Boronated Epidermal Growth Factor as a Potential Targeting Agent for Boron Neutron Capture Therapy of Brain Tumors

In order for boron neutron capture therapy (BNCT) to be successful, a large number (∼109) of 10B atoms must be delivered to each cancer cell in order to sustain a lethal 10B(n, α)7Li reaction. The majority of high grade gliomas express an amplified epidermal growth factor receptor (EGFR) gene, and increased numbers of EGFR are found on the cell surface. If a sufficiently large number of 10B atoms could be attached to EGF, the resulting bioconjugates might be useful for targeting brain tumors. In order to accomplish this, we have boronated a fourth-generation starburst dendrimer (SD) using an isocyanato polyhedral borane, Na(CH3)3NB10H8NCO. For conjugation, reactive thiol groups were introduced into the boronated SD using N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP), and EGF was derivatized with m-maleimidobenzoyl-N-hydroxysulfosuccinimide ester (sMBS). Subsequent reaction of thiol groups of derivatized BSD with maleimide groups of derivatized EGF produced stable BSD−EGF bioconjugates containing ∼960 atoms of boron per molecule of EGF. As determined by electron spectroscopic imaging, the BSD−EGF initially was bound to the cell surface membrane and then was endocytosed, which resulted in accumulation of boron in lysosomes. The favorable in vitro properties of these bioconjugates suggest that they may be useful for the in vivo targeting of EGFR positive brain tumors.