A simple and convenient method for production of 89Zr with high purity

Applied Radiation and Isotopes 118 (2016) 326–330

Contents lists available at ScienceDirect

Applied Radiation and Isotopes journal homepage: www.elsevier.com/locate/apradiso

A simple and convenient method for production of a

a

a,⁎

b

89

Zr with high purity b

b

Yu Tang , Shuntao Li , Yuanyou Yang , Wen Chen , Hongyuan Wei , Guanquan Wang , ⁎ Jijun Yanga, Jiali Liaoa, Shunzhong Luob, Ning Liua,

crossmark

a Key Laboratory of Radiation Physics and Technology, Ministry of Education, Institute of Nuclear Science and Technology, Sichuan University, Chengdu 610064, P. R. China b Institute of Nuclear Physics and Chemistry, CAEP, Mianyang 621900, P. R. China

A R T I C L E I N F O

A BS T RAC T

Keywords: Y target 89 Zr Production Separation Dowex1×8

A simple and convenient method for radiochemical separation 89Zr with no harmful substance was explored. The separated 89Zr was found to be [89Zr]Zr-chloride, and the recovery of the radioactivity was 85% ± 3% with high radionuclidic purity (99.99%). The yields of 89Zr via the reaction of (p, n) or (d, 2n) on Y target were also evaluated on CS-30 cyclotron, indicating the latter was more favorable for the production of 89Zr with a yield of 58 ± 4 MBq/μA·h.

1. Introduction 89

Zr, as a relatively moderate half-life (T1/2=78.41 h) positron emitting radionuclide, could decay by electron capture (77%), and positron emission (23%), with concomitant emission of a 909 keV gamma ray. The high abundance of the 909 keV gamma photons were emitted by 89Zr, which contribute greatly to the absorbed dose of 89Zr radiopharmaceuticals, especially in slower clearing agents (Zeng and Anderson, 2013; Thaddeus, 2010). In addition, the daughter nuclide, 89 Y, formed by the positron decay of zirconium, is stable and would not cause any damage in vivo (Kasbollah et al., 2013). These favorable decay characteristics of 89Zr indicate that this radionuclide has great potential in the application of nuclear medicine for labelling monoclonal antibodies, bio-distribution studies and immuno-positron emission tomography (PET) imaging (Ivanov et al., 2014; Omara et al., 2009). Despite of the promising application in vivo results, the nuclear medicine community has been slowly embracing the potential of 89Zr, basically because of the inefficient and complicated methods for its separation from the irradiated Y target material (Holland et al., 2009). Actually, one of the main problems encountered in the separation of the target nuclide is that the obtained 89Zr has always been contaminated from the long-lived isotopes, such as 88Zr (T1/2=83.4 d), 88Y (T1/ 65 Zn (T1/2=244.06 d) (Boellaard, 2003; Meijs et al., 2=106.65 d) and 1994; Zweit et al., 1991). Wilma E. Meijs and Iris Verel et al. found that radioactive impurities presented in the 89Zr solution (Boellaard, 2003; Meijs et al., 1994), and the radioactive impurity would introduce further problems with the chelation chemistry and is likely to compli-

⁎

cate analysis of in vivo PET imaging studies (Holland et al., 2009). Therefore, efficient separation methods to obtain 89Zr with high radionuclidic purity have been attracted considerable attention. In the previous reports, separation methods mainly including solvent extraction, cation and anion exchange chromatography and solid-phase hydroxamate resin have been described (Boellaard, 2003; Dejesus and Nickles, 1990; Kandil et al., 2007; Meijs et al., 1994). For example, Link et al. investigated the radiochemical separation of 89Zr by a double extraction protocol using TTA as extractant and anion exchange chromatography with oxalate eluting, to obtain 89Zr in an 80% recovery (Dutta et al., 2009). A modified method with 4 mol/L HF eluting 89Zr reported by Dejesus and Nickles yielded similar results (Dejesus and Nickles, 1990). Holland et al. isolated 89Zr as the form of oxalate by using a solid-phase hydroxamate resin with about 99.5% recovery of the radioactivity (Holland et al., 2009). Besides, Kandil et al. separated 88,89Zr by both solvent extraction (HDEHP in nheptane and TPPO in chloroform) and back-extraction of 89Zr into the aqueous phase with conc. H2SO4 and oxalic acid, followed anion exchange resin Dowex 21K and cation exchange resin Dowex 50WX8, of which the recovery was only 21.7% and 74.6% (Kandil et al., 2007). However, the mentioned approaches for the separation of 89Zr are always complicated and tedious (Holland et al., 2009). Moreover, some even use hydrofluoric acid, conc. sulfuric acid and oxalic acid which should not be considered, owing to their strong excitant, causticity and high toxic to human body (Dutta et al., 2009; Kasbollah et al., 2013). Fortunately, a relatively friendly procedure was explored by Zweit et al. which pretreated the irradiated yttrium target with hot 12 mol/L HCI and 20% H2O2, then the solution was

Corresponding authors at: Sichuan University, No. 29, Wang Jiang Road, Chengdu, Sichuan Province, P. R. China. Tel.: +86 28 85412613; Fax: +86 28 85412374. E-mail addresses: [email protected] (Y. Yang), [email protected] (N. Liu).

http://dx.doi.org/10.1016/j.apradiso.2016.09.024 Received 9 July 2016; Received in revised form 24 September 2016; Accepted 24 September 2016 Available online 26 September 2016 0969-8043/ © 2016 Elsevier Ltd. All rights reserved.

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(almost 25 µm, 89Y has a 100% abundancy, purity 99.99%) on a copper target substrate. In this process, the yttrium atoms were ejected as a result of momentum transfer between accelerated argon ions and the yttrium source. The yttrium atoms crossed a vacuum chamber (9×10−4 Pa) and finally deposited on the copper support. Irradiations were conducted by using variable particles with relevant beam energy and current. On CS-30 cyclotron accelerator facility in Sichuan University produced by U.S. Company TCC (The Cyclotron Corporation), the Y target was irradiated with 13 MeV proton-beam energy, with a beam current of 10–30 μA for 1 h and 15 MeV deuteron-beam energy, with a beam current of 10–15 μA for 1 h, respectively. The 89Zr was produced via the 89Y (p, n) 89Zr or 89Y (d, 2n) 89Zr transmutation reaction using a solid 89Y target mounted on a custom-made, water-cooled target with a 10° angle of incidence.

heated to dry after which it was redissolved in 12 mol/L HCI and left to cool before loading into Dowex 1×8 (Cl−) column. Final 89Zr with radioactive impurity 88Zr was eluted by 2 mol/L HCl with overall yield of 63% (Zweit et al., 1991). But, the process of treating the irradiated target in the published work was complicated, and the low recovery of 89 Zr and radioactive impurity results in further problems with the study of the related antibody for PET imaging. Hence, as a consequence of the challenges in separation, a simple and convenient method for the radiochemical separation to obtain high purity 89Zr, with no harmful substance and better recovery, needs to be further explored. Meanwhile, the most effective routes of 89Zr production appear to be the proton or deuteron irradiation of Y targets (Sadeghi et al., 2012). Of which, production of no-carrier added 89Zr through proton induced activation yttrium metal has been widely studied (Dejesus and Nickles, 1990; Dutta et al., 2009; Kandil et al., 2007; Tang, 2008; Uddin et al., 2005). Dejesus and Nickles, for example, obtained the yield of 89Zr about 13 MBq/μA h via 89Y (p, n) 89Zr reaction using the UW Medical Physics CT1 RDS I1 cyclotron (Dejesus and Nickles, 1990). Omara et al. produced 89Zr in a suitable activity and with a high purity provided by MGC-20 cyclotron for mounts to 58 MBq/µA h (Omara et al., 2009). Alternatively, 89Zr can also be produced through the 89Y (d, 2n) 89Zr reaction (Dutta et al., 2009; Lebeda et al., 2015; Zweit et al., 1991). Zweit is the first one to use deuterons induced activation on Y target to produce 89Zr, of which the yield is about 67 MBq/μA h with 0.008% 88Zr by the Nuflield Cyclotron at the University of Birmingham (Zweit et al., 1991). However, no comparison was conducted in a same cyclotron for producing 89Zr between the two methods mentioned above. The aim of this work is to develop a simple and convenient separation method on purification of the final product 89Zr with high purity and recovery efficency, no harmful substances. Additionally, a comparative study on yield of 89Zr by 89Y (p, n) 89Zr and 89Y (d, 2n) 89 Zr reactions would also be made on CS-30 cyclotron of our University.

2.4. Chemical separation procedure A simple and high separation efficiency method with high purity using anion exchange resin Dowex1×8 for purifying was explored. The simulated experiment was conducted before the separation procedure of radioactive experiment.

2.4.1. Simulated experiment Simulated solution containing 10 g/L of Y(Ⅲ), 20 mg/L of Zr(Ⅳ), 80 mg/L of Cu(Ⅱ) and 10 mg/L of Zn(Ⅱ) in 1 mol/L HCl was prepared. The stable Cu(Ⅱ) and Zn(Ⅱ) must be considered due to 65Cu (p, n) 65Zn reaction on Cu as a substrate. The simulated solution was purified by use of Dowex1×8 anion exchange resin needed to be activated. A summary of the activation process of the exchange resin included: Dowex1×8 anion exchange resin was loaded and eluted by 10% NaCl and 0.2% NaOH heated 80 ℃ with 2 h. Then, deionized water was used for the resin to adjust the pH≈7. Finally, the resin was eluted with 0.5% HCl for 1 h. Additionally, the procedure was repeated twice. Typically, about 10 mL of simulated solution was transferred to a glass column packed with Dowex1×8 anion exchange resin, which was primed with 12, 2 and 12 mol/L HCl in sequence prior to use. Before loaded of the simulated solution, the column was equilibrated with 12 mol/L HCl. Then, 240 mL of 12 mol/L HCl (8×30 mL) and 140 mL of 2 mol/L HCl (7×20 mL) were used to elute the column, respectively, at a flow rate of 1 mL/min. The samples of above acid eluent was checked for stable Y(Ⅲ), Zr(Ⅳ), Cu(Ⅱ) and Zn(Ⅱ) ions content using ICP-OES and were compared with the initial content of solution before transferring the resin column.

2. Experimental 2.1. Material and reagents For the anion exchange resin separation, a 22 cm long ×1 cm dia glass column, packed with Dowex1×8 ion exchange resin (chloride form, 100–200 mesh, USA), was placed behind 5 cm thick lead shields. Throughout all experiments, ultra-pure water was used. The used chemical reagents were all of analytical grade. 2.2. Instrumentation For obtaining γ-energy spectrum to determine radionuclidic purity, HPGe detector (GEM30P4-76) from ORTEC (USA) co. was used (The efficiency calibration of HPGe gamma probe was achieved by using combination of both distance transformation and multiple wire methods. First, all-around peak efficiency curve under the scale distance spaced was scaled by use of multi-line standard source (152Eu source). Then the all-around peak efficiency was measured by using single etalon (137Cs source). Finally, all-around peak efficiency was calculated to < 2%.). For more accurate quantification of 89Zr activity experimental samples, different acidity eluates were checked on the γ-well type scintillation intelligent detector FH463B (The China National Nuclear Corporation, Beijing, China). The inactive content of the samples was monitored via inductively coupled plasma optical emission spectrometry (ICP-OES) from Perkin Elmer instruments (Shanghai, China) co., LTD.

2.4.2. Radioactive experiment After bombardment, the irradiated Y target was dissolved in an electrolytic cell with 1 mol/L HCl at room temperature, followed by transferring into a small beaker. To determine whether there were other radioactive impurities, the dissolved solution was collected and taken trace samples for the investigation of γ-energy spectrum. After the column was pretreated with 12 mol/L HCl, the 89Zr solution was loaded onto the glass column packed with Dowex1×8 anion exchange resin. The radioactive separation procedure was similar with the chemical procedure of the simulated solution. Briefly, the column was washed with 12 mol/L HCl to remove the soluble Y(Ⅲ) ion and other impurities, then, the HCl molarity was then changed to be 2 mol/ L and the eluate was collected. A summary of the separation procedure of 89Zr was shown in Scheme 1. The activity of the samples in each fraction with above acid eluent were taken for γ-counts for 100 s and compared with initial count of solution before transferring the resin column..

2.3. Target and irradiation The Y target was prepared by magnetron sputtering a Y-layer 327

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energy spectrum was then investigated. It can be found that only 511 and 909 keV γ-rays could be consistent with the known spectrum of 89 Zr on the γ-energy spectrum of the sample solution which was given by the Y target via 89Y (p, n) 89Zr (Fig. 2). Then 12 mol/L HCl and 2 mol/L HCl were used as eluent for the dissolution of the target. Similarly, only the peaks of 89Zr could be detected in the spectrum of the final product (shown in Fig. 3). That is to say, these γ-energy spectrum showed that little radioactive impurity of 65Zn, 88Zr and 88Y presented in initial 89Zr solution, which proved that no stable Cu(Ⅱ) was dissolved by 1 mol/L HCl, as 65Zn produced from Cu, meaning the target nuclide solution had minimized stable metal impurity. Thus, the radionuclidic purity of 89Zr by the reaction (p, n) on Y target was up to 99.99%. Besides, the Y target was bombarded with 13 MeV protons typically for 1 h with a beam current of 10–30 μA to yield about 44 ± 4 MBq/μA h... As is shown in Fig. 4, elution of 89Zr was achieved with more than 85% recovery of the radioactivity by 6 successive 10 mL of 2 mol/L HCl, and appeared a peak at the volume of 20 mL..

Scheme 1. Schematic diagram of the radiochemical separation of

89

3.2.2. 89Y (d, 2n) 89Zr To compare with the product of proton inducing on Y target, a deuteron beam of 15 MeV with a beam current of 10–15 μA was also used to induce Y target for 1 h, in an attempt to produce radionuclide 89 Zr. The yield of this reaction was found to be 58 ± 5 MBq/μA h. The γ-energy spectrum of the deuteron-induced reaction with possibility of 65 Cu (d, 2n) 65Zn was similar as the reaction of 89Y (p, n) 89Zr, which also indicated that only 89Zr was obtained (Figs. 5 and 6). Thus, the radionuclidic purity of 89Zr by the reaction (d, 2n) on Y target was 99.99%... Also, being similar with the results of the (p, n) reaction, 89Zr was obatained with more than 80% recovery of the radioactivity through 3 times of successive elutions by 10 mL of 2 mol/L HCl, and appeared a peak at the volume of 20 mL (shown in Fig. 7)..

Zr.

3. Results and discussion 3.1. Simulated separation of Zr(Ⅳ) The final recovery rate of Y(Ⅲ), Zr(Ⅳ), Cu(Ⅱ) and Zn(Ⅱ) with simple chemical separation method using Dowex1×8 anion exchange resin, which was eluted by 12 mol/L HCl and 2 mol/L HCl, are separately listed in Table 1. All of the stable Y(Ⅲ), Cu(Ⅱ) and Zn(Ⅱ) were entirely eluted in 240 mL of 12 mol/L HCl and no presence of above ions in 2 mol/L HCl. The Zr(Ⅳ) ion was eluted with 2 mol/L HCl up to 87.6%, and a little was remained in the resin and 12 mol/L HCl solution. Hence, the final product Zr(Ⅳ)-chloride with high chemical purity was obtained to mean the complete separation with the metal impurity. In addition, the specific separation effect and profile is shown in Fig. 1. Total stable ion Y(Ⅲ) was entirely eluted in the first 90 mL of 12 mol/L HCl and appeared peak at 30 mL. Similarly, all stable ion Cu(Ⅱ) and Zn(Ⅱ) were collected in the first 180 mL and 120 mL of 12 mol/L HCl, respectively. The molarity of HCl was then changed to be 2 mol/L and the eluate was collected. More than 85% of Zr (Ⅳ) was eluted in the first 40 mL of 2 mol/L HCl with the peak at 20 mL, and the remainder of Zr(Ⅳ) was removed with 20 mL of 2 mol/L HCl. Hence, a single-step method that three kinds of impurity ions Y(Ⅲ), Cu(Ⅱ) and Zn(Ⅱ) could be entirely isolated from Zr(Ⅳ) ion by use of Dowex1×8 anion exchange resin was determined..

3.2.3. Comparison of investigated production yield of 89Zr The Q-values, particle energy, beam current and decay γ-ray characteristics of the reaction of 89Y (p, n) 89Zr and 89Y (d, 2n) 89Zr are listed in Table 2. Both 89Y (p, n) 89Zr and 89Y (d, 2n) 89Zr reaction offered high yield (shown in Table 3), and the latter reaction provided better production yield compared to the former one. Also, our data have been compared with other measurements and the differences pointed out were slight (Meijs et al., 1994; Zweit et al., 1991), while the yield of 89Zr is higher than the previously reported work (Dabkowski et al., 2012; Ciarmatori et al., 2011; Mustafa et al., 1988; Infantino et al., 2011). However, several investigations were carried out for the production of 89Zr by proton irradiations on Y target. In contrast, the deuteron-induced reactions were only measured for a few times. Generally, medical accelerator could only provide proton beam, further considering the availability and operation costs for the supply of deuterons and protons by cyclotrons, the 89Y (p, n) 89Zr reaction is practically superior to the 89 Y (d, 2n) 89Zr reaction (Lebeda et al., 2015).

3.2. Radioactive experiment According to the optimal separation method obtained from simulated experiments, a similar radioactive separation method was carried out. The method used for the isolation of 89Zr from the target is based on the differences in the distribution coefficients of 89Zr and the other elements on an anion exchange resin at different HCl concentrations.

Table 1 The recovery rate of Y(Ⅲ), Zr(Ⅳ), Cu(Ⅱ) and Zn(Ⅱ) in simulated experiment. Stable element

3.2.1. 89Y (p, n) 89Zr In radioimmunotherapy, the amounts of the high purity 89Zr must be reasonable, of which the separation should also be more simple and convenient. Generally, three reactions for 89Y (p, 2n) 88Zr, 89Y (p, pn) 88 Y and 65Cu (p, n) 65Zn were likely to exist, of which γ-ray peaks were 393 keV for 88Zr, 898 keV for 88Y and 1115 keV for 65Zn, respectively. The irradiated Y target was first dissolved by 1 mol/L HCl, and the γ-

Y Zr Cu Zn

328

Recovery rate 12 mol/L

2 mol/L

100% 8.3% 99.8% 102.4%

0 87.6% 0 0

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Fig. 4. Elution profile of 89Zr with 2 mol/L HCl using Dowex1×8 resin via 89Y (p, n) 89Zr. Fig. 1. Elution profile of stable Y(Ⅲ), Zr(Ⅳ), Cu(Ⅱ) and Zn(Ⅱ) with 12 and 2 mol/L HCl.

Fig. 5. The γ-energy spectrum diagram of deuteron irradiated Y target after 1 mol/L HCl dissolution.

Fig. 2. The γ-energy spectrum diagram of proton irradiated Y target after 1 mol/L HCl dissolution.

Fig. 6. The γ-energy spectrum diagram of 2 mol/L HCl eluent via Fig. 3. The γ-energy spectrum diagram of 2 mol/L HCl eluent via

89

Y (p, n)

89

89

Y (d, 2n)

89

Zr.

Zr.

4. Conclusion In summary, a simple and convenient separation method by use of anion exchange resin Dowex1×8 with 2 mol/L HCl eluting as [89Zr]Zrchloride was determined. The radionuclidic purity of the isolated 89Zr was found to be 99.99%, and an appropriate recovery rate up to 85% ± 3% was obtained, resulting in use of medical research practically, securely and efficiently. Besides, compared with 89Y (p, n) 89Zr, 89Y (d, 2n) 89Zr reaction is more suitable for the production of 89Zr. Hence, high radionuclidic purity of 89Zr was conducted by the above detailed method using ion exchange chromatography via 89Y (d, 2n) 89Zr reaction on Y target. The strategy proposed in this study might facilitate the possible future clinical developments of 89Zr in nuclear medicine.

Fig. 7. Elution profile of 89 Zr.

329

89

Zr with 2 mol/L HCl using Dowex1×8 resin via

89

Y (d, 2n)

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Table 2 Related parameters comparison of proton and deuteron induced activation of Y target. Incident particle

Nuclear reaction

Q-values (MeV)

Particle energy (MeV)

Irradiated time (h)

Beam current (μA)

Cooling time (h)

Energies of principal γ-rays, keV

ProtonsDeuterons

89

−3.56−5.97

1315

11

10–3010–15

4848

511, 909511, 909

Y(p,n)89Zr89Y(d,2n)89Zr

Table 3 Production comparison of proton and deuteron induced activation of Y target. Nuclear reaction

Beam energy (MeV)

Beam current (μA)

Irradiated time (h)

Thickness

Yield (MBq/μA h)

Reference

89

Y (p,n)89Zr

89

Y (d, n)89Zr

14 14.5 11.6 9.8 14 12–6 18–10 12.6–11.2 12.6–9.5 13 16–7

10–30 20 30 20 100 1 12 20 20 10–15 3–5

1 1 2–3 2–3 1 2 2 1 1 1 0.3

25 µm 57 mg/cm2 400 µm 500 µm 25 µm 5−11 mg/cm2 150 µm 150 µm 300 µm 25 µm 240 mg/cm2

44 ± 4 17 15 8.8 48 43 12.5 ± 0.5 8.95 ± 0.75 19.2 ± 2.1 58 ± 5 67

This work (Tang, 2008) (Dabkowski et al., 2012) (Dabkowski et al., 2012) (Meijs et al., 1994) (Mustafa et al., 1988) (Walther et al., 2011) (Ciarmatori et al., 2011) (Infantino et al., 2011) This work (Zweit et al., 1991)

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Acknowledgements This work was financially supported by the China National Natural Science Foundation (No. 21371124). We would like to thank the cyclotron operation crew Xiaodong Liao of Scihuan University for his help in performing irradiations. References Boellaard, R., 2003. 89Zr immuno-PET: comprehensive procedures for the production of 89 Zr-labeled monoclonal antibodies. J. Nucl. Med. 44, 1271. Ciarmatori, A., Cicoria, G., Pancaldi, D., Infantino, A., Boschi, S., Fanti, S., Marengo, M., 2011. Some experimental studies on 89Zr production. Radiochim. Acta 99, 631–634. Dabkowski, A.M.Probst, K.Marshall, C., 2012. Cyclotron production for the radiometal Zirconium-89 with an IBA cyclone 18/9 and COSTIS solid target system (STS), AIP Conference Proceedings 1509, 108. Dejesus, O., Nickles, R., 1990. Production and purification of 89Zr, a potential PET antibody label. International journal of radiation applications and instrumentation. Part A Appl. Radiat. Isot. 41, 789–790. Dutta, B., Maiti, M., Lahiri, S., 2009. Production of 88, 89Zr by proton induced activation of natY and separation by SLX and LLX. J. Radioanal. Nucl. Chem. Art. 281, 663–667. Holland, J.P., Sheh, Y., Lewis, J.S., 2009. Standardized methods for the production of high specific-activity zirconium-89. Nucl. Med. Biol. 36, 729–739. Infantino, A., Cicoria, G., Pancaldi, D., Ciarmatori, A., Boschi, S., Fanti, S., Marengo, M., Mostacci, D., 2011. Prediction of 89Zr production using the Monte Carlo code FLUKA. Appl. Radiat. Isot. 69, 1134–1137. Ivanov, P., Jerome, S., Bozhikov, G., Maslov, O., Starodub, G.Y., Dmitriev, S., 2014. Cyclotron production and radiochemical purification of 88, 89Zr via α-particle induced reactions on natural strontium. Appl. Radiat. Isot. 90, 261–264. Kandil, S., Scholten, B., Saleh, Z., Youssef, A., Qaim, S., Coenen, H., 2007. A comparative study on the separation of radiozirconium via ion-exchange and solvent extraction techniques, with particular reference to the production of 88Zr and 89Zr in proton

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