Process development of [64Cu]Cu-ATSM: efficient stabilization and sterilization for therapeutic applications

Abstract

Hypoxia plays an important role in tumor prognosis. [64Cu]Cu-ATSM, a hypoxia-targeted radioactive agent, reportedly shows antitumor effect in vivo. For clinical application, [64Cu]Cu-ATSM must be manufactured at high concentrations to allow the administration of a therapeutic dose with safe intravenous bolus injection. Fifteen radical scavengers were tested to stabilize [64Cu]Cu-ATSM against radiolysis, and sodium l-ascorbate was selected. The optimal sterilization membrane filter was evaluated from polyvinylidene fluoride (PVDF), polyether sulfone, and mixed cellulose esters; PVDF showed the most efficient radiochemical yield after filtration. The proposed procedures can be used for the practical manufacturing of [64Cu]Cu-ATSM for therapeutic use.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. 1.

    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109

    Article  Google Scholar 

  2. 2.

    Hsieh CH, Shyu WC, Chiang CY, Kuo JW, Shen WC, Liu RS (2011) NADPH oxidase subunit 4-mediated reactive oxygen species contribute to cycling hypoxia-promoted tumor progression in glioblastoma multiforme. PLoS ONE 6:e23945

    CAS  Article  Google Scholar 

  3. 3.

    Rong Y, Durden DL, Van Meir EG, Brat DJ (2006) ‘Pseudopalisading’ necrosis in glioblastoma: a familiar morphologic feature that links vascular pathology, hypoxia, and angiogenesis. J Neuropathol Exp Neurol 65:529–539

    Article  Google Scholar 

  4. 4.

    Merighi S, Benini A, Mirandola P, Gessi S, Varani K, Leung E, Maclennan S, Borea PA (2006) Adenosine modulates vascular endothelial growth factor expression via hypoxia-inducible factor-1 in human glioblastoma cells. Biochem Pharmacol 72:19–31

    CAS  Article  Google Scholar 

  5. 5.

    Lopez-Lazaro M (2006) Hypoxia-inducible factor 1 as a possible target for cancer chemoprevention. Cancer Epidemiol Biomark Prev 15:2332–2335

    CAS  Article  Google Scholar 

  6. 6.

    Huang WJ, Chen WW, Zhang X (2016) Glioblastoma multiforme: effect of hypoxia and hypoxia inducible factors on therapeutic approaches. Oncol Lett 12:2283–2288

    CAS  Article  Google Scholar 

  7. 7.

    Lewis J, Laforest R, Buettner T, Song S, Fujibayashi Y, Connett J, Welch M (2001) Copper-64-diacetyl-bis(N 4-methylthiosemicarbazone): an agent for radiotherapy. Proc Natl Acad Sci USA 98:1206–1211

    CAS  Article  Google Scholar 

  8. 8.

    Lewis JS, McCarthy DW, McCarthy TJ, Fujibayashi Y, Welch MJ (1999) Evaluation of 64Cu-ATSM in vitro and in vivo in a hypoxic tumor model. J Nucl Med 40:177–183

    CAS  PubMed  Google Scholar 

  9. 9.

    Obata A, Kasamatsu S, Lewis JS, Furukawa T, Takamatsu S, Toyohara J, Asai T, Welch MJ, Adams SG, Saji H et al (2005) Basic characterization of 64Cu-ATSM as a radiotherapy agent. Nucl Med Biol 32:21–28

    CAS  Article  Google Scholar 

  10. 10.

    Fujibayashi Y, Taniuchi H, Yonekura Y, Ohtani H, Konishi J, Yokoyama A (1997) Copper-62-ATSM: a new hypoxia imaging agent with high membrane permeability and low redox potential. J Nucl Med 38:1155–1160

    CAS  PubMed  Google Scholar 

  11. 11.

    Obata A, Yoshimi E, Waki A, Lewis JS, Oyama N, Welch MJ, Saji H, Yonekura Y, Fujibayashi Y (2001) Retention mechanism of hypoxia selective nuclear imaging/radiotherapeutic agent cu-diacetyl-bis(N 4-methylthiosemicarbazone) (Cu-ATSM) in tumor cells. Ann Nucl Med 15:499–504

    CAS  Article  Google Scholar 

  12. 12.

    Dearling JL, Lewis JS, Mullen GE, Welch MJ, Blower PJ (2002) Copper bis(thiosemicarbazone) complexes as hypoxia imaging agents: structure–activity relationships. J Biol Inorg Chem 7:249–259

    CAS  Article  Google Scholar 

  13. 13.

    Oh M, Tanaka T, Kobayashi M, Furukawa T, Mori T, Kudo T, Fujieda S, Fujibayashi Y (2009) Radio-copper-labeled Cu-ATSM: an indicator of quiescent but clonogenic cells under mild hypoxia in a Lewis lung carcinoma model. Nucl Med Biol 36:419–426

    CAS  Article  Google Scholar 

  14. 14.

    Tanaka T, Furukawa T, Fujieda S, Kasamatsu S, Yonekura Y, Fujibayashi Y (2006) Double-tracer autoradiography with Cu-ATSM/FDG and immunohistochemical interpretation in four different mouse implanted tumor models. Nucl Med Biol 33:743–750

    CAS  Article  Google Scholar 

  15. 15.

    Yoshii Y, Yoneda M, Ikawa M, Furukawa T, Kiyono Y, Mori T, Yoshii H, Oyama N, Okazawa H, Saga T, Fujibayashi Y (2012) Radiolabeled Cu-ATSM as a novel indicator of overreduced intracellular state due to mitochondrial dysfunction: studies with mitochondrial DNA-less rho0 cells and cybrids carrying MELAS mitochondrial DNA mutation. Nucl Med Biol 39:177–185

    CAS  Article  Google Scholar 

  16. 16.

    Holland JP, Giansiracusa JH, Bell SG, Wong LL, Dilworth JR (2009) In vitro kinetic studies on the mechanism of oxygen-dependent cellular uptake of copper radiopharmaceuticals. Phys Med Biol 54:2103–2119

    CAS  Article  Google Scholar 

  17. 17.

    Bowen SR, van der Kogel AJ, Nordsmark M, Bentzen SM, Jeraj R (2011) Characterization of positron emission tomography hypoxia tracer uptake and tissue oxygenation via electrochemical modeling. Nucl Med Biol 38:771–780

    CAS  Article  Google Scholar 

  18. 18.

    McMillan DD, Maeda J, Bell JJ, Genet MD, Phoonswadi G, Mann KA, Kraft SL, Kitamura H, Fujimori A, Yoshii Y, Furukawa T, Kato TA (2015) Validation of 64Cu-ATSM damaging DNA via high-LET Auger electron emission. J Radiat Res 56:784–791

    CAS  Article  Google Scholar 

  19. 19.

    Pouget JP, Santoro L, Raymond L, Chouin N, Bardiès M, Bascoul-Mollevi C, Huguet H, Azria D, Kotzki PO, Pèlegrin M, Vivès E, Pèlegrin A (2008) Cell membrane is a more sensitive target than cytoplasm to dense ionization produced by auger electrons. Radiat Res 170:192–200

    CAS  Article  Google Scholar 

  20. 20.

    Yoshii Y, Matsumoto H, Yoshimoto M, Zhang MR, Oe Y, Kurihara H, Narita Y, Jin ZH, Tsuji AB, Yoshinaga K, Fujibayashi Y, Higashi T (2018) Multiple administrations of 64Cu-ATSM as a novel therapeutic option for glioblastoma: a translational study using mice with xenografts. Transl Oncol 11:24–30

    Article  Google Scholar 

  21. 21.

    Lopci E, Grizzi F, Russo C, Toschi L, Grassi I, Cicoria G, Lodi F, Mattioli S, Fanti S (2017) Early and delayed evaluation of solid tumours with 64Cu-ATSM PET/CT: a pilot study on semiquantitative and computer-aided fractal geometry analysis. Nucl Med Commun 38:340–346

    Article  Google Scholar 

  22. 22.

    Lewis JS, Laforest R, Dehdashti F, Grigsby PW, Welch MJ, Siegel BA (2008) An imaging comparison of 64Cu-ATSM and 60Cu-ATSM in cancer of the uterine cervix. J Nucl Med 49:1177–1182

    Article  Google Scholar 

  23. 23.

    Ohya T, Nagatsu K, Suzuki H, Fukada M, Minegishi K, Hanyu M, Fukumura T, Zhang MR (2016) Efficient preparation of high-quality 64Cu for routine use. Nucl Med Biol 43:685–691

    CAS  Article  Google Scholar 

  24. 24.

    Japanese Pharmaceutical Excipients Dictionary (2016) Yakuji Nippo Limited, Tokyo

  25. 25.

    DaTscan Ioflupane I 123 Injection prescribing information (2011) GE Healthcare, Arlington Heights, USA

  26. 26.

    Amyvid Florbetapir F 18 Injection prescribing information (2012) Ely Lilly, Indianapolis, USA

  27. 27.

    Vizamyl Flutemetamol F 18 Injection prescribing information (2013) GE Healthcare, Arlington Heights, USA

  28. 28.

    Dehdashti F, Grigsby PW, Lewis JS, Laforest R, Siegel BA, Welch MJ (2008) Assessing tumor hypoxia in cervical cancer by PET with 60Cu-labeled diacetyl-bis(N 4-methylthiosemicarbazone). J Nucl Med 49:201–205

    CAS  Article  Google Scholar 

  29. 29.

    U.S. department of Health and Human Services/National Toxicology Program; Report on Carcinogens, Fourteenth Edition. November 2016: Butylated Hydroxyanisole. CAS No. 25013-16-5

Download references

Acknowledgements

This study was supported by Japan Agency for Medical Research and Development (AMED) programs of “Practical Research for Innovative Cancer Control (18ck0106373h0002)”. We would like to thank Editage (www.editage.jp) for English language editing.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Yukie Yoshii.

Ethics declarations

Conflict of interest

HM and EK are employees of Nihon Medi-Physics Co., Ltd. All the other authors declare that they have no conflict of interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Matsumoto, H., Igarashi, C., Kaneko, E. et al. Process development of [64Cu]Cu-ATSM: efficient stabilization and sterilization for therapeutic applications. J Radioanal Nucl Chem 322, 467–475 (2019). https://doi.org/10.1007/s10967-019-06738-9

Download citation

Keywords

  • [64Cu]Cu-ATSM
  • Hypoxia
  • Internal radiotherapy
  • Process development
  • Stabilization
  • Sterilization