The development of new
boron-delivery agents is a high priority for improving the effectiveness of
boron neutron capture therapy. In the present study, 1-amino-3-borono-cyclopentanecarboxylic
acid (cis-ABCPC) as a mixture of its L- and D-enantiomers was evaluated in vivo using the
B16 melanoma model for the human
tumor and the F98 rat
glioma as a model for human
gliomas. A secondary ion mass spectrometry (SIMS) based imaging instrument, CAMECA IMS 3F SIMS Ion Microscope, was used for quantitative imaging of
boron at 500 nm spatial resolution. Both in vivo and in vitro studies in
melanoma models demonstrated that
boron was localized in the cytoplasm and nuclei with some cell-to-cell variability. Uptake of cis-ABCPC in B16 cells was time dependent with a 7.5:1 partitioning ratio of
boron between cell nuclei and the nutrient medium after 4 hrs. incubation. Furthermore, cis-ABCPC delivered
boron to cells in all phases of the cell cycle, including S-phase. In vivo SIMS studies using the F98 rat
glioma model revealed an 8:1
boron partitioning ratio between the main
tumor mass and normal brain tissue with a 5:1 ratio between infiltrating
tumor cells and contiguous normal brain. Since cis-ABCPC is water soluble and can cross the blood-brain-barrier via the L-type
amino acid transporters (LAT), it may accumulate preferentially in infiltrating
tumor cells in normal brain due to up-regulation of LAT in high grade
gliomas. Once trapped inside the
tumor cell, cis-ABCPC cannot be metabolized and remains either in a free pool or bound to cell matrix components. The significant improvement in
boron uptake by both the main
tumor mass and infiltrating
tumor cells compared to those reported in animal and clinical studies of
p-boronophenylalanine strongly suggest that cis-ABCPC has the potential to become a novel new
boron delivery agent for
neutron capture therapy of
gliomas and
melanomas.