title: Toward a cancer therapy with boron-rich oligomeric phosphate diesters that target the cell nucleus.
abstract: The viability of boron neutron capture therapy depends on the development of tumor-targeting agents that contain large numbers of boron-10 (10B) atoms and are readily taken up by cells. Here we report on the selective uptake of homogeneous fluorescein-labeled nido-carboranyl oligomeric phosphate diesters (nido-OPDs) by the cell nucleus and their long-term retention after their delivery into the cytoplasm of TC7 cells by microinjection. All nido-OPDs accumulated in the cell nucleus within 2 h after microinjection. However, nido-OPDs in which the carborane cage was located on a side chain attached to the oligomeric backbone were redistributed between both the cytoplasm and nucleus after 24 h of incubation, whereas nido-OPDs in which the carborane cage was located along the oligomeric backbone remained primarily in the nucleus. Furthermore, cell-free incubation of digitonin-permeabilized TC7 cells with the nido-OPDs resulted in nuclear accumulation of the compounds, thus corroborating the microinjection studies. Our observation of fluorescence primarily located in the cell nucleus indicates that nuclear-specific uptake of sufficient amounts of 10B for effective boron neutron capture therapy ( approximately 10(8)-10(9) 10B atoms/tumor cell) via nido-OPDs is achievable.
authors.affiliation: Department of Molecular, Cell, and Developmental Biology and the Molecular Biology Institute, University of California, 405 Hilgard Avenue, Los Angeles, CA 90095, USA.
authors.forename: A
authors.initials: A
authors.lastname: Nakanishi
authors.forename: L
authors.initials: L
authors.lastname: Guan
authors.forename: R R
authors.initials: RR
authors.lastname: Kane
authors.forename: H
authors.initials: H
authors.lastname: Kasamatsu
authors.forename: M F
authors.initials: MF
authors.lastname: Hawthorne
mesh_terms: D001692:Biological Transport; D001896:Boron Compounds / Q000378:metabolism*; D016754:Boron Neutron Capture Therapy; D002451:Cell Compartmentation; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D005452:Fluoresceins / Q000378:metabolism; D008845:Microinjections; D009369:Neoplasms / Q000628:therapy; D010755:Organophosphates / Q000378:metabolism*
chemical_list: D001896:Boron Compounds; D005452:Fluoresceins; D010755:Organophosphates