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In vitro and in vivo targeting of different folate receptor-positive cancer cell lines with a novel 99mTc-radiofolate tracer

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

Abstract

Purpose

For the assessment of folate-based radiopharmaceuticals, human nasopharyngeal KB carcinoma cells are traditionally used although nasopharyngeal cancer is rare. On the other hand, the folate receptor (FR) is frequently overexpressed on diverse cancer types, the highest frequency (>90%) being on ovarian carcinomas. The goal of our study was the in vitro and in vivo assessment of different FR-positive human carcinoma cells. In addition, a murine sarcoma cell line was assessed as a pre-clinical alternative to human xenograft models.

Methods

FR-positive human nasopharyngeal, cervical, ovarian and colorectal cancer cell lines and the transgenic mouse sarcoma (24JK-FBP) cell line were targeted with a novel 99mTc-tricarbonyl folate derivative 2. Comparative in vitro cell binding studies were carried out under standardised folate-deficient conditions. In vivo studies were performed in nude mice and C6 black mice.

Results

The in vitro cell experiments revealed only FR-specific binding (unspecific <0.02%), ranging from 3.5% to 52% of complex 2 owing to variable levels of FR expression of the cell lines. In vivo tumour uptake of radiotracer 2 varied less than in vitro. It ranged from 0.66±0.17% ID/g (LoVo) through 1.16±0.64% ID/g (IGROV-1) and 1.55±0.43% ID/g (24JK-FBP) to 2.33±0.36% ID/g (KB) 4 h p.i.

Conclusion

These pre-clinical studies indicate that in vitro data obtained in FR-positive cancer cells do not necessarily correspond with or predict in vivo radiofolate uptake in corresponding (xeno)grafts. In addition, the murine 24JK-FBP cell line proved to be a valuable pre-clinical alternative to human tumour models.

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Notes

  1. Experiments were performed with 3H-folic acid at 4°C because under these conditions endocytosis is largely attenuated. Time-dependent cell binding studies, performed over a period of 4 h revealed maximal binding after 2 h. Experiments with excess unlabelled folic acid in order to block FRs revealed negligible amounts (<0.5%) of unspecific cell binding of 3H-folic acid and could therefore be neglected (data not shown).

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Acknowledgements

We thank Dr. Ilse Novak, Dr. Robert Waibel and Dr. Elisa Garcia-Garayoa for valuable discussions and Alain Blanc, Judith Stahel and Christine De Pasquale for technical assistance. This work was financially supported by Mallinckrodt-Tyco Inc. and Merck Eprova AG.

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Authors and Affiliations

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

    Cristina Müller, P. August Schubiger & Roger Schibli

  2. Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, 8093, Zurich, Switzerland

    P. August Schubiger & Roger Schibli

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  1. Cristina Müller
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  2. P. August Schubiger
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Correspondence to Roger Schibli.

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Müller, C., Schubiger, P.A. & Schibli, R. In vitro and in vivo targeting of different folate receptor-positive cancer cell lines with a novel 99mTc-radiofolate tracer. Eur J Nucl Med Mol Imaging 33, 1162–1170 (2006). https://doi.org/10.1007/s00259-006-0118-2

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  • DOI: https://doi.org/10.1007/s00259-006-0118-2

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