Biodistribution and subcellular localization of an unnatural boron-containing amino acid (cis-ABCPC) by imaging secondary ion mass spectrometry for neutron capture therapy of melanomas and gliomas

• Published in: PloS one Vol. 8; no. 9; p. e75377
• Main Authors: Chandra, Subhash, Barth, Rolf F, Haider, Syed A, Yang, Weilian, Huo, Tianyao, Shaikh, Aarif L, Kabalka, George W
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18-09-2013; Public Library of Science (PLoS)
• Subjects: Acids; Amino acids; Amino Acids - chemical synthesis; Amino Acids - chemistry; Amino Acids - pharmacokinetics; Amino Acids - pharmacology; Animal models; Animals; Antineoplastic agents; Atoms & subatomic particles; Biomedical engineering; Blood-brain barrier; Blood-Brain Barrier - metabolism; Blood-Brain Barrier - pathology; Boron; Boron Compounds - chemical synthesis; Boron Compounds - chemistry; Boron Compounds - pharmacokinetics; Boron Compounds - pharmacology; Boron Neutron Capture Therapy - methods; Brain; Brain cancer; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain Neoplasms - radiotherapy; Brain tumors; Cancer therapies; Cancer treatment; Cell cycle; Clinical trials; Cytoplasm; Enantiomers; Glioma; Glioma - diagnostic imaging; Glioma - metabolism; Glioma - pathology; Gliomas; Humans; Imaging; In vivo methods and tests; Incubation; Ionizing radiation; Localization; Male; Mass spectrometry; Mass spectroscopy; Melanoma; Melanoma - metabolism; Melanoma - pathology; Melanoma - radiotherapy; Microscopy; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Neoplasms, Experimental - radiotherapy; Neuroimaging; Neutrons; Nuclear capture; Nuclei (cytology); Nuclei (nuclear physics); Partitioning; Pathology; Quality; Radiography; Rats; Rats, Inbred F344; S Phase - drug effects; S Phase - radiation effects; Scientific imaging; Secondary ion mass spectrometry; Spatial discrimination; Spatial resolution; Spectrometry, Mass, Secondary Ion; Spectroscopy; Studies; Therapy; Tumor cells; Tumors; New York; Ohio; United States > US; Tennessee
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0075377

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.