Biological evaluation of boronated unnatural amino acids as new boron carriers

George Kabalka, M. L. Yao, S. R. Marepally, S. Chandra

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

There is a pressing need for new and more efficient boron delivery agents to tumor cells for use in boron neutron capture therapy (BNCT). A class of boronated unnatural cyclic amino acids has demonstrated a remarkable selectivity toward tumors in animal and cell culture models, far superior to currently used agents in clinical BNCT. One of these amino acids, 1-amino-3-boronocyclopentanecarboxylic acid (ABCPC), has shown a tumor to blood ratio of 8 and a tumor to normal brain ratio of nearly 21 in a melanoma bearing mouse model. This work represents further biological characterization of this compound for tumor targeting in an EMT6 murine mammary carcinoma mouse model and a T98G human glioblastoma cell line. Female BALB/c mice bearing EMT6 tumors were injected with the fructose complex form of racemic mixtures of cis and trans isomers of ABCPC in identical concentrations. Boron concentrations were measured in the tumor, blood, brain, skin, and liver tissues at 1, 3, and 5 h post-injection. These observations revealed a remarkable difference in racemic mixtures of cis and trans isomers in tumor targeting by boron. This implies that further separation of the L and D forms of this compound may enhance tumor targeting to an even higher degree than that provided by the racemic mixtures. Since the uptake measurements were made in homogenized tumor and normal tissues, little is known about the subcellular location of the boron arising from the various isomeric forms of the amino acid. To study subcellular delivery of boron from ABCPC in T98G human glioblastoma cells, we employed secondary ion mass spectrometry (SIMS) based technique of ion microscopy, which is capable of quantitatively imaging isotopic (elemental) gradients in cells and tissues at 500 nm spatial resolution. The T98G cells were exposed to the nutrient medium containing 100 ppm boron equivalent of a mixture of both L and D isomers of ABCPC in the form of a fructose complex for 1 h. Following this treatment, the cells were fast frozen, freeze-fractured, and freeze-dried for SIMS analysis. Within an hour of exposure, ABCPC provided partitioning of intracellular to extracellular boron of 3/1. SIMS imaging revealed that boron from ABCPC was distributed throughout the cell, including the nucleus. This level of boron delivery within an hour of exposure is superior to p-boronophenylalanine (BPA) and sodium borocaptate (BSH), which have been previously studied by SIMS in the same cell line. These encouraging observations provide compelling support for further isomeric separations of ABCPC into the D and L forms for enhanced tumor targeting and continued testing of these compounds as new boron carriers in BNCT.

Original languageEnglish (US)
JournalApplied Radiation and Isotopes
Volume67
Issue number7-8 SUPPL.
DOIs
StatePublished - Jul 1 2009
Externally publishedYes

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amino acids
boron
tumors
evaluation
acids
secondary ion mass spectrometry
mice
therapy
cells
delivery
isomers
cultured cells
neutrons
blood
brain
nutrients
pressing
liver
animals
spatial resolution

All Science Journal Classification (ASJC) codes

  • Radiation

Cite this

Biological evaluation of boronated unnatural amino acids as new boron carriers. / Kabalka, George; Yao, M. L.; Marepally, S. R.; Chandra, S.

In: Applied Radiation and Isotopes, Vol. 67, No. 7-8 SUPPL., 01.07.2009.

Research output: Contribution to journalArticle

Kabalka, George ; Yao, M. L. ; Marepally, S. R. ; Chandra, S. / Biological evaluation of boronated unnatural amino acids as new boron carriers. In: Applied Radiation and Isotopes. 2009 ; Vol. 67, No. 7-8 SUPPL.
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