Automated two column generator systems for medical radionuclides

https://doi.org/10.1016/j.apradiso.2009.07.019Get rights and content

Abstract

This work describes automated chromatographic methods for the separation of medically useful radionuclides from source material containing their parent radionuclides. The separation techniques employ two chromatographic columns to ensure high chemical and radiochemical purity of the product radionuclide. The separations were performed using an automated system, the automated radionuclide separator (ARS2), consisting of syringe pumps and multiport valves controlled through a computer interface. Generator systems for 68Ga, 99mTc, 188Re and 213Bi will be described.

Introduction

A wide range of radionuclides have been studied for the detection and treatment of various diseases (Imam, 2001; Knapp and Butler, 1984; Mirzadeh and Knapp, 1996; Lambrecht et al., 1997; Dietz and Horwitz, 2000). Because of their in vivo application, radionuclides produced for use in diagnostic and therapeutic nuclear medicine must meet stringent purity standards mandated by various government bodies (Imam, 2001). Often, the separations involved in the preparation of the medical radionuclides must be performed quickly due to the short half-lives of the desired nuclides. Conventional radionuclide generator systems often immobilize a long-lived parent nuclide onto a chromatographic support, from which the desired daughter nuclide is periodically eluted. This method works very well for systems, such as 99Mo/99mTc, with relatively low linear energy transfer (LET) nuclides, where the parent nuclide can be produced in high specific activity. However, the traditional generator system approach has several disadvantages when applied to systems with high LET radionuclides (nuclides, such as 225Ac or 213Bi, which are high energy alpha emitters or have daughters which are high energy alpha emitters) or low specific activity parent nuclides (such as 99Mo or 188W prepared from non-isotopically enriched targets). In systems with high LET nuclides, radiolytic damage to the chromatographic support can lead to decreased yields of the desired nuclide, increased break through of the parent nuclide and decreased flow through the chromatographic column. Additionally, the damage inflicted by these high LET nuclides can limit the size of the radionuclide generator and therefore the dose available for administration in the nuclear medicine procedure. For systems employing low specific activity parent nuclides, the size of the chromatographic column necessary for efficient retention of the parent can lead to large elution volumes, requiring concentration of the daughter product prior to administration.

An alternative to the conventional radionuclide generator system is the multicolumn selectivity inversion generator, MSIG (Fig. 1, Table 1) (Horwitz and Bond, 2003, Horwitz and Bond, 2006; Bond and Horwitz, 2005). In the MSIG, the parent radionuclide is stored in solution, where radiolytic damage will have little effect on the performance of the generator system. The solution of parent radionuclide is eluted through a chromatographic column specific for the desired daughter radionuclide (primary separation column, PSC). The daughter nuclide is retained on the PSC, while the parent passes through unretained. A small volume of rinse solution is then passed through the PSC to ensure near complete recovery of the parent nuclide. The solution of parent nuclide is then stored for ingrowth of the desired daughter and future processing. The daughter nuclide is stripped from the PSC, and this strip solution is passed through a second column (guard column), which is specific for the parent nuclide. The guard column provides additional decontamination of the parent radionuclide from the daughter product.

The MSIG offers several potential advantages over the conventional generator system. Radiolytic damage to the chromatographic material is minimized because the parent nuclide is stored in solution and the daughter is only adsorbed to the support for a short time (several minutes). Damage to the chromatographic material can be further reduced by using fresh columns for each preparation of the medical radionuclide. Selectively retaining the desired daughter radionuclide can be done on a very small column, since the mass of the daughter is very small. This allows for recovery of the desired radionuclide in a very small volume of solution which can then be diluted for the appropriate dose for clinical use. The MSIG is particularly advantageous when the parent radionuclide is of low specific activity, where conventional generator systems would require large chromatographic columns, large elution volumes and concentration of the eluted product before dose administration. Since the MSIG selectively retains the nearly massless daughter, the column size and the elution volume are essentially independent of the parent nuclide specific activity and the activity of the generator. The combination of the PSC and the guard column enables one to produce the desired radionuclide in very high radionuclidic purity (decontamination factors of 106 or greater). Additionally, storage of the parent nuclide in solution allows for continuous recycling or purification and concentration of the parent nuclide, which can extend the useful lifetime of the generator system.

Automation of the separation procedure also offers several advantages for the preparation of the medical radionuclide, including, reducing the radiation dose to workers preparing the radionuclide, offering consistent performance of the generator system, and providing a log of the steps performed in the preparation of the medical radionuclide (Young and Hines, 2004; Bond et al., 2003, Bond et al., 2004; Bray et al., 2000). In this work, the preparation of 99mTc, 188Re and 213Bi using MSIG concepts and an automated system, the automated radionuclide separator (ARS2), will be described. Additionally, the preparation of 68Ga using a novel two column generator system will be described. (The 68Ga system employs two columns selective for the 68Ga daughter, and therefore, cannot be classified as a true MSIG.)

Section snippets

Experimental

Trace metal grade nitric and hydrochloric acids were obtained from Fisher Scientific. Sodium chloride, sodium acetate, acetic acid and sodium hydroxide were obtained from Sigma-Aldrich. Deionized water was obtained from a Milli-Q2 water purification system. UTEVA resin, ABEC resin, pre-filter resin (Amberchrom GC71m), Diphonix resin, DNNSA resin, AG1x8 anion exchange resin and AG50Wx8 cation exchange resin were obtained from Eichrom Technologies, LLC. 188W and 229Th were obtained from Oak Ridge

225Ac/213Bi

Fig. 2 shows the retention of Ac and Bi on the primary separation column and guard column materials. For the 225Ac/213Bi system, the primary separation column is UTEVA resin. From HCl, 213Bi is retained on the UTEVA resin, while 225Ac exhibits no retention. The optimum Bi uptake is observed at 0.1–0.2 M HCl and is likely due to the retention of the [H3O+][BiCl4] species by the UTEVA resin. The 213Bi can be stripped from the UTEVA resin using a sodium chloride/sodium acetate buffer at pH=4.0.

Conclusion

Automated chromatographic generator systems for the separation of 68Ga, 99mTc, 188Re and 213Bi from their parent radionuclides have been developed. The generators employ multicolumn techniques, in which the parent radionuclides are stored in solution, minimizing the damage to the chromatographic supports, providing a consistent high purity product in a small volume of solution.

Acknowledgements

The authors wish to thank Northstar Medical Radioisotopes, Inc. for supplying the ARS2 and for partial funding of the project. The authors also wish to thank James Harvey, Glenn Isensee, Michael Krummey and Lionel Johnson of Northstar Engineered Technologies for helpful discussions on operating the ARS2.

References (21)

  • S.K. Imam

    Advancements in cancer therapy with alpha emitters: a review

    Int. J. Radiat. Oncol. Biol. Phys.

    (2001)
  • A.H. Bond et al.

    Design, synthesis and uptake performance of ABEC resins for the removal of pertechnetate from alkaline radioactive wastes

    Ind. Eng. Chem. Res.

    (1999)
  • A.H. Bond et al.

    A compact automated separation system for nuclear medical applications

    Czech. J. Phys.

    (2003)
  • Bond, A.H. Hines, J.J., Young, J.E., Horwitz, E.P., 2004. Automated radionuclide separation system and method. US...
  • Bond, A.H., Horwitz, E.P., 2005. Production of ultra-pure bismuth-213 for use in therapeutic nuclear medicine. US...
  • L.A. Bray et al.

    Development of a unique bismuth (Bi-213) automated generator for use in cancer therapy

    Ind. Eng. Chem. Res.

    (2000)
  • R.M. Diamond et al.

    Resin selectivity in aqueous solutions

  • M.L. Dietz et al.

    Applications of extraction chromatography in the development of radionuclide generator systems for nuclear medicine

    Ind. Eng. Chem. Res.

    (2000)
  • E.P. Horwitz et al.

    Purification of radionuclides for nuclear medicine: the multicolumn selectivity inversion generator concept

    Czech. J. Phys.

    (2003)
  • E.P. Horwitz et al.

    Novel extraction chromatographic resins based on tetraalkyldiglycolamides: characterization and potential applications

    Solvent Extr. Ion Exch.

    (2005)
There are more references available in the full text version of this article.

Cited by (63)

  • Study of <sup>99m</sup>Tc absorption on micro-sized ion exchange resins to achieve high activity for SPECT

    2022, Applied Radiation and Isotopes
    Citation Excerpt :

    Furthermore, high activity in the point source is essential for noise reduction, resulting in limited acquisition time, posing a significant challenge to producing a point source for system matrix calibration. The most popular isotope for SPECT is 99mTc (Martini et al., 2018; Müller and Schibli, 2013), which emits a 141 keV gamma ray with a half-life of 6.02 h. Several projects have adopted the resin particle adsorption method for 99mTc point source production (Wirth et al., 1983; English et al., 2002; McAlister and Horwitz, 2009). The absorption on ion exchange resins has been well studied in chemistry.

  • Radionuclide generators

    2022, Nuclear Medicine and Molecular Imaging: Volume 1-4
View all citing articles on Scopus
View full text