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Direct in vitro and in vivo comparison of 161Tb and 177Lu using a tumour-targeting folate conjugate

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

The radiolanthanide 161Tb (T 1/2 = 6.90 days, Eβ− av = 154 keV) was recently proposed as a potential alternative to 177Lu (T 1/2 = 6.71 days, Eβ− av = 134 keV) due to similar physical decay characteristics but additional conversion and Auger electrons that may enhance the therapeutic efficacy. The goal of this study was to compare 161Tb and 177Lu in vitro and in vivo using a tumour-targeted DOTA-folate conjugate (cm09).

Methods

161Tb-cm09 and 177Lu-cm09 were tested in vitro on folate receptor (FR)-positive KB and IGROV-1 cancer cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) viability assay. In vivo 161Tb-cm09 and 177Lu-cm09 (10 MBq, 0.5 nmol) were investigated in two different tumour mouse models with regard to the biodistribution, the possibility for single photon emission computed tomography (SPECT) imaging and the antitumour efficacy. Potentially undesired side effects were monitored over 6 months by determination of plasma parameters and examination of kidney function with quantitative SPECT using 99mTc-dimercaptosuccinic acid (DMSA).

Results

To obtain half-maximal inhibition of tumour cell viability a 4.5-fold (KB) and 1.7-fold (IGROV-1) lower radioactivity concentration was required for 161Tb-cm09 (IC50 ~0.014 MBq/ml and ~2.53 MBq/ml) compared to 177Lu-cm09 (IC50 ~0.063 MBq/ml and ~4.52 MBq/ml). SPECT imaging visualized tumours of mice with both radioconjugates. However, in therapy studies 161Tb-cm09 reduced tumour growth more efficiently than 177Lu-cm09. These findings were in line with the higher absorbed tumour dose for 161Tb-cm09 (3.3 Gy/MBq) compared to 177Lu-cm09 (2.4 Gy/MBq). None of the monitored parameters indicated signs of impaired kidney function over the whole time period of investigation after injection of the radiofolates.

Conclusion

Compared to 177Lu-cm09 we demonstrated equal imaging features for 161Tb-cm09 but an increased therapeutic efficacy for 161Tb-cm09 in both tumour cell lines in vitro and in vivo. Further preclinical studies using other tumour-targeting radioconjugates are clearly necessary to draw final conclusions about the future clinical perspectives of 161Tb.

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Acknowledgments

We thank Ulli Köster (Institut Langevin, Grenoble, France) for the target irradiation at ILL and Nadja Romano for technical assistance of the experiments at PSI. This project was financially supported by the Swiss National Science Foundation (Ambizione, Grants PZ00P3_121772 & PZ00P3_138834), COST-BM0607 (C08.0026), the Swiss Cancer League (KLS-02762-02-2011) and the Swiss South African Joint Research Program (JRP 12). Peter Bernhardt was supported by the Swedish National Cancer Society, Swedish Radiation Safety Authority, and the King Gustav V Jubilee Cancer Research Foundation.

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Authors and Affiliations

  1. Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, Villigen-PSI, Switzerland

    Cristina Müller, Josefine Reber, Stephanie Haller & Roger Schibli

  2. Laboratory of Radiochemistry and Environmental Chemistry, Paul Scherrer Institute, Villigen-PSI, Switzerland

    Holger Dorrer, Konstantin Zhernosekov & Andreas Türler

  3. Laboratory of Radiochemistry and Environmental Chemistry, Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland

    Holger Dorrer & Andreas Türler

  4. Department of Radiation Physics, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Peter Bernhardt

  5. Department of Medical Physics and Medical Bioengeneering, Sahlgrenska University Hospital, Gothenburg, Sweden

    Peter Bernhardt

  6. Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland

    Roger Schibli

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  1. Cristina Müller
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Correspondence to Cristina Müller or Roger Schibli.

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Müller, C., Reber, J., Haller, S. et al. Direct in vitro and in vivo comparison of 161Tb and 177Lu using a tumour-targeting folate conjugate. Eur J Nucl Med Mol Imaging 41, 476–485 (2014). https://doi.org/10.1007/s00259-013-2563-z

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  • DOI: https://doi.org/10.1007/s00259-013-2563-z

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