title: Intratumoral delivery of boronated epidermal growth factor for neutron capture therapy of brain tumors.
abstract: The gene for epidermal growth factor receptor (EGFR) is amplified or overexpressed in high-grade gliomas but is low or undetectable in normal brain. Recently, there has been increasing interest in using epidermal growth factor (EGF)-based bioconjugates as targeting agents for brain tumors. In the present study, we have investigated the potential use of boronated EGF as a delivery agent for boron neutron capture therapy, which is based on the capture reaction that occurs when 10B, a stable isotope, is irradiated with low-energy thermal neutrons. A fourth generation starburst dendrimer was boronated and linked to EGF using heterobifunctional reagents. Either wild-type or EGFR gene transduced C6 glioma cells (C6EGFR), which expressed 10(5)-10(6) receptor sites/cell, were stereotactically implanted into the right cerebral hemisphere of Fischer rats. Four weeks later, the rats received either i.v. or intratumoral (i.t.) injection of 131I-labeled boronated starburst dendrimer (BSD) or BSD-EGF. The biodistribution of 131I-BSD-EGF and 131I-BSD was studied by means of whole-body scintigraphy, autoradiography, and gamma scintillation counting. Following i.t. injection of 131I-BSD-EGF, 21.8% of the injected dose per gram tissue (% ID/g) was localized in C6EGFR tumors at 24 h and 16.3% at 48 h compared to 5 and 1.3% ID/g in C6 wild-type tumors, respectively, and 0.01 and 0.006% ID/g, respectively, for i.v. injected animals at the corresponding times. In contrast, following i.t. injection of BSD-EGF, only 0.01-0.1% ID/g was localized in the liver and spleen at 24 and 48 h compared to 5-12% ID/g following i.v. injection. Our data indicate that direct i.t. injection can selectively deliver BSD-EGF to EGFR-positive gliomas and suggest that intracerebral administration may be the most effective way for delivering EGF-based bioconjugates to EGFR-positive brain tumors.
authors.affiliation: Department of Pathology, The Ohio State University, Columbus 43210, USA.
authors.forename: W
authors.initials: W
authors.lastname: Yang
authors.forename: R F
authors.initials: RF
authors.lastname: Barth
authors.forename: D M
authors.initials: DM
authors.lastname: Adams
authors.forename: A H
authors.initials: AH
authors.lastname: Soloway
mesh_terms: D000818:Animals; D001895:Boron / Q000008:administration & dosage*; D016754:Boron Neutron Capture Therapy; D001932:Brain Neoplasms / Q000532:radiotherapy*; D004815:Epidermal Growth Factor / Q000008:administration & dosage* / Q000493:pharmacokinetics; D066246:ErbB Receptors / Q000187:drug effects; D005910:Glioma / Q000532:radiotherapy*; D015552:Injections, Intralesional; D007275:Injections, Intravenous; D007554:Isotopes; D009363:Neoplasm Proteins / Q000187:drug effects; D051381:Rats; D014407:Tumor Cells, Cultured
chemical_list: D007554:Isotopes; D009363:Neoplasm Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D001895:Boron