Toward a cancer therapy with boron-rich oligomeric phosphate diesters thattarget the cell nucleus

The viability of boron neutron capture therapy depends on the development o f tumor-targeting agents that contain large numbers of boron-10 (B-10) atom s and are readily taken up by cells. Here we report on the selective uptake of homogeneous fluorescein-labeled nido-carboranyl oligomeric phosphate di esters (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. Howev er, nido-OPDs in which the carborane cage was located on a side chain attac hed to the oligomeric backbone were redistributed between both the cytoplas m and nucleus after 24 h of incubation, whereas nido-OPDs in which the carb orane cage was located along the oligomeric backbone remained primarily in the nucleus. Furthermore, cell-free incubation of digitonin-permeabilized T C7 cells with the nido-OPDs resulted in nuclear accumulation of the compoun ds, thus corroborating the microinjection studies. Our observation of fluor escence primarily located in the cell nucleus indicates that nuclear-specif ic uptake of sufficient amounts of 10B for effective boron neutron capture therapy (approximate to 10(8)-10(9) B-10 atoms/tumor cell) via nido-OPDs is achievable.