Evaluation of systemically administered radiolabeled epidermal growth factor as a brain tumor targeting agent

We have previously reported a method for labeling epidermal growth factor (EGF) with technetium-99m and have shown that Tc-99m-EGF localized in EGF receptor (R) positive intracerebral C6(EGFR) rat gliomas following intratumoral (i.t.) injection of the radioligand. In the present study, we have evaluated the potential use of Tc-99m-EGF as a tumor targeting agent after systemic administration to Fischer rats bearing intracerebral implants of C6(EGFR) 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 gamma -scintillation counting, 4 h after i.c. injection of Tc-99m-EGF, 0.34% of the injected dose per gram (% ID/g) was localized in C6(EGFR) tumors, which expressed 10(5)-10(6) 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 gamma -scintigraphy in rats bearing C6(EGFR) but not C6 wildtype gliomas, thereby establishing that radiolocalization was dependent upon receptor expression. Intracarotid administration of Tc-99m-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 Tc-99m-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 Tc-99m-EGF was similar to4-9% ID/g in the liver and 12-20% ID/g in the kidneys after i.c. or i.v. administration. External gamma -scintigraphy of regions of interest over the liver and kidneys revealed that similar to 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 Tc-99m-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.