title: Boron neutron capture therapy: linkage of a boronated macromolecule to monoclonal antibodies directed against tumor-associated antigens.
abstract: Two new protein-binding polyhedral boron derivatives, isocyanatoundecahydro-closo-dodecaborate(2-) (1) and isocyanato(trimethylamino)octahydro-closo-decaborate(1 -) (2), were synthesized. These anionic isocyanates have long hydrolysis half-lives at pH 7 and react readily with primary or secondary aliphatic amines resulting in spontaneous urea linkage. Utilizing 1, 1100 boron atoms (7.3% boron by weight) were incorporated per molecule of a polyclonal antibody directed against human thymocytes (anti-thymocyte globulin) without denaturation. However, immunoreactivity of the conjugates was lost. Reaction of 1 and 2 with polylysine yielded boronated macromolecules containing 21-28% boron by weight (up to 2000 boron atoms per molecule). Polylysine boronated with 2 was successfully linked to antibody molecules employing the heterobifunctional linking molecules N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP) and m-maleimidobenzoyl sulfosuccinimide ester (sulfo-MBS). Separation of the conjugated antibody from the free boronated macromolecules and unconjugated antibody molecules has been achieved by gel filtration on a Sephacryl S-300 column. By linking boronated polylysine to antibodies, greater than 10(3) boron atoms were incorporated with the attachment of this species to one or more sites on the antibody molecule. The resulting immunoconjugates contained greater than 10(3) boron atoms per molecule, retained their immunoreactivity, and potentially might be useful for the selective delivery of large numbers of boron atoms to tumor cells.
authors: College of Pharmacy, Ohio State University, Columbus 43210.
authors: F
authors: F
authors: Alam
authors: A H
authors: AH
authors: Soloway
authors: R F
authors: RF
authors: Barth
authors: N
authors: N
authors: Mafune
authors: D M
authors: DM
authors: Adams
authors: W H
authors: WH
authors: Knoth
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000936:Antigen-Antibody Complex / Q000032:analysis; D000951:Antigens, Neoplasm / Q000276:immunology; D001881:Borates; D001896:Boron Compounds / Q000138:chemical synthesis* / Q000627:therapeutic use; D003485:Cyanates / Q000627:therapeutic use; D007202:Indicators and Reagents; D017953:Isocyanates; D007554:Isotopes; D008546:Melanoma, Experimental / Q000276:immunology; D051379:Mice; D009502:Neutrons; D013329:Structure-Activity Relationship
chemical_list: D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D000951:Antigens, Neoplasm; D001881:Borates; D001896:Boron Compounds; D003485:Cyanates; D007202:Indicators and Reagents; D017953:Isocyanates; D007554:Isotopes; C061250:isocyanato(trimethylamino)octahydrodecaborate; C061249:isocyanatoundecahydrododecaborate