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In-vivo detection of the erythropoietin receptor in tumours using positron emission tomography

  • Molecular Imaging
  • Published:
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Abstract

Objective

Recombinant human erythropoietin (rhuEpo) is used clinically to treat anaemia. However, rhuEpo-treated cancer patients show decreased survival rates and erythropoietin receptor (EpoR) expression has been found in patient tumour tissue. Thus, rhuEpo application might promote EpoR+ tumour progression. We therefore developed the positron emission tomography (PET)-probe 68Ga-DOTA-rhuEpo and evaluated its performance in EpoR+ A549 non-small-cell lung cancer (NSCLC) xenografts.

Methods

68Ga-DOTA-rhuEpo was generated by coupling DOTA-hydrazide to carbohydrate side-chains of rhuEpo. Biodistribution was determined in tumour-bearing mice 0.5, 3, 6, and 9 h after probe injection. Competition experiments were performed by co-injecting 68Ga-DOTA-rhuEpo and rhuEpo in five-fold excess. Probe specificity was further evaluated histologically using Epo-Cy5.5 stainings.

Results

The blood half-life of 68Ga-DOTA-rhuEpo was 2.6 h and the unbound fraction was cleared by the liver and kidney. After 6 h, the highest tumour to muscle ratio was reached. The highest 68Ga-DOTA-rhuEpo accumulation was found in liver (10.06 ± 6.26%ID/ml), followed by bone marrow (1.87 ± 0.53%ID/ml), kidney (1.58 ± 0.39 %ID/ml), and tumour (0.99 ± 0.16%ID/ml). EpoR presence in these organs was histologically confirmed. Competition experiments showed significantly (p < 0.05) lower PET-signals in tumour and bone marrow at 3 and 6 h.

Conclusion

68Ga-DOTA-rhuEpo shows favourable pharmacokinetic properties and detects EpoR specifically. Therefore, it might become a valuable radiotracer to monitor EpoR status in tumours and support decision-making in anaemia therapy.

Key Points

• PET-probe 68 Ga-DOTA-rhuEpo was administered to assess the EpoR status in vivo

• 68 Ga-DOTA-rhuEpo binds specifically to EpoR positive organs in vivo

• Tumour EpoR status determination might enable decision-making in anaemia therapy with rhuEpo

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Abbreviations

BFU-E:

burst forming unit erythroid

CFU-E:

colony forming unit erythroid

DMEM:

Dulbecco’s Modified Eagle’s Medium

DOTA:

1,4,7,10-tetraazo-cyclododecane-tetraacetic acid

DTPA:

diethylene-triamine-pentaacetic acid

Epo:

Erythropoietin

EpoR:

erythropoietin receptor

FMT:

fluorescence-mediated tomography

NIRF:

near infrared fluorescence

NOTA:

1,4,7-triazacyclononane-1,4,7-triacetic acid

NSCLC:

non-small-cell lung cancer

OSEM:

ordered subset expectation maximization

PET:

positron emission tomography

rhuEpo:

recombinant human erythropoietin

ROI:

region of interest

SD:

Standard Deviation

SPECT:

single photon emission computed tomography

TLC:

Thin Layer Chromatography

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Acknowledgements

The scientific guarantor of this publication is Fabian Kiessling. The authors of this manuscript declare relationships with the following companies: Roche Diagnostics GmbH; Philips Research. This study received funding from the German Ministry for Education and Research/Bundesministerium für Bildung und Forschung (BMBF) project numbers 0315415C and 0316042 F. Felix Gremse received funding from Philips (Philips Research, Aachen,Germany). Axel Wessner is employee of Roche Diagnostics GmbH. The authors would also like to thank Sebastian Lowins from the organic chemistry department for intensive discussions and help. No complex statistical methods were necessary for this paper. Institutional Review Board approval was not required because it was not applicable. Approval from the institutional animal care committee was obtained. No study subjects or cohorts have been previously reported. Methodology: prospective, experimental, multicenter study.

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Authors and Affiliations

  1. Department for Experimental Molecular Imaging (ExMI), Medical Faculty, RWTH Aachen University, Pauwelsstraße 20, 52074, Aachen, Germany

    Felix Fuge, Dennis Doleschel, Anne Rix, Felix Gremse, Wiltrud Lederle & Fabian Kiessling

  2. Roche Diagnostics GmbH, R&D RPD Protein Chemistry, Penzberg, Germany

    Axel Wessner

  3. Clinic for Nuclear Medicine, University Clinic RWTH Aachen, Aachen, Germany

    Oliver Winz & Felix Mottaghy

Authors
  1. Felix Fuge
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  2. Dennis Doleschel
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Correspondence to Fabian Kiessling.

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Felix Fuge and Dennis Doleschel shared first authorship.

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Fuge, F., Doleschel, D., Rix, A. et al. In-vivo detection of the erythropoietin receptor in tumours using positron emission tomography. Eur Radiol 25, 472–479 (2015). https://doi.org/10.1007/s00330-014-3413-5

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  • DOI: https://doi.org/10.1007/s00330-014-3413-5

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