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The viability of boron neutron capture therapy depends on the development of tumor-targeting agents that contain large numbers of boron-10 ( 10 B) atoms and are readily taken up by cells. Here we report on the selective uptake of homogeneous f luorescein-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 f luorescence primarily located in the cell nucleus indicates that nuclear-specific uptake of sufficient amounts of 10 B for effective boron neutron capture therapy (Ϸ10 8 -10 9 10 B atoms͞tumor cell) via nido-OPDs is achievable.Boron neutron capture therapy (BNCT) is a binary radiation therapy for cancer, which entails the capture of thermal neutrons by boron-10 ( (1) is required for effective cytotoxicity with BNCT. By targeting the tumor cell nucleus, lower concentrations of boron are required for successful therapy because a single neutron-10 B capture event within tumor cell DNA would be lethal to the cell (2).Modalities under development for the delivery of 10 B to tumor include porphyrins, monoclonal antibodies, nucleosides, amino acids, and liposomes (1, 3). Of major importance in determining the efficacy of any of these delivery vehicles is the resulting subcellular localization of the boron. Recently, a number of homogeneous nido-carboranyl oligomeric phosphate diesters (nido-OPDs) have been developed that selectively accumulate in EMT6 tumors grown in BALB͞c mice (unpublished results), but the mechanism of transport of these nido-OPDs across the plasma membrane is unknown. Subcellular localization of these nido-OPDs has not been previously investigated and appeared to merit immediate examination because of their versatile structures, ready availability, and potential for specific cellular targeting with liposomes.To explore possible subcellular boron localization by both closo-and nido-OPDs, microinjection studies and experiments with permeabilized cells were conducted. Microinjection and permeabilization of cells were used because of the inability of the OPDs to enter TC7 cells under culture conditions. TC7 cells, a subline of African green monkey kidney cells, were used in all experiments because of their apparent resilience to the process of microinjection and our desire to use a mammalian cell line. Microinjection studies were conducted to investigate the subcel...

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