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 (similar to 10(9)) of B-10 atoms must be delivered to eac h cancer cell in order to sustain a lethal B-10(n, alpha)Li-7 reaction . The majority of high grade gliomas express an amplified epidermal gr owth factor receptor (EGFR) gene, and increased numbers of EGFR are fo und on the cell surface. If a sufficiently large number of B-10 atoms could be attached to EGF, the resulting bioconjugates might be useful for targeting brain tumors. In order to accomplish this, we have boron ated a fourth-generation starburst dendrimer (SD) using an isocyanato polyhedral borane, Na(CH3)(3)NB10H8NCO. For conjugation, reactive thio l groups were introduced into the boronated SD using N-succinimidyl 3- (2-pyridyldithio)propionate (SPDP), and EGF was derivatized with m-mal eimidobenzoyl-N-hydroxysulfosuccinimide ester (sMBS). Subsequent react ion of thiol groups of derivatized ESD with maleimide groups of deriva tized EGF produced stable ESD-EGF bioconjugates containing similar to 960 atoms of boron per molecule of EGF. As determined by electron spec troscopic imaging, the ESD-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 bioconj ugates suggest that they may be useful for the in vivo targeting of EG FR positive brain tumors.