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Evaluation of Systemically Administered Radiolabeled Epidermal growth Factor as a Brain Tumor Targeting Agent

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Abstract

We have previously reported a method for labeling epidermal growth factor (EGF) with technetium-99m and have shown that 99mTc-EGF localized in EGF receptor (R) positive intracerebral C6EGFR rat gliomas following intratumoral (i.t.) injection of the radioligand. In the present study, we have evaluated the potential use of 99mTc-EGF as a tumor targeting agent after systemic administration to Fischer rats bearing intracerebral implants of C6EGFR gliomas. Radiolocalization was determined following intravenous (i.v.) or intracarotid (i.c.) injection with or without hyperosmotic mannitol induced disruption of the blood–brain barrier (BBB-D). As determined by γ-scintillation counting, 4 h after i.c. injection of 99mTc-EGF, 0.34% of the injected dose per gram (% ID/g) was localized in C6EGFR tumors, which expressed 105–106 EGFR sites per cell, compared to 0.07% ID/g in animals bearing C6 wildtype gliomas, which do not express EGFR. The corresponding tumor to brain ratios were 5.6 and 1.6, respectively. Tumors could be visualized by external γ-scintigraphy in rats bearing C6EGFR but not C6 wildtype gliomas, thereby establishing that radiolocalization was dependent upon receptor expression. Intracarotid administration of 99mTc-EGF significantly increased tumor uptake compared to i.v. injection (0.34 vs 0.14% ID/g, p<0.04). BBB-D disruption, followed by i.c. injection of 99mTc-EGF, however, did not significantly enhance tumor uptake compared to i.c. injection without BBB-D (0.45% vs 0.34% ID/g, p>0.1). The uptake of 99mTc-EGF was ∼4–9% ID/g in the liver and 12–20% ID/g in the kidneys after i.c. or i.v. administration. External γ-scintigraphy of regions of interest over the liver and kidneys revealed that ∼70–80% of the whole body radioactivity accumulated in these organs, and only 0.47–0.83% in the tumor following i.v. or i.c. administration of 99mTc-EGF. Our study has demonstrated that EGF can be used as a specific targeting agent for EGFR (+) rat brain tumors. However, it is unlikely that systemic injection of EGF-based bioconjugates can deliver sufficient amounts of the ligand to brain tumors for therapeutic purposes and direct delivery by means of either intratumoral injection or a variant of it such as convection enhanced delivery will be required.

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Author notes

  1. Renee Leveille

    Present address: VDIC, Clackmas, OR, USA

Authors and Affiliations

  1. Department of Pathology, The Ohio State University, Columbus, OH, USA

    Weilian Yang, Rolf F. Barth & Dianne M. Adams

  2. Department of Veterinary Clinical Sciences, The Ohio State University, Columbus, OH, USA

    Renee Leveille

  3. VDIC, Clackmas, OR, USA

    Michael Ciesielski & Robert A. Fenstermaker

  4. Department of Radiation Sciences, Uppsala University, Uppsala, Sweden

    Jacek Capala

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Yang, W., Barth, R.F., Leveille, R. et al. Evaluation of Systemically Administered Radiolabeled Epidermal growth Factor as a Brain Tumor Targeting Agent. J Neurooncol 55, 19–28 (2001). https://doi.org/10.1023/A:1013017821166

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