Development of a titanium tungstate-based 188 W/ 188 Re gel generator using tungsten of natural isotopic abundance a Australian Nuclear Science and Technology Organization, PMB 1, Menai,
Trang 1Development of a titanium tungstate-based 188 W/ 188 Re gel generator using tungsten of natural isotopic abundance
a
Australian Nuclear Science and Technology Organization, PMB 1, Menai, NSW 2234, Australia
b Stevens Institute of Technology, Hoboken, NJ, USA c
Nuclear Research Institute, Dalat, Viet Nam Received 23 November 2001; received in revised form 25 February 2002; accepted 12 June 2002
Abstract
The feasibility of developing titanium tungstate-based188W/188Re gel generator using tungsten of natural isotopic abundance irradiated in a moderate flux reactor has been investigated Influence of temperature, pH and eluent concentration on generator performance was studied It was found that ‘‘post-formed’’ approach allows to construct gel generators with elution performance and188Re elution yields very close to those of conventional alumina188W/188Re generator Curie-level185W radionuclidic impurity presents a challenge during the processing of target material and subsequent elution of the generator In the future use of semi-enriched with186W target material (50–60% enrichment) would be beneficial in the development of titanium tungstate-based188W/188Re gel generators r 2002 Elsevier Science Ltd All rights reserved
1 Introduction
Rhenium-188 (188Re) has recently emerged as a useful
therapeutic radioisotope in a variety of clinical trials
such as cancer radioimmunotherapy, palliation of
skeletal bone pain, endovascular brachytherapy to
prevent restenosis after angioplasty (Knapp, 1998;
Hoher et al., 2000; Seitz et al., 1999; Murray et al.,
2001) as well as in the pre-clinical development of novel
radiopharmaceuticals (Dadachova and Chapman, 1998;
Emfietzoglou et al., 2001; Arteaga de Murphy et al.,
2001) Rhenium is a chemical analogue of technetium
and exhibits practically identical chemical and
biodis-tribution properties (Deutsch et al., 1986) Emission
characteristics and physical properties of 188Re (16.7 h
half-life) make it suitable for application in radionuclide
therapy—its high energy beta particles
range, sufficient to eradicate medium or large tumors by
a ‘‘cross-fire’’ effect (O’Donoghue et al., 1995), while its low energy and low abundance gamma photons (155 keV, 15% abundance) are suitable for imaging (Saha, 1997)
Carrier-free 188Re is obtained from the 188W/188Re generators in a similar fashion to 99mTc The parent radionuclide 188W (69 days half-life) is produced in a nuclear reactor via 186W(2n,g)188W nuclear reaction Much work has been carried out on development of
188
W/188Re generator systems In188W/188Re generators available from the US from Oak Ridge National Laboratory the irradiated tungsten is absorbed on the alumina column in 188W-tungstate form, and 188 Re-perrhenate is eluted from the column with saline (Mikheev et al., 1972; Knapp et al., 1994; Kamioki
et al., 1994) Availability of high specific activity188W (B5 mCi/mg) is crucial for production of inorganic adsorbent-based 188Re/188W generators as only very limited amount of tungsten can be absorbed onto conventional inorganic adsorbents such as alumina (Ehrhardt et al., 1987; Kamioki et al., 1994) Production
of high specific activity 188W requires irradiation of
*Corresponding author Department of Nuclear Medicine,
Albert Einstein College of Medicine of Yeshiva University,
1695A Eastchester Rd., Bronx, NY 10461, USA Tel.:
+1-718-405-8485; fax: +1-718-824-1369.
E-mail address: edadacho@aecom.yu.edu (E Dadachova).
{ Deceased.
0969-8043/02/$ - see front matter r 2002 Elsevier Science Ltd All rights reserved.
PII: S 0 9 6 9 - 8 0 4 3 ( 0 2 ) 0 0 1 7 8 - 1
Trang 2expensive 186W-enriched targets (96% enrichment in
186
W also helps to reduce185W in the final product) for
several months in a high flux reactor (with neutron flux
of at least 5 1014n cm2s1) as the yields in double
neutron capture nuclear reactions are proportional to
the square of neutron flux
As an alternative 188W/188Re gel generator system
which utilizes zirconium or other metal [188
W]W-tungstate gel has been developed (Ehrhardt et al.,
1992; Vanderheyden et al., 1992; Dadachov and
Lambrecht, 1995) Gel generators permit use of low
specific activity 188W, thus making it possible to
irradiate semi-enriched W (50–50% enrichment in
186
W) or, theoretically, even W targets of natural
isotopic abundance (28.6% abundance for186W) in the
reactors with low or moderate neutron flux
Here we describe our experience in developing
titanium tungstate-based 188W/188Re gel generator
utilizing W targets with natural isotopic abundance
irradiated in a moderate flux reactor
2 Experimental
2.1 Materials and reagents
WO3of ‘‘SpecPure’’ grade and TiCl4of ‘‘Pure’’ grade
were supplied by B.D.H All other chemicals used for
experiments were of ‘‘Reagent’’ grade
2.2 Reactor activation of W targets and radioactivity
measurements
3.5 g WO3 of natural isotopic abundance or 0.5 g
samples of titanium tungstate gel (further referred in the
text as TiW) were placed in metallic titanium container
and irradiated in HIFAR (ANSTO, Australia) nuclear
reactor in thermal neutron flux of 5 1013n cm2s1for
192 days After irradiation the targets were allowed to
‘‘cool’’ for one month before chemical processing (in
case of tungsten oxide) or column packing (in case of
TiW gel samples) Irradiated targets were processed in a
hot cell
The gross radioactivity of 188W and 188Re samples
was measured in a calibrated ionization chamber The
gamma-spectrometry of 188W, 188W/188Re at
decay-growth equilibrium (291 and 155 keV photo peaks,
respectively) as well as determination of radioactive
impurities in generator eluate was performed in Ge(Li)
detector coupled with multichannel analyser (EG & G
Ortec)
2.3 Preparation of titanium tungstate gels
Two techniques were employed for the preparation of
TiW gel generators When ‘‘post-formed’’ technique was
used, the gel generator was synthesized through several steps from radioactive reactor-irradiated WO3of natural isotope abundance Conversely, ‘‘pre-formed’’ TiW gel was prepared from inactive WO3, irradiated in the reactor and used directly for generator column packing 2.3.1 ‘‘Post-formed’’ TiW gel preparation
Neutron-irradiated 3.5 g WO3target was dissolved in 52.5 ml of 8M NaOH solution To facilitate the dissolution of the target 10 ml 30% H2O2solution was added and the mixture was stirred at 801C until clear solution of sodium tungstate was formed 39 ml 10 M HCl was added to sodium tungstate to adjust its pH to 4.5 Following filtration through a fine filter paper, the solution of sodium tungstate was diluted to 100 ml with distilled water The tungstate concentration of this solution was 0.15 M To precipitate TiW gel, 100 ml 0.15 M TiCl4solution, pH=1.0, was added to tungstate solution under stirring at 601C White TiW gel formed in this step was filtered, washed and dried at 801C for 2 h forming a final product with particle size o1 mm The gel precipitation yield (percentage of W complexed in the gel) was 96% For preparation of 188Re/188W generator 4.8g TiW gel was packed into a 12 mm-diameter glass column fitted with sintered glass bottom The column which contained 25 mCi188W and B3.5 Ci
185
W was washed extensively with water, and188Re was eluted with normal saline
2.3.2 ‘‘Pre-formed’’ TiW gel preparation
In the ‘‘pre-formed’’ approach TiW gel of natural isotopic abundance was prepared in the same manner as
in ‘‘post-formed’’ approach except that it was irradiated
in the reactor after the preparation Following 192 days irradiation and 1 month cooling 0.5 g TiW gel contain-ing 3.8mCi 188W and 0.51 Ci 185W was packed into generator column, and 188Re elution with saline was performed directly or after treating the generator with 0.1 M K2CrO4
2.4 Structural characteristics of TiW gel The crystallinity of TiW was determined by X-ray powder diffraction using a CuKaradiation
2.5 Investigation of the elution performance of TiW gel generators
The effects of different drying temperatures, pH and NaCl concentration of the eluent on188Re elution yields and W breakthrough were investigated To evaluate
188
Re elution profile 1-ml portions of the generator eluate were collected and counted in an ionization chamber For evaluation of 185,188W breakthrough the eluate portions were combined, left to decay for 2 weeks and188W contents determined by gamma spectrometry
Trang 3from the intensity of the 155 keV g-ray of188Re Direct
detection of185W in the presence of188Re is difficult, as
125 keV peak emitted by 185W has only 0.019%
abundance, thus making it hard to observe it under
the Compton background of188Re 155 keV peak with an
abundance of 15% Fortunately, the ratio of188W/185W
activities in the target or generator which in our study
was 0.0076 at EOB can be calculated at any moment of
time using 185W and 188W half-lives As chemical
properties of 185W and 188W isotopes are identical,
185
W breakthrough was calculated from 188W
break-through and the ratio of188W/185W activities
In some experiments the generators were connected to
a small 1.5 g alumina column for the purpose of
purification/concentration of generator eluate
3 Results and discussion
The gel generator approach makes it possible to
manufacture 99mTc/99Mo and 188Re/188W generators
using low specific activity 99Mo and 188W obtainable
from a variety of low to medium flux nuclear reactors In
addition, the possibility of using W of natural isotopic
abundance in place of expensive 186W-enriched targets
would further decrease the price of 188Re/188W
gen-erators
Previously, we reported the results of the development
of99mTc/99Mo and188Re/188W gel generators based on
multivalent metal molybdate or tungstate gels,
respec-tively (Dadachov and Lambrecht, 1995; Le Van So and
Lambrecht, 1994) Of these, Ti is of particular interest
for gel generator development because of its low cost,
non-toxicity and low solubility of its compounds
For construction of generators we utilized both
traditional ‘‘post-formed’’ technique when the gel
generator was synthesized through several steps from
radioactive reactor-irradiated WO3, and ‘‘pre-formed’’
technique when TiW gel was prepared from inactive
WO3, irradiated in the reactor and used directly for
generator column packing Use of ‘‘pre-formed’’
col-umns eliminated several radiochemical processing steps
preceding generator elution
3.1 Titanium tungstate gel formation and characteristics
The reaction between TiCl4and Na2WO4(1:1 molar
ratio) resulted in formation of TiW gel in 96% yield The
X-ray diffraction pattern (Fig 1) of dried TiW gel
revealed its amorphous nature Our later EXAFS study
of the local structure of tungstate-based gel generators
(Dadachov et al., 1999) proved that Re7+(0.56 (A) born
in the same place as its parent isotope W6+(0.65 (A) is
located in the highly distorted octahedral oxygen
coordination, and being too small to be stable in this
environment, can be easily removed by even slightly polar solvents in the form of perrhenate188ReO4 Fig 2 demonstrates the dependence of 188Re elution yields on the drying temperature of the gel Practically linear drop in yields was observed in the interval of 80–1051C We have recently shown with the help of EXAFS spectroscopy (Dadachov et al., 1999) that in gel generators tungsten atoms are coordinated by six oxygen ligands and are too loose to fit octahedral hole The structure of the generator can be easily destabilized
by thermal dehydration, which removes oxygen atoms belonging to OH groups and H2O and lowers coordina-tion number of tungsten atoms At >1201C drying temperatures188Re elution yields dropped dramatically This drop in yields of TiW generator can be attributed to the collapse of the gel structure caused by the loss of most of the structural water
Fig 3 displays the effect of pH and NaCl concentra-tion of the eluent on 188Re elution yield and 188W breakthrough Both 188Re elution yield and 188W breakthrough increase with the increasing eluent pH
0 50 100 150 200 250 300 350 400 450 500
2 theta
Fig 1 X-ray diffraction pattern of TiW gel.
0 20 40 60 80 100
Temperature o C
Fig 2 Effect of drying temperature on188Re elution yields of
‘‘post-formed’’ TiW gel generator.
Trang 4and molar concentration which can be explained by
swelling of TiW gel structure resulting in easier 188Re
elution and higher dissolution of tungstate
3.2 Elution performance of ‘‘post-formed’’ gel generator
The elution performance data and elution profile
of ‘‘post-formed’’ TiW gel column are shown in
Table 1 and Fig 4, respectively It is evident that both
elution performance and elution profile of the gel
column were quite similar to those of the conventional
alumina-based generator (Kamioki et al., 1994) The use
of additional 1.5 g alumina clean-up column (so-called
‘‘tandem’’ generator design) not only decreased W
breakthrough below detection limits but also allowed
to concentrate the eluate from 9–15 to 2–3 ml This was
achieved by eluting gel generator with water onto the
alumina clean-up column, which was later eluted with
saline to obtain the purified and concentrated 188Re
eluate
As gel generators described in this paper were
prepared from W targets of natural isotopic abundance,
it was important to assess the radionuclidic impurities in
the generator itself and in its eluate The main
radio-nuclidic impurity in the generator was 185W This
isotope (75.1 day half-life, b-emission 0.433 MeV) is a
product of184W (n,g)185W nuclear reaction, as184W has
30.7% isotopic abundance Because of its high
radio-activity and long half-life185W, apparently, causes the
biggest problem in the preparation of 188W/188Re
generators from W of natural isotopic abundance as a
reactor irradiation target As a consequence, rigorous
separation is required to obtain188Re eluate essentially free from not only 188W parent isotope but also from
185
W Our gamma-spectrometry measurements showed that out of B3.5 Ci185W in the target material 3.2 Ci was converted into TiW gel, B2.5 mCi was trapped on alumina clean-up column per elution and none was detected in 188Re eluate Besides 185W other radio-nuclides were found in much smaller quantities in target material, such as124Sb (B100 mCi) and182Ta (B50 mCi) About 50 mCi 124Sb and 10 mCi 182Ta were converted into TiW gel; 10 mCi124Sb and none of182Ta was found
on alumina column after 1st elution; and none of these isotopes were present in 188Re eluate The alumina column was changed after every 2 elutions Also, other methods of concentrating 188Re eluate have been recently described (Blower, 1993; Guhlke et al., 2000) employing combinations of commercially available disposable ion exchange cartridges
3.3 Elution performance of ‘‘pre-formed’’ gel generator
We investigated a possibility of preparing gel gen-erator from the ‘‘cold’’ precursors then irradiating the
formed’’ column in the reactor The use of ‘‘pre-formed’’ columns would eliminate several radiochemical processing steps during which an accidental loss of valuable target material could occur Irradiation of 0.5 g samples of TiW gel in the reactor for 192 days resulted in color change of the gel from white to dark brown Numerous radionuclidic impurities were detected in the target material such as185W,60Co,46Sc,124Sb,59Fe and
182Ta Attempts to elute188Re with saline after packing
0 0.1 0.2 0.3
0 20 40 60 80 100
Acidity of 0.9% NaCl solution, pH
NaCl concentration of eluent, [mol/L]
Fig 3 Dependence of188Re elution yields and188W breakthrough of ‘‘post-formed’’ TiW gel generator on NaCl concentration and
pH of the eluent.
Trang 5the irradiated gel into the generator column resulted in very low yields of B5% Soaking the generator for 2 days in 0.1 M K2CrO4 oxidizing solution caused the change of generator color to light green.188Re elution yields also improved and varied within 30–32% range which was still significantly lower than the B80% elution yields of ‘‘post-formed’’ generator It is known that neutron irradiations result in significant increase in target temperature and in profound chemical changes in target material especially in oxyanions (McKay, 1971) The poor performance of ‘‘pre-formed’’ gel generator can be explained by partial gel structure collapse and reduction of W and Ti to lower oxidation states caused
by prolonged exposure to high dose radiation and high temperatures during irradiation
4 Conclusion
We have investigated the feasibility of developing titanium tungstate-based188W/188Re gel generator using tungsten of natural isotopic abundance irradiated in the moderate flux reactor While elution performance and
188
Re elution yields of ‘‘post-formed’’ generator were very close to those of conventional alumina188W/188Re, Curie-level 185W radionuclidic impurity presented a challenge during processing of target material and subsequent elution of the generator In the future use
of semi-enriched with 186W target material (50–60% enrichment) would be beneficial in the development of titanium tungstate-based188W/188Re gel generators
Acknowledgements The research was funded by the Commonwealth of Australia
a and
188
Re eluate volume, [ml]
A B C
Waste
A B
C
4.8g TiW
1.5g Al 2 O 3
H 2 O 0.9%NaCl
0.9%NaCl
Fig 4 188 Re elution profiles of ‘‘post-formed’’ TiW gel generator.
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