title: Molecular targeting of the epidermal growth factor receptor for neutron capture therapy of gliomas.
abstract: Success of boron neutron capture therapy (BNCT) is dependent on cellular and molecular targeting of sufficient amounts of boron-10 to sustain a lethal (10)B (n, alpha) (7)Li 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 10(5) 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 (125)I-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 microg/g and 9.2 microg/g, respectively. Boron concentrations in normal brain, blood, liver, kidneys, and spleen all were at nondetectable levels (<0.5 microg/g). On the basis of these results, BNCT was initiated at the Brookhaven National Laboratory Medical Research Reactor. Two weeks after implantation of 10(3) F98(EGFR) or F98(WT) tumor cells, rats received an i.t. injection of BSD-EGF (approximately 60 microg (10)B/approximately 15 microg 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.
authors.affiliation: Department of Pathology, The Ohio State University, 1645 Neil Avenue, Columbus, OH 43210, USA. barth.1@osu.edu
authors.forename: Rolf F
authors.initials: RF
authors.lastname: Barth
authors.forename: Weilian
authors.initials: W
authors.lastname: Yang
authors.forename: Dianne M
authors.initials: DM
authors.lastname: Adams
authors.forename: Joan H
authors.initials: JH
authors.lastname: Rotaru
authors.forename: Supriya
authors.initials: S
authors.lastname: Shukla
authors.forename: Masaru
authors.initials: M
authors.lastname: Sekido
authors.forename: Werner
authors.initials: W
authors.lastname: Tjarks
authors.forename: Robert A
authors.initials: RA
authors.lastname: Fenstermaker
authors.forename: Michael
authors.initials: M
authors.lastname: Ciesielski
authors.forename: Marta M
authors.initials: MM
authors.lastname: Nawrocky
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Coderre
mesh_terms: D000818:Animals; D001896:Boron Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016754:Boron Neutron Capture Therapy / Q000379:methods*; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D004815:Epidermal Growth Factor / Q000008:administration & dosage / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution; D014162:Transfection
chemical_list: D001896:Boron Compounds; D004815:Epidermal Growth Factor; D066246:ErbB Receptors