Content area
A scheme for producing the α-emitters ^sup 212^Pb and ^sup 212^Bi, to be used in a promising method of diagnostics and therapy in oncology - radioimmunotherapy, is proposed. The technology is based on two generators operating in tandem: ^sup 228^Th/^sup 212^Pb and ^sup 212^Pb/^sup 212^Bi. The first one is based on separation from an initial solution containing thorium isotopes and gaseous ^sup 220^Rn, which secures the purity of the desired products ^sup 212^Pb and ^sup 212^Bi. For a ^sup 228^Th/^sup 212^Pb model generator, the efficiency of ^sup 220^Rn extraction from solution was ~60%. After conditioning, the ^sup 212^Pb solution from the ^sup 228^Th/^sup 212^Pb generator was used to charge a column, which functioned as a ^sup 212^Pb/^sup 212^Bi generator, with a cation exchanger.[PUBLICATION ABSTRACT]
Atomic Energy, Vol. 111, No. 6, April, 2012 (Russian Original Vol. 111, No. 6, December, 2011)
P. P. Boldyrev,1 A. I. Bortash,1V. A. Zagryadskii,1 A. S. Zakharov,1V. I. Nikolaev,1 M. A. Proshin,1D. Yu. Chuvilin,1 A. V. Shatrov,1 and S. P. Vesnovskii2
A scheme for producing the -emitters 212Pb and 212Bi, to be used in a promising method of diagnostics and therapy in oncology radioimmunotherapy, is proposed. The technology is based on two generators operating in tandem: 228Th/212Pb and 212Pb/212Bi. The first one is based on separation from an initial solution containing thorium isotopes and gaseous 220Rn, which secures the purity of the desired products
212Pb and 212Bi. For a 228Th/212Pb model generator, the efficiency of 220Rn extraction from solution was ~60%. After conditioning, the 212Pb solution from the 228Th/212Pb generator was used to charge a column, which functioned as a 212Pb/212Bi generator, with a cation exchanger.
Radioimmunotherapy, based on the application of -emitting radionuclides which are used to label monoclonal antibodies, synthetic peptides, or other compounds which can be directly delivered to a cancer cell, is one of the promising methods for treating malignant tumors [1, 2].
The first patented and authorized radioimmunological preparations contained the -emitters 90Y and 131I (2002), which are 10100 times less efficient that -emitters. Only five years later Alpharadin, a preparation with 223Ra that is manufactured by the Algeta ASA Company (Norway), became the first pharmaceutical based on -emitting radionuclides which were cleared for clinical application in treating prostate and breast cancers [3].
Because the travel distance of -particles is short, a high local irradiation dose to a malignant cell is formed. The most interesting -emitters are 212Bi (T1/2 60 min), 213Bi (T1/2 46 min), 223Ra (T1/2 11.4 days), and 225Ac (T1/2 10 days) [4]. However, the difficulty of obtaining -emitting radionuclides and the lack of an adequate raw-material supply are impediments to large-scale adoption of radioimmunotherapy in medical practice. For this reason, radioimmunotherapy methods are of limited use.
The objective of the present work was to validate experimentally the production of 212Bi from the initial raw material a solution of a mixture of thorium isotopes 228,229,232Th in arbitrary ratios by removing gaseous 220Rn.
212Bi Production. This isotope is formed in the decay chain of 232U, which can be obtained via a chain of the following reactions by irradiating natural thorium in a nuclear reactor [5]:
232Th(n, )233Th 233Pa(, n)232Pa 232U;
1 National Research Center Kurchatov Institute, Moscow.
2 Russian Federal Nuclear Center All-Russia Research Institute of Experimental Physics (RFYaTs VNIIEF), Sarov.
Translated from Atomnaya nergiya, Vol. 111, No. 6, pp. 348352, December, 2011. Original article submitted May 30, 2011.
1063-4258/12/11106-0422 2012 Springer Science+Business Media, Inc.
422
212Pb/212Bi GENERATOR FOR NUCLEAR MEDICINE
UDC 621.039.8
Fig. 1. Experimental procedure: t0, t1 start and end of bubbling of the solution, respectively; A0Rn 220Rn activity at time t0; ARn 220Rn activity after start of bubbling of the solution; A1Pb, A1Ra activity of 212Pb and 224Ra in solution at completion of bubbling.
232Th(n, 2n)231Th 231Pa(n, )232Pa 232U;
232Th(, n)231Th 231Pa(n, )232Pa 232U.
Depending on the irradiation conditions, the 232U concentration is 20200 ppm [6].
In the 1950s, as part of the Atomic Project, a small amount of 233U was obtained with 232U as an impurity [7].
228Th accumulated in the uranium because of the long storage time, but it can be separated by a known radiochemical method.
There are two known methods for obtaining 212Bi from the parent 228Th: 1) separation of 228Th and 212Bi by means of ion-exchange resins and 2) extraction, by decay, of the rare gas 220Rn (T1/2 55.6 sec) from the thorium-containing material [811]. The ion-exchange generator 228Th/212Pb/212Bi provides a long operating regime because the half-life of the parent
228Th is long (T1/2 1.9 yr); however, radiation can destroy the organic sorbent [9]. One variant of a generator of the second type consists of a set of closely packed plates with thin layers of 228Th-containing barium stearate [Ba(C18H5O2)] which are blown by a stream of air [10]. The 220Rn diffuses from the layers into the air flow and is carried along a closed loop into a storage tank, where over 1015 min it decays into 212Bi. However, even in this case, radiolytic damage to the organic carrier of 228Th lowers the radon yield.
The problem of the destruction of sorbents by radiation can be solved by using thorium-containing water solutions as the starting material and removing 220Rn by bubbling air or other gas through the solution. The solubility of radon in water solutions is low so that radon is easily removed [12]. The solubility of radon in water is 460 ml/liter (at 0C). Bubbling sharply intensifies 220Rn extraction. Radon diffuses into the ascending gas bubbles and is carried to the surface of the solution. Allowing the air to flow along gas pipelines, 220Rn can be carried to a remote tank where a chain of decays occurs:
220Rn 216Po 212Pb 212Bi. As a result, the desired 212Bi accumulates in the collecting tank.The presence of the relatively long-lived precursor 212Pb makes it possible to create the generator system
212Pb/212Bi, which could become the foundation for the production of preparations based on -emitting 212Bi. In this case, the technological process will include the successive operation of two generators 228Th/212Pb and 212Pb/212Bi.
Experimental Procedure. According to the chosen experimental scheme, as bubbles flow through the initial solution containing 228,229,232Th part of the 220Rn is carried out and transported by the air flow into the catching system. The objective of the experiment was to study how effectively 220Rn is carried out of the solution.
Because its content in solution does not change during bubbling, 224Ra was chosen as the reference radionuclide for determining how effectively 220Rn is removed from the solution. Since the half-life of 220Rn is short, 212Pb (T1/2 = 10.6 h)
423
Fig. 2. Setup for obtaining 212Pb: 1) bubbler + flask with the initial solution; 2) container + trap; 3) peristaltic pump; 4, 5) pipelines; 6) protection; 7) aerosol filter.
can be used to monitor the change of the radionuclide composition of the solution. For simplicity, we shall assume that the chain of radionuclides 224Ra, 220Rn, 212Pb, 212Bi, and 208Tl is in equilibrium, i.e., ARa = ARn = APb ... The experimental procedure is represented graphically, with an indication of the sampling of the solution, in Fig. 1.
After bubbling of the solution starts at the time t0, the 220Rn activity A0Rn starts to decrease and assumes a new value ARn = A0Rn, where is the radon extraction coefficient. The activity ARn is reached in time no longer than 45T1/2 220Rn,i.e., 45 min.
An abrupt change of the 220Rn content in solution disrupts the equilibrium of the chain 220Rn 216Po 212Pb 212Bi.
To attain equilibrium at a new level of 220Rn activity, the solution must be continually bubbled for 45 half-lives of the longest-lived radionuclide in the chain 212Pb, i.e., 4050 h. The new equilibrium state of the chain 220Rn 216Po 212Pb 212Bi is established at time t1. If bubbling of the solution is stopped at this moment, the 220Rn concentration rapidly returns to its initial state, adjusted for the temporal correction exp(Rn[t1 t0]) because of the natural decay of 224Ra; the activity of 212Pb, 212Bi, and 208Tl in the solution starts to increase slowly and after the 4050 h it once again reaches equilibrium with
224Ra at time t2.We shall define the coefficient of extraction of 220Rn from solution as follows:
(1)
where A1Pb and A1Ra are, respectively, the activity of 212Pb and 224Ra at time t1.
Thus, we shall determine the radon extraction coefficient from measurements of the post-bubbling radionuclide composition of the solution at time t1 as the activity ratio 212Pb/224Ra.
Experiment. In the experiments, 233U kept standing for many years with 232U admixture (2030 ppm) served as the source of 228Th. The extraction method was used to separate uranium and thorium.
After the uranium metal sample was dissolved in hydrochloric acid, the acidity of the solution was adjusted to 6M HCl by adding hydrogen peroxide. This system was chosen because of the large difference of the separation coefficients of uranium (5060) and thorium (0.020.03) [13]. Three successive extraction procedures removed at least 99.9% of the uranium from the solution. The water phase of extraction contained a mixture of thorium isotopes, traces of uranium (~0.1%), inorganic impurities (~0.010.05 mg/ml), and a small quantity of tributyl phosphate (TBP). The isotopic composition of thorium was determined by means of -, -spectrometric measurements: 232Th ~ 93%, 229Th ~ 6.5%, and 228Th ~trace amounts.
The activity ratio 228Th/229Th was 12.8 and the mass ratio 228Th/229Th was 3.3103. The 228,229,232Th isotopes separated from uranium were located in the collector, which consisted of a flask holding a mixture of a solution of thorium isotopes
424
=
1 A A
Pb
1
1 / ,
Ra
TABLE 1. Coefficients of 220Rn Extraction from Solution Measured According to Several Radionuclides
Activity in a sample at time t, Bq
A(t1), 104
2.54
Nuclide
224Ra
212Pb
212Bi
208Tl
and the anion-exchanger Dowex-1 in 8M HNO3 in the volume ratio 1:1. In this system, thorium was distributed between the solution and the anion exchanger in the ratio 7:93 and the daughter products from thorium decay were present in the solution.
The experimental setup shown in Fig. 2 was used to study how effectively 220Rn was removed from a solution of the mixture 228,229,232Th.
A 5 ml sample was extracted from the initial solution in the flask. Since organic impurities (Dowex 18 and TBP) can be present in the solution, the water and organic phases had to be separated. For this, the solution was placed in a 50 ml separating funnel and 5 ml 8M HNO3 and 10 ml decane were added. After the phases were separated, the water phase was channeled into the bubbler-flask.
The radionuclide composition of the initial solution was measured before bubbling commenced. For this, standard sources for performing measurements in a spectrometer with an ultrapure germanium detector were prepared from 50 l control samples extracted from the solution. The sources were 10 mm in diameter disks made of filter paper on which the solution was deposited. A polyethylene film was used to seal the external side of the disks.
At the time t0 (see Fig. 1), a peristaltic pump 3 channeled air at the rate ~50 ml/min into the flask 1. Radon exited the bubbler together with the air along the tube 4, passed through the aerosol filter 7, and entered the container 2 a 10 m long Teflon tube with inner diameter 6 mm. 220Rn remained in the storage volume for about 10 min, enough time for all 220Rn to decay into 212Pb. A UIM-2-20 radiometer with an external BDMG-41 monitor was used for in-line monitoring of the 212Pb accumulation.
The solution was bubbled for ~50 h, which made it possible to bring the content of the daughter products of 216Po,
212Pb, 212Bi, and 208Tl decay to the equilibrium level in the decay chain. After the flow of air into the solution was stopped, at the time t1 50 l samples were extracted once again and used to make the master sources.
The activity of the solution samples was measured with a GEM-25185 gamma spectrometer with an ultrapure germanium detector (V ~ 110 cm3; ORTEC Company, USA). The measurement error for the radionuclide content in the solutions was ~10%.
As follows from Table 1, before solution bubbling was commenced the 212Pb, 212Bi, and 208Tl activity A(t0) was the same to within 5%, attesting to equilibrium of this group of radionuclides. A very small deviation is observed for 224Ra,
which can be explained by partial escape of gaseous 220Rn during storage of the solution. Having a low solubility in water and a small diffusion constant, the radon above the open surface of the solution migrates into the air, as a result of which the content of its daughter products 212Pb 212Bi 208Tl in the solution decreases by ~10%.
After solution bubbling commences, the rate of escape of radon and the daughter products of its decay increases sharply. Only the 224Ra activity A(t1) remains unchanged. Subtracting from A(t1) the activity of the daughter products of the decay of trace 228Th we obtained the true activity A*(t1) of the radionuclides. It turned out that in the bubbling process more than half of the 212Pb, 212Bi, and 208Tl passes into the air. The average 220Rn extraction coefficient according to a series of measurements of the activity of the samples was ~60% of the theoretical value. The 212Pb, 212Bi, and 208Tl obtained after the
loop is washed are characterized by high purity and to within the sensitivity of the spectrometric apparatus contain no radioactive impurities.
425
, %
A(t0), 104
A*(t1), 103
2.42
11.9
2.15
1.76
4.11
65
2.23
1.86
5.1
57
2.26
1.81
4.63
61
A model of the 212Bi generator used for medical-biological studies was built on the basis of the experimental setup shown in Fig. 2. The model incorporated two main elements 228Th/212Pb and 212Pb/212Bi generators. The setup was supplemented with a facility for washing 212Pb from the container-trap and conditioning the solution used for charging the ion-exchange column of the 212Pb/212Bi generator.
As 212Bi is obtained, the desired radionuclide is lost. Because of the short half-life of 220Rn parasitic volumes in the bubbler-flask and pipelines can make a considerable contribution to the losses. To evaluate these losses, the container-trap in the model was replaced with a filter consisting of three layers of activated carbon. The 212Pb activity is distributed over the layers as follows: 75%:25%:traces. The total 212Pb activity on the carbon filter was 56% of its activity in the initial solution. The 212Pb losses on an aerosol filter did not exceed 3% of its activity in the initial solution before bubbling commenced. The total activity on the two filters corresponds to the measured value of the coefficient of radon extraction from solution. No admixture of thorium and radium isotopes is observed for the chosen rate of air flow onto the aerosol filter. Almost all the radon extracted from the solution reaches the container-trap.
The effectiveness of 212Pb extraction was determined as follows. After 212Pb accumulated for 2 days, the container-trap was disconnected from the flask holding the initial solution, a laving solution was sucked in, the tips of the tubes were connected, and the peristaltic pump forced the laving solution along the closed loops of the accumulator, after which the solution was poured off. This procedure was repeated three times with a mixture of 2M nitric (or hydrochloric) acid, water, and ethyl alcohol in different combinations. The volume of each laving solution was 1540 ml; the circulation time along the tube was 1030 min. As a result, ~100 ml containing up to 40% 212Pb of the initial solution were obtained. The solution obtained was evaporated to 0.5 ml, diluted with 5 ml ethyl alcohol, conditioned to 0.5 M nitric (or hydrochloric) acid, and eluted in a column with the cation-exchanger Dowex 50. As it accumulated, the 212Bi was washed from the column with a 0.10.3 M solution of nitric (or hydrochloric) acid.
212Pb with activity to 100 MBq was simultaneously deposited on the ion-exchange column separating 212Pb and
212Bi; this was sufficient for studying on laboratory animals for a period of 2 days a radioimmunological antitumor preparation with 212Bi as the therapeutic agent.
For a long time, the generator model operated reliably and was easy to maintain; initial solutions containing a mixture of the isotopes 228,229,232Th in arbitrary ratios could be used and the desired product could be obtained without admixtures of the parent radionuclides 228Th and 224Ra.
In summary, in experiments about 60% 220Rn and its daughter decay products 212Pb and 212Bi were separated from a water solution of mixtures of the isotopes 228,229,232Th. A model generator was built and 212Bi of high radionuclide purity was obtained and used in medical-biological experiments to obtain biocompatible nanosize structures with radioisotopes as therapeutic agents. The simplicity of the scheme and the high 212Pb extraction efficiency open up prospects for using the generator to produce 212Bi on commercial scales.
This work was performed under Rosnauka Government Contract No. 02.513.12.3093 and Russian Foundation for Basic Research Grant No. 11-02-00885-a.
REFERENCES
1. J. Jurcic, M. McDavitt, G. Sgouros, et al., Targeted -particle immunotherapy for myeloid leukemia, Blood, 100, No. 4, 12331239 (2002).
2. R. Huneke, C. Pippin, R. Squire, et al., Effective -particle mediated radioimmunotherapy of murine leukemia, Cancer Res., 52, 58185820 (1992).
3. V. I. Shvets and Yu. M. Krasnopolskii, Liposomes in pharmacy. Products of nanobiology, Provizor, No. 3, 1517 (2008).
4. G.-J. Beyer, Alpha-emitting radionuclides production and application, in: Isotopes: Properties, Production, and Application, edited by V. Yu. Baranov, Fizmatlit, Moscow (2005), Vol. 2.
426
5. V. M. Murogov, M. F. Troyanov, and A. N. Shmelev, Use of Thorium in Nuclear Reactors, Energoatomizdat, Moscow (1983).
6. C. Forsberg and L. Lewis, Uses for Uranium-233: What Should be Kept for Future Needs? ORNL-6952 (1999).7. G. V. Kiselev and V. N. Konev, Implementation history of the thorium regime in the Soviet Atomic Project, Usp. Fiz. Nauk, 177, No. 12, 13611384 (2007).
8. L. I. Guseva and N. N. Dogadkin, Tandem generator for obtaining and separating short-lived -radionuclides, Radiokhimiya, 50, No. 3, 269273 (2008).
9. R. Atcher, A. Friedman, and J. Hines, An improved generator for the production of 212Pb and 212Bi from 224Ra, Appl. Rad. Isot., 39, No. 4, 283286 (1988).
10. S. Hassfjell and P. Hoff, A generator for production of 212Pb and 212Bi, ibid., 45, No. 10, 10211025 (1994).11. S. Hassfjell, A 212Pb generator based on a 228Th source, ibid., 55, No. 4, 433439 (2001).12. A. S. Serdyukova and Yu. T. Kapitanov, Radon Isotopes and Their Decay Products in Nature, Atomizdat, Moscow (1975).
13. S. Mirzadeh, Generator-produced alpha-emitters, Intern. J. Appl. Rad. Isot., 49, 345349 (1998).
427
Springer Science+Business Media, Inc. 2012