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 (< or = 0.025 eV) to yield high LET alpha particles and recoiling 7Li nuclei [10B + nth-->[11B]-->4He(alpha) + 7Li + 2.39 MeV]. Approximately 10(9) boron-10 atoms must be delivered to each target cell in order to sustain a lethal 10B(n,alpha)7Li 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 MoAbIB16-6, 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Barth
R F
RF
Department of Pathology, Ohio State University, Columbus 43210.
Adams
D M
DM
Soloway
A H
AH
Alam
F
F
Darby
M V
MV
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000627:therapeutic use; D001896:Boron Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016754:Boron Neutron Capture Therapy / Q000379:methods*; D000922:Immunotoxins / Q000378:metabolism / Q000627:therapeutic use*; D007457:Iodine Radioisotopes; D046911:Macromolecular Substances; D008546:Melanoma, Experimental / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D001896:Boron Compounds; D000922:Immunotoxins; D007457:Iodine Radioisotopes; D046911:Macromolecular Substances