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 r eaction that occurs when boron-10, a stable isotope, is irradiated wit h low-energy or thermal neutrons (less-than-or-equal-to 0.025 eV) to y ield 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 atom s 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 epito pe 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 heav ily boronate MoAbs, we have utilized starburst dendrimers (SD), which are precise, spherical macromolecules composed of repetitive poly(amid oamino) groups. Second- and fourth-generation dendrimers, having 12 an d 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-hydroxysulfosuccin imide ester (sulfo-MBS). The MoAb IB16-6, which is directed against th e murine B16 melanoma, was derivatized with N-succinimidyl 3-(2-pyridy ldithio)propionate (SPDP). The MBS-derivatized BSD and SPDP-derivatize d MoAb were reacted to yield stable immunoconjugates. The in vivo dist ribution patterns of I-125-labeled native and boronated MoAb IB16-6 an d 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 abs olute amount appeared to be directly related to the molecular weight a nd number of reactive terminal amino groups. Further studies are requi red to determine whether the properties of the boronated dendrimers ca n be modified so as to reduce their hepatic and splenic localization.