BORONATED STARBURST DENDRIMER MONOCLONAL-ANTIBODY IMMUNOCONJUGATES - EVALUATION AS A POTENTIAL DELIVERY SYSTEM FOR NEUTRON-CAPTURE THERAPY

Boron neutron capture therapy (BNCT) is based on the nuclear capture reaction that occurs when boron-10, a stable isotope, is irradiated with low-energy or thermal neutrons (less-than-or-equal-to 0.025 eV) to yield high LET alpha particles and recoiling Li-7 nuclei [B-10+n(th)-->[B-11]-->He-4(alpha)+Li-7+2.39 MeV]. Approximately 10(9) boron-10 atoms must be delivered to each target cell in order to sustain a lethal B-10(n,alpha)Li-7 reaction. If MoAbs are to be used for targeting boron-10, then it is essential that they recognize a surface membrane epitope that is highly expressed on tumor cells and that a large number of boron-10 atoms be attached to each antibody molecule. In order to heavily boronate MoAbs, we have utilized starburst dendrimers (SD), which are precise, spherical macromolecules composed of repetitive poly(amidoamino) groups. Second- and fourth-generation dendrimers, having 12 and 48 reactive terminal amino groups and molecular weights of 2414 and 10 632 Da, respectively, were boronated using an isocyanato polyhedral borane, Na(CH3)3NB10H8NCO. The boronated starburst dendrimers (BSD), in turn, were derivatized with m-maleimidobenzoyl N-hydroxysulfosuccinimide ester (sulfo-MBS). The MoAb IB16-6, which is directed against the murine B16 melanoma, was derivatized with N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP). The MBS-derivatized BSD and SPDP-derivatized MoAb were reacted to yield stable immunoconjugates. The in vivo distribution patterns of I-125-labeled native and boronated MoAb IB16-6 and SD were studied in normal and tumor-bearing C57Bl/6 mice carrying sc implants of the B16 melanoma. The data obtained demonstrated that SD have a propensity to localize in the liver and spleen and that the absolute amount appeared to be directly related to the molecular weight and number of reactive terminal amino groups. Further studies are required to determine whether the properties of the boronated dendrimers can be modified so as to reduce their hepatic and splenic localization.