Abstract
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.
Highlights
Boron Neutron Capture Therapy (BNCT) is a binary modality that has been used to treat a variety of malignancies, the most important of which have been high grade gliomas and recurrent cancer of the head and neck region [1]
Since there was no significant difference in boron concentrations in tumor cells between the 2.5 and 4 hr. postinjection treatments, the intracellular boron pool in these time points most likely represented the bound form of cis-ABCPC in the cell matrix components of tumor cells
We have evaluated the boron-delivery potential of an unnatural cyclic amino acids (UNAAs), cis-ABCPC as a mixture of its L- and Denantiomers, at single cell and subcellular scales resolution with a sophisticated technique of dynamic secondary ion mass spectrometry (SIMS) ion microscopy
Summary
Boron Neutron Capture Therapy (BNCT) is a binary modality that has been used to treat a variety of malignancies, the most important of which have been high grade gliomas and recurrent cancer of the head and neck region [1]. BNCT is based on the neutron capture and fission reactions [10B(n, a)7Li] that occur when 10B atoms capture thermal neutrons and undergo instantaneous nuclear fission to produce high linear energy transfer (LET) alpha particles (stripped down 4He atoms) and recoiling 7Li nuclei. These particles have short path-lengths (5 m for 7Li and 9 m for 4He), which is approximately the diameter of a single cell. Study of the distribution of 10B atoms at the subcellular scale is critical for the development of new boron delivery agents for neutron capture therapy (NCT) [1,8]
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