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Evaluation of a novel radiofolate in tumour-bearing mice: promising prospects for folate-based radionuclide therapy

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

Abstract

Purpose

Folate-based radiopharmaceuticals have the potential to be used for imaging and therapy of tumours positive for the folate receptor (FR). We describe the in vitro and in vivo evaluation of a DOTA–folate conjugate.

Methods

Radiolabelling of the DOTA-folate was carried out via standard procedures using 111InCl3 and 177LuCl3, respectively. The distribution coefficient (log D) was determined in octanol/PBS (pH 7.4). Tissue distribution was investigated in nude mice bearing KB tumour xenografts at different time points after administration of 111In-DOTA-folate (radiofolate 1) or 177Lu-DOTA-folate (radiofolate 2) (1 MBq, 1 nmol per mouse). Pemetrexed (PMX, 400 μg) was injected 1 h prior to the radiofolate in order to reduce renal uptake. Images were acquired with a SPECT/CT camera 24 h after injection of the radiofolate (40–50 MBq, 3 nmol per mouse).

Results

The hydrophilic character of the DOTA-folate was represented by a low log D value (radiofolate 1 −4.21±0.11). In vivo, maximal tumour uptake was found 4 h after injection (radiofolate 1 5.80±0.55% ID/g; radiofolate 2 7.51±1.25% ID/g). In FR-positive kidneys there was considerable accumulation of the radiofolates (radiofolate 1 55.88±3.91% ID/g; radiofolate 2 57.22±11.05% ID/g; 4 h after injection). However, renal uptake was reduced by preinjection of PMX (radiofolate 1 9.52±1.07% ID/g; radiofolate 2 13.43±0.54% ID/g; 4 h after injection) whereas the tumour uptake was retained (radiofolate 1 6.32±0.41% ID/g; radiofolate 2 8.99±0.43% ID/g; 4 h after injection). SPECT/CT images clearly confirmed favourable tissue distribution of the novel radiofolates and the positive effect of PMX.

Conclusion

The preliminary requirements for the therapeutic use of the novel DOTA-folate are met by its favourable tissue distribution that can be ascribed to its hydrophilic properties and combined administration with PMX.

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Acknowledgments

We thank Dr. Christian Lackas and Dr. Nils Schramm for support with the NanoSPECT/CT (Bioscan).

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Authors and Affiliations

  1. Center for Radiopharmaceutical Science ETH-PSI-USZ, Paul Scherrer Institute, 5232, Villigen PSI, Switzerland

    Cristina Müller & Roger Schibli

  2. Department of Nuclear Medicine, Erasmus MC, 3015 CE, Rotterdam, The Netherlands

    Cristina Müller & Marion de Jong

  3. Department of Chemistry and Applied Biosciences, ETH Zurich, 8093, Zurich, Switzerland

    Thomas L. Mindt & Roger Schibli

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  1. Cristina Müller
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  2. Thomas L. Mindt
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Correspondence to Cristina Müller.

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Müller, C., Mindt, T.L., de Jong, M. et al. Evaluation of a novel radiofolate in tumour-bearing mice: promising prospects for folate-based radionuclide therapy. Eur J Nucl Med Mol Imaging 36, 938–946 (2009). https://doi.org/10.1007/s00259-008-1058-9

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