Evaluation of unnatural cyclic amino acids as boron delivery agents for treatment of melanomas and gliomas

Abstract

Unnatural cyclic amino acids (UNAA) are a new class of boron delivery agents that are in a pre-clinical stage of evaluation. In the present study, the biodistribution of racemic forms of the cis-and trans- isomers of the boronated UNAA 1-amino-3-boronocyclopentanecarboxylic acid (ABCPC) and 1-amino-3-boronocycloheptanecarboxylic acid (ABCHC) was studied in B16 melanoma bearing mice and this was compared to L-p-boronophenylalanine (BPA). Boron concentrations were determined by inductively coupled plasma-optical emission spectroscopy (ICPOES) at 2.5 hrs following intraperitoneal (i.p.) injection of the test agents at a concentration equivalent to 24 mg B/kg. While all compounds attained comparable tumor boron concentrations, the tumor/blood (T/Bl) boron concentration ratios were far superior for both cis-ABCPC and cis-ABCHC compared to BPA (T/Bl = 16.4, and 15.1 vs. 5.4). Secondary ion mass spectrometry (SIMS) imaging revealed that the cis-ABCPC delivered boron to the nuclei, as well as the cytoplasm of B16 cells. Next, a biodistribution study of cis-ABCPC and BPA was carried out in F98 glioma bearing rats following i.p. administration. Both compounds attained comparable tumor boron concentrations but the tumor/brain (T/Br) boron ratio was superior for cis-ABCPC compared to BPA (6 vs. 3.3). Since UNAAs are water soluble and cannot be metabolized by tumor cells, they potentially could be more effective boron delivery agents than BPA. Our data suggest that further studies are warranted to evaluate these compounds prior to the initiation of clinical studies.

Evaluation of a novel sodium borocaptate-containing unnatural amino acid as a boron delivery agent for neutron capture therapy of the F98 rat glioma

“…Extensive studies relating to the use of unnatural amino acids as boron delivery agents for BNCT have been reported by Barth, Chandra and Kabalka [17–19]. In the present study, we designed and synthesized ACBC-BSH, which is chemically modified BSH with a tumor-avid synthetic unnatural amino acid, ACBC.…”

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

“…Since BNCT is a non-invasive therapeutic modality, which has the potential of killing the individual infiltrating tumor cells in normal brain, it is essential that a new compound be rigorously tested for its efficacy in appropriate models to allow such single cell studies. Indeed, the present single cell boron imaging study is an extension of our recent work on cis -ABCPC on homogenized tissue measurements with inductively coupled plasma–optical emission spectroscopy (ICP-OES) [22]. In this study we found that: (i) cis -ABCPC was comparable to the clinically used compound BPA in delivering the net boron content to B16 and F98 tumors, as measured by means of ICP-OES, and (ii) cis -ABCPC was far superior to BPA in providing a higher boron partitioning ratio of tumor-to-blood in B16 mouse melanoma model and the main tumor mass-to-healthy brain tissue boron ratio in the F98 rat glioma model [22].…”

“…Indeed, the present single cell boron imaging study is an extension of our recent work on cis -ABCPC on homogenized tissue measurements with inductively coupled plasma–optical emission spectroscopy (ICP-OES) [22]. In this study we found that: (i) cis -ABCPC was comparable to the clinically used compound BPA in delivering the net boron content to B16 and F98 tumors, as measured by means of ICP-OES, and (ii) cis -ABCPC was far superior to BPA in providing a higher boron partitioning ratio of tumor-to-blood in B16 mouse melanoma model and the main tumor mass-to-healthy brain tissue boron ratio in the F98 rat glioma model [22]. The later indicates a highly desirable feature of cis -ABCPC as a boron delivery agent.…”

“…The cis -ABCPC was further purified by removing the contaminant of ammonium chloride produced during its synthesis [22]. The chemical structures of L- and D- enantiomers of cis -ABCPC are shown in Fig.…”

“…The boron containing unnatural cyclic amino acids (UNAAs) are a class of water soluble compounds that have shown the potential to be the new and more efficient boron carriers [20], [21]. A recent evaluation of several UNAAs, based on homogenized tissue boron measurements with inductively coupled plasma–optical emission spectroscopy (ICP-OES), identified cis- ABCPC to be far superior than BPA in producing tumor-to-blood boron ratios in B16 mouse melanoma model and tumor-to-normal brain boron ratios in F98 rat glioma model [22]. These observations provide compelling support for subcellular scale characterization of cis -ABCPC, so that the boron-targeting of the nucleus of individual tumor cells and boron-partitioning between the infiltrating tumor cells and the normal brain tissue can be assessed.…”