Patent Grant
12100528
This is a National Stage application of PCT international application PCT/FR2019/052675, filed on Nov. 8, 2019, which claims the priority of French Patent Application No. 1860561, filed Nov. 15, 2018, both of which are incorporated herein by reference in their entirety.
The invention relates to the field of the production of radioactive isotopes, also known as radioisotopes.
More specifically, it relates to a method for preparing one or more generators with a high radium-228 content from an aqueous solution comprising thorium-232 and radium-228.
This or these generators can particularly serve to produce thorium-228 from which radium-224, then lead-212 and bismuth-212 can be obtained.
The method and the generator(s) that it allows preparing are therefore likely to find applications notably in the manufacture of radiopharmaceuticals based on lead-212 or bismuth-212, suitable for use in nuclear medicine and, in particular, in targeted alpha radiotherapy for cancer treatment.
Targeted alpha radiotherapy, also known as targeted alphatherapy, consists of injecting a radioactive isotope bound to a vector, such as an antibody, capable of very precisely targeting specific sites present on the surface of cancer cells. The energy emitted by the natural radioactive decay of the radioisotope then makes it possible to destroy cancer cells while limiting damage to surrounding healthy cells.
Some decay products of thorium-232 and, in particular, lead-212 and bismuth-212, which is the daughter radioisotope of lead-212, can be used in targeted alphatherapy, particularly in the treatment of pancreatic cancers, other intraperitoneal cancers and melanomas, diseases for which targeted alphatherapy has been the subject of preclinical tests, in particular in the USA.
As shown in appended
The production of lead-212, radium-224 and thorium-228 can be carried out by means of what is known as a “generator”, i.e. a liquid chromatography column which typically comprises a solid stationary phase whereon the parent radioisotope is fixed selectively and which is washed regularly with a liquid phase making it possible to elute the daughter radioisotope(s) which are formed by radioactive decay of the parent radioisotope.
To prepare a generator intended for the production of thorium-228 and comprising, therefore, radium-228 as a parent radioisotope, it is known to circulate an aqueous solution of a natural thorium salt comprising both thorium-232 and radium-228 in a column wherein the solid stationary phase is capable of retaining radium selectively with respect to thorium.
A stationary phase material capable of retaining radium selectively with respect to thorium is, for example, that offered by the company IBC Advanced Technologies, Inc., under the reference AnaLig™ Ra-01 for concentrating radiated aqueous solutions before analysis and for separating radium from interfering substances.
In theory, the quantity of radium-228 retained by the stationary phase of a chromatography column is expected to increase with the volume of thorium salt solution placed in circulation in this column within the limits, obviously, of the theoretical radium-228 retention capacity by the stationary phase material as indicated by the supplier of this material.
However, in practice, this is not the case since a decrease in the radium-228 retention yield by the stationary phase material occurs as the volume of thorium salt solution placed in circulation in the chromatography column increases, with, consequently, an increase in the quantity of radium-228 which is eluted together with thorium-232.
By way of example, for a chromatography column comprising 36 g of AnaLig™ Ra-01 particles, the Inventors observed that the radium-228 retention yield by these particles, which is initially 99%, is not more than about 50% after circulation in the chromatography column of 2200 L of a thorium salt solution (unpublished data).
Thus, the effective capacity of the stationary phase material, which corresponds to its actual ability to retain radium-228 under given operating conditions, is considerably less than its theoretical retention capacity as indicated by its supplier.
A consequence thereof is that, when the chromatography column is subsequently used as a thorium-228 generator, the production capacity of this generator is less than what it might be if the retention of radium-228 by the stationary phase were better. This results, on one hand, in the fact that the subsequent elutions of this generator that are carried out to retrieve thorium-228 lead to eluates which not only are less charged in available thorium-228 but wherein the latter is more diluted and, on the other hand, in the need to replace the generator more often.
Furthermore, radium-228 which is not retained by the stationary phase material when preparing the generator must be recycled, otherwise this radium is lost.
The Inventors therefore set themselves the aim of finding a solution for these problems.
More specifically, they set themselves the aim of successfully increasing the effective capacity of a stationary phase material capable of retaining radium selectively with respect to thorium, i.e. increasing the quantity of radium-228 retained by this material per unit of weight of material or, in other words, producing a generator with a high radium-228 content from a solution of thorium-232 and radium-228.
This aim is achieved by the invention which proposes a method for preparing at least one generator comprising radium-228 from an aqueous solution A1 comprising thorium-232 and radium-228, the method comprising the following steps:
According to the invention, the aqueous solution A1, which comprises thorium-232 and radium-228, is, preferably, an aqueous solution obtained from the dissolution in water of a salt of natural thorium, i.e. thorium extracted from a thorium ore such as a monazite or a thorite.
This natural thorium salt is preferably a thorium nitrate, in which case the aqueous solution A1 comprises nitric acid.
However, the natural thorium salt can also be a salt other than a nitrate such as a thorium chloride, in which case the aqueous solution A1 comprises hydrochloric acid.
According to the invention, the material constituting the first and second stationary phases can be any stationary phase material which is capable of retaining radium selectively with respect to thorium.
Such a material can comprise a solid substrate that is inorganic (such as silica or alumina particles or a silica gel), organic (such as a polymer) or inorganic-organic, which is functionalised, by grafting or impregnation, by organic molecules capable of retaining by ion exchange, molecular recognition or any other mechanism, the radium ions (Ra2+) present in the aqueous solution A1 selectively from the thorium ions (Th4+) also present in this aqueous solution.
It can particularly consist of a material which comprises silica particles grafted with molecules of an organic ligand of radium, for example an oxacryptand. One material which is particularly well suited to the implementation of the method according to the invention is, for example, that offered by the company IBC Advanced Technologies, Inc. under the reference AnaLig™ Ra-01.
The nitric acid content of the aqueous solution A1 is located, preferably, in the acidity range recommended by the supplier of the stationary phase material, for example from 0.01 mol/L to 4 mol/L of nitric acid for AnaLig™ Ra-01 particles.
The aqueous solution A2 is advantageously an acidic aqueous solution which comprises the same acid and the same acid concentration as the aqueous solution A1.
Therefore, it consists, preferably, of an aqueous solution comprising nitric acid, at a concentration from 0.01 mol/L to 4 mol/L, if the aqueous solution A1 itself has such a nitric acid concentration.
In step c), the radium-228 retained by the first stationary phase is eluted by means of an agent which will detach this radium-228 from the first stationary phase by complexation or chelation (both terms being considered here as synonymous).
According to the invention, this complexing or chelating agent is, preferably, an aminopolycarboxylic acid or an aminopolycarboxylic acid salt.
Thus, it can particularly consist of nitrilotriacetic acid (or NTA), ethylenediaminetetraacetic acid (or EDTA), diethylenetriaminepentaacetic acid (or DTPA) or of one of the salts thereof, preference being, however, given to EDTA and to the salts thereof such as the sodium salts thereof.
Therefore, the aqueous solution A3 is preferentially a solution which comprises EDTA or a salt thereof, at a concentration advantageously between 0.03 mol/L and 0.1 mol/L and, more preferably, equal to 0.09 mol/L of EDTA and whose pH is brought, preferably, to a value ranging from 10 to 11 by adding a strong base such as sodium hydroxide.
The eluate thus obtained—or aqueous solution A4—therefore comprises radium-228 but in a complexed form.
Therefore, step d) is intended to dissociate the radium-228 complexes present in the eluate with a view to being able, in step e), to load the second chromatography column with an aqueous solution comprising decomplexed or, in other words, free radium-228.
According to the invention, this dissociation is carried out by modifying the pH of the aqueous solution A4 so as to bring this pH to a value at which the ability of the complexing agent to complex radium-228 is reduced.
Thus, for example, if the complexing agent is EDTA or one of the salts thereof, the dissociation of the radium-228 complexes is carried out by acidifying the aqueous solution A4 to bring the pH of this solution to a value at least equal to 3 in order to prevent EDTA from precipitating and, preferably, at most equal to 5 so that the complexing power of EDTA with respect to radium-228 is sufficiently reduced. In this case, a preferred pH value is between 4 and 5.
This acidification can be carried out by simply adding an acid to the aqueous solution A4, which can be a weak acid such as acetic acid but is, preferably, a strong acid such as nitric acid, to limit the volume of acid to be added.
However, within the scope of the invention, the acidification of the aqueous solution A4 is, preferably, carried out by washing the first stationary phase with at least one acidic aqueous solution and by adding all or part of the aqueous solution issued from this washing to the aqueous solution A4.
More preferably, to acidify the aqueous solution A4, it is preferred to wash the first stationary phase twice:
Indeed, it is advantageous to follow this procedure as this makes it possible not only to acidify the aqueous solution A4 but also, with the first washing, to remove the free EDTA as well as the 228Ra-EDTA complexes retained in the interstitial volume of the first stationary phase and, with the second washing, to recondition the first stationary phase with a view to subsequent reuse of this stationary phase.
When the acidification of the aqueous solution A4 is carried out by adding one or more solutions issued from the washing of the first stationary phase, then the method can comprise, between steps d) and e), a monitoring of the pH of the aqueous solution A5 resulting from this acidification and, if required, an adjustment of this pH to a value between 3 and 5 and, preferably, between 4 and 5.
In step e), the loading of the second chromatography column with the aqueous solution A5 consists of simply circulating this mixture in this column but which is preferably carried out at a low flow rate, for example from 1 mL/min to 5 mL/min, so as to favour the retention of radium-228 by the second stationary phase.
As mentioned above, once the second chromatography column is loaded with the aqueous solution A5, the second stationary phase contained in this column undergoes at least one washing with an aqueous solution A6 (step f) of the method), which aqueous solution A6 is, preferably, an acidic aqueous solution.
More preferably, the second stationary phase undergoes two washings:
According to the invention, step a) is, preferably, performed as long as the radium-228 retention yield by the first stationary phase is greater than or equal to a threshold value. In other words, step a) is stopped as soon as the radium-228 retention yield by the first stationary phase falls below this threshold value.
As a result, the volume V1 of aqueous solution A1 from step a) corresponds to the volume of aqueous solution A1 circulating in this column as long as the radium-228 retention yield by the first stationary phase is greater than or equal to the threshold value.
Preferably, this threshold value is 80% and, more preferably, 90%.
In a first preferred implementation of the method according to the invention, a single first chromatography column and a single second chromatography column are used, and:
In a second preferred implementation of the invention, a single first chromatography column, m second chromatography columns and m second stationary phases are used, and:
In a third preferred implementation of the method according to the invention, a single first chromatography column and a single second chromatography column are used, and:
In a fourth preferred implementation of the method according to the invention, a single first chromatography column and a single second chromatography column are used, and:
In a fifth preferred implementation of the method according to the invention, a single first chromatography column, m second chromatography columns and m second stationary phases are used, and:
In a sixth preferred implementation of the method according to the invention, a single first chromatography column, m second chromatography columns and m second stationary phases are used, and:
In a seventh preferred implementation of the method according to the invention, a single first chromatography column and a single second chromatography column are used, and:
In an eighth preferred implementation of the method according to the invention, a single first chromatography column and a single second chromatography column are used, and:
In a ninth preferred implementation of the method according to the invention, l first chromatography columns, l first stationary phases and a single second chromatography column are used, and:
In a tenth preferred implementation of the method according to the invention, l first chromatography columns, l first stationary phases and a single second chromatography column are used, and:
In an eleventh preferred implementation of the method according to the invention, l first chromatography columns, l first stationary phases and a single second chromatography column are used, and:
In a twelfth preferred implementation of the method according to the invention, l first chromatography columns, l first stationary phases and a single second chromatography column are used, and:
In a thirteenth preferred implementation of the method according to the invention, l first chromatography columns, l first stationary phases and a single second chromatography column are used, and:
It will be noted that, when embodiments nine to thirteen are implemented with an integer l which is equal to n, then this means that, to carry out n times steps a) to c) or a) to d), a different first column is used each time.
Regardless of the implementation of the method according to the invention, the generator(s) obtained is (are) preferably intended to produce thorium-228.
Further features and advantages of the method according to the invention will emerge on reading the following supplementary description and which relates to two of the preferred implementations of this method.
Obviously, these implementations are merely given by way of illustrations of the subject matter of the invention, and in no way represent restrictions of this subject matter.
Reference is firstly made to
In this first implementation, the method is intended to prepare a single generator.
It firstly comprises carrying out n times, by means of a single first chromatography column 10 comprising a stationary phase 20, the following sequence of steps a) to d):
Steps c) and d) of the n sequences of steps a) to d) can be carried out using n receptacles 30, each receptacle serving for a single step c) and a single step d), in which case, after the final step d) of the n sequences of steps a) to d), n aqueous solutions A5 are obtained.
Alternatively, steps c) and d) of the n sequences of steps a) to d) can be carried out using a single receptacle 30, in which case, after the final step d) of the n sequences of steps a) to d), a mixture of n aqueous solutions A5 is obtained.
Then, the method comprises carrying out, by means of a single second chromatography column 40 comprising a stationary phase 50, the following two steps:
All the steps of the method, which are detailed hereinafter, are, preferably, performed at ambient temperature, i.e. at a temperature of 20° C. to 25° C.
*Step a):
The column 10 comprises a stationary phase 20 which consists of AnaLig™ Ra-01 particles. This stationary phase retains radium, regardless of the isotope, selectively with respect to thorium, regardless of the isotope.
By way of example, this column has a bed volume (or BV) of 78.54 mL and contains from 34 to 37 g of AnaLig™ Ra-01 particles.
Prior to carrying out the first step a) of the n sequences of steps, the stationary phase 20 is conditioned by percolating an aqueous solution comprising from 0.01 mol/L to 4 mol/L, preferably from 0.05 mol/L to 1 mol/L and, more preferably, 0.1 mol/L of nitric acid.
Once this conditioning has been performed, the column 10 is supplied with the aqueous solution A1 which is obtained from dissolving a natural thorium nitrate in water and which has a nitric acid content which is between 0.01 mol/L and 4 mol/L, preferably between 0.05 mol/L and 1 mol/L and, more preferably, 0.1 mol/L.
This aqueous solution contains radium-228 (for example, at a rate of 1 MBq/L), preferably at radioactive equilibrium with the thorium-232 from which it originates.
The column 10 is continuously supplied with aqueous solution, at a flow rate typically between 10 mL/min and 100 mL/min, as long as the radium-228 retention yield is greater than or equal to a threshold value which is, preferably, 80% and, more preferably, 90%.
When the radium-228 retention yield falls below the threshold value, then the supply of the column 10 is stopped.
The retention yield, referenced RT, is calculated by determining the activity of radium-228 in samples of the aqueous solution A1 which are taken at the entry and exit thereof from the column 10 and by applying the following formula:
where:
As known per se, the activity of radium-228 is determined indirectly, namely it is calculated from the activity exhibited by its daughter, actinium-228, at the end of a period of 4 days after taking the samples, the activity of actinium-228 being itself measured directly in the samples by gamma spectrometry.
*Step b):
The washing of the stationary phase 20 is carried out by circulating in the column 10 several BVs, for example 15 BVs, of aqueous solution A2, which comprises from 0.01 mol/L to 4 mol/L, preferably from 0.05 mol/L to 1 mol/L and, more preferably, 0.1 mol/L of nitric acid, at a flow rate, for example, of 40 mL/min.
*Step c):
The elution of the radium-228 from the stationary phase 20 is carried out by circulating in the column 10 the aqueous solution A3 which comprises from 0.03 mol/L to 0.1 mol/L and, preferably, 0.09 mol/L of EDTA and whose pH is brought to a value preferably from 10 to 11 by adding a strong base such as sodium hydroxide.
The number of BVs of aqueous solution A3, which are placed in circulation in the column 10, is selected in such a way that it corresponds to a volume of aqueous solution A3 between 0.005% and 1% and, preferably, between 0.01% and 1% of the volume of aqueous solution A1 having circulated in this column during step a), to obtain a concentrating elution of radium-228, i.e. an elution of radium-228 which gives rise to an aqueous solution A4 wherein the activity of radium-228 is at least 100 times higher than that of radium-228 in the aqueous solution A1.
Thus, for example, for a volume of 1000 L to 1200 L of aqueous solution A1 having circulated in the column 10, the elution of radium-228 is carried out with a number of BVs of aqueous solution A3 corresponding to a volume between 50 mL and 12 L, preferably between 250 mL and 12 L, i.e., for example, 6 BVs for a column 10 having a BV of 78.54 mL.
For optimal elution, the aqueous solution A3 is, preferably, placed in circulation in the column 10 in two steps. Thus, for example, for 6 BVs, 2 BVs are first used at a flow rate of 10 mL/min, then, after a break of 20 minutes, the remaining 4 BVs are used at a flow rate of 5 mL/min.
However, it is completely possible to circulate the aqueous solution A3 in the column 10 continuously (i.e. without envisaging a break) and/or at a single flow rate, this flow potentially ranging from 1 mL/min to 30 mL/min.
On the other hand, it is important to keep the pH of the aqueous solution A3 at a value at most equal to 11 to minimise the risks of dissolving the silica particles forming the solid substrate of the stationary phase 20.
*Step d):
As stated above, this step consists of subjecting the stationary phase 20 to two successive washings and of collecting the solutions obtained from these two washings in the receptacle 30 wherein in step c) the eluate, or aqueous solution A4, comprising radium-228 in the form of 228Ra-EDTA complexes has been collected.
The first washing, which makes it possible to remove from the stationary phase 20 the free EDTA as well as the 228Ra-EDTA complexes retained in the interstitial volume of this stationary phase, is carried out by circulating in the column 10 several BVs, for example 5 BVs, of a buffer solution whose pH is at least equal to 3 to prevent EDTA from precipitating inside the column 10 and at most equal to 5.
This buffer solution is, for example, a sodium acetate buffer solution of pH 4.5. The second washing, which itself makes it possible to recondition the stationary phase 20 with a view to the reuse thereof in the implementation of the following sequence of steps a) to d), is carried out by circulating in the column 10 several BVs, for example 5 BVs, of a nitric aqueous solution whose acidity enables a purification of the stationary phase 20 but without the addition of the solution obtained from this second washing to the mixture already present in the receptacle 30 lowering the pH of this mixture below 3 to prevent EDTA from precipitating.
Therefore, this nitric aqueous solution has, preferably, a nitric acid content from 0.1 mol/L to 1 mol/L and, more preferably, 0.1 mol/L.
The circulation rates of the buffer solution and the nitric aqueous solution in the column 10 are advantageously 10 mL/min but can range from 1 mL/min to 60 mL/min.
The collection of the solutions from these two washings is carried out under stirring such that the washing solutions are mixed with the eluate as they are collected and, thus, acidifying this eluate.
This makes it possible to lower the complexing power of EDTA with respect to radium-228 and, thereby, obtain an aqueous solution A5 wherein radium-228 is decomplexed.
*Step e):
The chromatography column 40 is, preferably, a column fully identical to the column 10, with the same BV and the same mass quantity of Analig™ Ra-01 particles.
Before carrying out step e), the stationary phase 50 is conditioned by percolating a solution of a buffer solution whose pH is at least equal to 3 to prevent the EDTA present in the n aqueous solutions A5 (if n receptacles 30 were used during steps c) and d) of the n sequences of steps a) to d)) or the mixture of aqueous solutions A5 (if a single receptacle 30 was used during the n sequences of steps a) to d)) from precipitating inside the column 40 and at most equal to 5.
This buffer solution is, for example, a sodium acetate buffer solution of pH 4.5.
Once this conditioning has been performed, and after an optional adjustment of the pH to a value at least equal to 3 and, preferably, at most equal to 5, and ideally from 4 to 5, of the n aqueous solutions A5 or of the mixture of aqueous solutions A5, the column 40 is loaded with the n aqueous solutions A5 or the mixture thereof.
This loading is carried out by circulating in this column the n aqueous solutions A5 (injected into the column one after the other) or the mixture of aqueous solutions A5, at a low flow rate, for example from 1 mL/min to 5 mL/min, to favour the retention of radium-228 by the Analig™ Ra-01 particles.
*Step f):
As stated above, this step consists of subjecting the stationary phase 50 to two successive washings, the first with a buffer solution of pH between 3 and 5 and the second with a nitric aqueous solution.
The first washing, which makes it possible to remove from the stationary phase 50 the free EDTA retained in the interstitial volume of this stationary phase, is carried out by circulating in the column 40 several BVs, for example 2.5 BVs, of a buffer solution whose pH is at least equal to 3 to prevent, once again, EDTA from precipitating inside the column 40 and at most equal to 5 to prevent the interstitial EDTA from recomplexing the radium-228.
As in the case of the first washing of step d), this buffer solution is, for example, a sodium acetate buffer solution of pH 4.5.
The second washing, which makes it possible to condition the stationary phase 50, is carried out by circulating in the column 40 several BVs, for example 3 BVs, of a weakly concentrated aqueous nitric acid solution such as an aqueous solution comprising from 0.1 mol/L to 1 mol/L and, preferably, 0.1 mol/L of nitric acid.
The circulation rates of the buffer solution and the aqueous nitric acid solution in the column 40 are advantageously 5 mL/min but can range from 1 mL/min to 5 mL/min.
Reference is now made to
This implementation, which is intended to prepare a plurality of generators, only differs from that illustrated in
Thus, step e) comprises loading the m second columns 40 with the n aqueous solutions A5 or with the mixture of aqueous solutions A5 obtained after step d) of the last of the n sequences of steps a) to d) with, preferably, an equitable distribution, i.e. with equal fractions, of the n aqueous solutions A5 or of the mixture of aqueous solutions A5 between the m second columns 40.
Step f) then comprises two successive washings of each of the m stationary phases 50, the first with a buffer solution of acid pH to remove from the stationary phases 50 the free EDTA retained in these stationary phases, and the second with an aqueous solution comprising nitric acid to condition the second stationary phases 50 with a view to the subsequent use of the m second chromatography columns 40 as generators.
Example of Implementation of the Method According to the Invention
The method according to the invention was implemented according to the thirteenth implementation described in “Disclosure of the invention”, to provide a single generator containing radium-228.
The following were used in this example:
After the two reiterations of steps a) to f), a column 40 comprising 82 MBq of radium-228 per g of AnaLig™ Ra-01 particles, i.e. in total 3018 MBq of radium-228, was obtained.
This means that the effective capacity of the AnaLig™ Ra-01 particles forming the stationary phase 50 was increased by a factor of 2.5 with respect to the effective capacity of the AnaLig™ Ra-01 particles forming the stationary phases 20.
| Number | Date | Country | Kind |
|---|---|---|---|
| 1860561 | Nov 2018 | FR | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/FR2019/052675 | 11/8/2019 | WO |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2020/099769 | 5/22/2020 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 20040052705 | Tranter | Mar 2004 | A1 |
| 20060153760 | Meikrantz et al. | Jul 2006 | A1 |
| 20060213329 | Meikrantz | Sep 2006 | A1 |
| 20150170776 | Torgue et al. | Jun 2015 | A1 |
| 20180308600 | Torgue et al. | Oct 2018 | A1 |
| Number | Date | Country |
|---|---|---|
| 3174068 | May 2017 | EP |
| 0205859 | Jan 2002 | WO |
| WO-03065381 | Aug 2003 | WO |
| WO-2008108888 | Sep 2008 | WO |
| WO-2008113792 | Sep 2008 | WO |
| Entry |
|---|
| International Search Report for PCT/FR2019/052675 dated Mar. 12, 2020. |
| Written Opinion for PCT/FR2019/052675 dated Mar. 12, 2020. |
| Search Report for French application No. FR1860561 dated Sep. 10, 2019. |
| Specification and drawing for U.S. Appl. No. 17/278,479 entitled Method for Producing Lead-212 From an Aqueous Solution Comprising Thorium-228 and Daughters Thereof, filed Mar. 22, 2021. |
| Number | Date | Country | |
|---|---|---|---|
| 20220013246 A1 | Jan 2022 | US |
