ( ¹⁸ F-BPA).

FIG. 2. Distribution of labeled boron compound ( ¹³¹ I-BSH) in tissues:
1 - accumulation in the tumor;
2 - accumulation in the surrounding tissue;
3 - an area in which neutron capture therapy can be performed.

FIG. 3. The computer image of the paw with a tumor, obtained for the point 24 hours:
1 - surrounding tissue; 2 - a tumor; 3 - excretory organs.

Здесь хлористый йод, меченный йодом-131, получали изотопным обменом нерадиоактивного IC1 (HICl₂) с Na¹³¹I при простом смешении их водных растворов. Реакцией S-монотиурониевого производного додекабората (I) с меченным хлористым йодом при комнатной температуре получали меченое соединение (II), которое без выделения обрабатывали водным раствором КОН для получения соединения (III), содержащего прочную связь бор - йод (В-I). Радиохимический выход этого соединения составил 95-97%.Method implementation examples
Example 1. In the proposed technical solution, a tumor -otropic boron-containing compound labeled with a gamma emitter was used (sodium mercaptododecaborate Na ₂ B ₁₂ H ₁₁ SH (BSH), labeled ¹³¹ I ( ¹³¹ I-BSH)). The scheme of its synthesis can be represented as follows:

Here, iodine chloride labeled with iodine-131 was obtained by isotopic exchange of non-radioactive IC1 (HICl ₂ ) with Na ¹³¹ I by simple mixing of their aqueous solutions. The reaction of the S-monothiuronium derivative of dodecaborate (I) with labeled iodine chloride at room temperature yielded labeled compound (II), which was treated without treatment with an aqueous KOH solution to obtain compound (III) containing a strong boron - iodine bond (B-I). The radiochemical yield of this compound was 95-97%.

Pharmacokinetic studies have shown that ¹³¹ I-BSH lingers for a long time in the tumor (Table 1).

 In accordance with the prototype, the use of boron-containing compounds labeled with positron-emitting isotopes for planning NRT is difficult due to the rapid decay of isotopes, which excludes the possibility of synchronizing the process of physical decay of isotopes with the kinetics of drug accumulation in the tumor (Fig. 1, curve 2).

Thus, for planning NRT, the advantages of the proposed method are important:
the ability to study the dynamics of the accumulation and elimination of boron over a long time interval (more than 48 hours); high stability of boron - iodine bonds.

Example 2. To obtain a tumor image, an intraperitoneal administration of a tumorotropic boron-containing preparation Na ₂ B ₁₂ H ₁₁ SH (BSH) labeled with an indicator amount of radioiodine ( ¹³¹ I-BSH) (60 μCi activity) to laboratory tumor-bearing animals (mice with B-16 melanoma was performed) ) Using a special device, the mouse was fixed on the desktop of the gamma-ray tomograph. The first point of measurement of the emitter activity was performed using a gamma tomograph 15-30 minutes after the introduction of the compound, which allows us to determine the effectiveness of the gamma tomograph counting for a specific organism. To study the dynamics of the accumulation of the labeled compound, measurements were performed after 20 minutes, 1, 3, 6, 9, 12, 24, and 48 hours from the moment of administration (Fig. 2, curves 1 and 2). The recording interval of a single image was set from 5 to 30 min in inverse proportion to the radioactivity of the labeled compound. The resulting images of the distribution of ¹³¹ l-BSH were recorded in computer memory for subsequent computer processing (figure 3).

Example 3. The planning scheme of NRT. The obtained radiometric data on the dynamics of accumulation and excretion of labeled boron-containing compounds ( ¹³¹ I-BSH) allow us to present an algorithm for selecting the NRT modes.

Necessary conditions for NRT:
1. C _tumor (t) / C _tissue (t)>1;
2. C _tumor (t)> ^min C _tumor > C _tissue (t),
where C is the _tumor (t) and C _tissue (t) is the concentration of boron in the tumor and surrounding tissues, μg / g of tissue;
^min C _tumor - the minimum concentration of boron in the tumor at which exposure to thermal neutrons forms an effective absorbed dose.

The formula for calculating the radiation dose rate due to the neutron capture reaction (n _t + ¹⁰ B -> ⁷ Li + ⁴ He + γ) has the following form:
P = F • (C _tumor • N _A / M • σ • E • K,
where P is the dose rate, sGy / s;
Ф - thermal neutron flux density, n / (cm ² • s);
C _tumor - concentration of ¹⁰ V in the tumor, g / g of tissue;
N _A is the Avogadro number, 6.02 • 10 ²³ 1 / mol;
M — molecular weight ¹⁰ V, g / mol;
σ is the reaction cross section, σ = 3838 • 10 ^-24 cm ² ;
E is the energy from the reaction products, E = 2.34 MeV;
K is the coefficient of coordination of the dimension, K = 1.6 • 10 ^-8 cGy • g / MeV.

From (figure 2) it follows:
1) for a time interval of 0-2 h, the situation is C _tumor (t) / C _tissue (t) <1, C _tissue (t)> C _tumor (t)> ^min C _tumor , which does not satisfy the necessary conditions for NRT;
2) for a time interval of 2-14 hours, the situation is C _tumor (t)> C _tissue (t)> ^min C _tumor , which violates condition 2;
3) for a time interval of 14-26 hours, all necessary conditions are met;
4) for a time interval of 26-48 hours, the situation is ^min C _tumor > C _tumor (t)> C _tissue (t), which violates condition 2.

 Thus, it is advisable to carry out neutron capture therapy in a time interval of 14-26 hours from the moment of administration of the boron-containing compound.

For the most optimal start time of NRT (21 hours after the introduction of the boron-containing compound), with a thermal neutron flux density of 2.5 • 10 ⁹ n / cm ² s and boron concentration in the tumor of 30 μg / g, the dose rate due to the neutron capture reaction will 0.39 Gy / min. Moreover, the dose in the surrounding tissues will be 25% compared with the dose in the tumor, which will ensure maximum tumor damage with minimal damage to surrounding tissues.

Feasibility
The proposed technical solution provides the opportunity to study the dynamics of the accumulation of boron in the tumor and surrounding tissues in vivo. It extends the range of studies of boron accumulation up to several days due to the introduction of a boron-containing compound labeled with a radioiodine into the body. The method allows to increase the list of boron-containing preparations studied and used in practice, improves the quality of NRT by choosing the tumor / surrounding tissue ratio that is optimal for a particular patient, and thereby reduces the radiation effect on normal tissues when irradiated with thermal neutrons. The procedure for establishing optimal conditions for NRT improves the effectiveness of treatment. At the same time, the preparatory procedure for the implementation of the proposed method is greatly simplified through the use of a gamma-ray tomograph, a device available for most medical centers. These factors allow individual planning of NRT in the treatment of patients with the most complex forms of malignant neoplasms and ultimately create the conditions for the clinical use of NRT in our country.

List of references
1. Haritz D., Gabel D., Huiskamp R. Clinical phase-I study of Na ₂ B ₁₂ H ₁₁ SH (BSH) in patients with malignant glioma as precondition for boron neutron capture therapy (BNCT). // J. Radiat. Oncol. Biol. Phys., 1994, Vol. 28, No.5, P.1175-1181.

2. Nikitina R. G., Frolova E. I. Method for determining ¹⁰ V in biological samples. // Medical radiology. 1981, 1, pp. 44-48.

3. Takagaki M., Oda Y., Miyatake S., Kikuchi H., Kobayashi T., Sakurai Y., Osawa M., Mori K., Ono K. Boron neutron capture therapy: preliminary study of BNCT with sodium borocaptate ( Na ₂ B ₁₂ H ₁₁ SH) on glioblastoma. // J. Neurooncol, 1997, Vol. 35, No.2, P.177-185.

 4. Moore D. E. A review of techniques for the analysis of boron in the development of neutron capture therapy agents. // J. Pharmaceutical & Biomedical Analysis, 1990, Vol.8, No.7, P.547-553.

5. Raaijmakers C.P., Konijnenberg MW, Dewit L., Haritz D., Huiskamp R., Philipp K., Siefert A. Monitoring of blood - ¹⁰ B concentration for boron neutron capture therapy using prompt gamma-ray analysis. // Acta Oncol., 1995, Vol. 34, No.4, P.517-523.

 6. Imahori Y., Ueda S., Ohmori Y., Sakae K., Kusuki T., Kobayashi T., Takagaki M., Ono K., Ido T. Positron emission tomography-based boron neutron capture therapy using boronophenylalanine for high -grade gliomas. // Clin. Cancer Res., 1998, Vol.4, No.8, P.1825-1841.

Claims (3)

1. A method for planning neutron capture therapy, comprising introducing into the body a tumor substance with a high thermal neutron capture cross section, measuring the dynamics of drug accumulation in the tumor and surrounding tissues, characterized in that a tumor substance with a high thermal neutron capture cross section, labeled with a gamma emitter, is introduced , measure the dynamics of accumulation and excretion of the drug using a gamma-ray tomograph and select a time interval for neuron-capture therapy, provided that C _tumor (t) / C _tissue (t) > 1 and C _tumor (t)> ^min C _tumor > C _tissue (t), where C _tumor (t) and C _tissue (t) is the concentration of a chemical element with a high thermal neutron capture cross section in the tumor and surrounding tissues, ^min C _tumor - the minimum concentration of a chemical element with a high thermal neutron capture cross section in the tumor, at which thermal neutron irradiation forms an effective absorbed dose, and the dose rate of the radiation resulting from the neutron capture reaction is calculated.  2. The method according to p. 1, characterized in that the dynamics of accumulation of the labeled compound is investigated in the range from the time of administration to 48 hours 3. The method according to p. 1, characterized in that the dose rate is determined by the ratio P = F • (C _tumor • N _A / M) • σ • E • K, where P is the dose rate, sGy / s; Ф - thermal neutron flux density, n / (cm ² • s); N _A is the Avogadro number; M is the molecular mass of a chemical element with a high capture cross section of thermal neutrons; σ is the capture cross section of thermal neutrons, cm ² ; E is the energy from the reaction products, MeV; K - coefficient of coordination of dimensions - 1.6 • 10 ^-8 cGy • g / MeV.

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