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Molecular Targeting of the Epidermal Growth Factor Receptor for Neutron Capture Therapy of Gliomas¹

Department of Pathology [R. F. B., W. Y., D. M. A., J. H. R.] and the College of Pharmacy [S. S., M. S., W. T.], The Ohio State University, Columbus, Ohio 43210; Department of Neurosurgery, Roswell Park Cancer Institute, Buffalo, New York 14263 [R. A. F., M. C.]; and Medical Department, Brookhaven National Laboratory, Upton, New York 11973 [M. M. N., J. A. C.]

Success of boron neutron capture therapy (BNCT) is dependent on cellular and molecular targeting of sufficient amounts of boron-10 to sustain a lethal ¹⁰B (n, ) ⁷Li capture reaction. The purpose of the present study was to determine the efficacy of boronated epidermal growth factor (EGF) either alone or in combination with boronophenylalanine (BPA) as delivery agents for an epidermal growth factor receptor (EGFR) -positive glioma, designated F98_EGFR. A heavily boronated precision macromolecule [boronated starburst dendrimer (BSD)] was chemically linked to EGF by heterobifunctional reagents. Either F98 wild-type (F98_WT) receptor (-) or EGFR gene-transfected F98_EGFR cells, which expressed 5 x 10⁵ receptor sites/cell, were stereotactically implanted into the brains of Fischer rats, and 2 weeks later biodistribution studies were initiated. For biodistribution studies rats received an intratumoral (i.t.) injection of ¹²⁵I-labeled BSD-EGF and were euthanized either 6 or 24 h later. At 6 h, equivalent amounts of BSD-EGF were detected in F98_EGFR and F98_WT tumors. Persistence of the bioconjugate in F98_EGFR tumors was specifically determined by EGFR expression. By 24 h 33.2% of injected dose/g of EGF-BSD was retained by F98_EGFR gliomas compared with 9.4% % of injected dose/g in F98_WT gliomas, and the corresponding boron concentrations were 21.1 µg/g and 9.2 µg/g, respectively. Boron concentrations in normal brain, blood, liver, kidneys, and spleen all were at nondetectable levels (<0.5 µg/g). On the basis of these results, BNCT was initiated at the Brookhaven National Laboratory Medical Research Reactor. Two weeks after implantation of 10³ F98_EGFR or F98_WT tumor cells, rats received an i.t. injection of BSD-EGF (60 µg ¹⁰B/15 µg EGF) either alone or in combination with i.v. BPA (500 mg/kg). Rats were irradiated at the Brookhaven Medical Research Reactor 24 h after i.t. injection, which was timed to coincide with 2.5 h after i.v. injection of BPA for those animals that received both capture agents. Untreated control rats had a mean survival time (MST) ± SE of 27 ± 1 day, and irradiated controls had a MST of 31 ± 1 day. Animals bearing F98_EGFR gliomas, which had received i.t. BSD-EGF and BNCT, had a MST of 45 ± 5 days compared with 33 ± 2 days for animals bearing F98_WT tumors (P = 0.0032), and rats that received i.t. BSD-EGF in combination with i.v. BPA had a MST of 57 ± 8 days compared with 39 ± 2 days for i.v. BPA alone (P = 0.016). Our data are the first to show in vivo efficacy of BNCT using a high molecular weight boronated bioconjugate to target amplified EGFR expressed on gliomas, and they provide a platform for the future development of combinations of high and low molecular weight agents for BNCT.

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