Toward a cancer therapy with boron-rich oligomeric phosphate diesters that target the cell nucleus.
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.
Nakanishi
A
A
Department of Molecular, Cell, and Developmental Biology and the Molecular Biology Institute, University of California, 405 Hilgard Avenue, Los Angeles, CA 90095, USA.
Guan
L
L
Kane
R R
RR
Kasamatsu
H
H
Hawthorne
M F
MF
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*
D001896:Boron Compounds; D005452:Fluoresceins; D010755:Organophosphates