[en] Boron delivery characteristics of cis and trans isomers of a boronated unnatural amino acid, 1-amino-3-boronocyclopentanecarboxylic acid (ABCPC) were tested in the B16 mouse model for human melanoma. Both ABCPC isomers delivered comparable boron to B16 melanoma tumor cells as L-p-boronophenylalanine (BPA). Secondary ion mass spectrometry (SIMS) analysis revealed the presence of boron throughout the tumor from these compounds, and a near homogeneous distribution between the nucleus and cytoplasm of B16 cells grown in vitro. These encouraging observations support further studies of these new boron carriers in BNCT.

[en] The present study was undertaken to evaluate the effects of L-DOPA pre-loading on the uptake of BPA using the F98 rat glioma and the murine B16 melanoma models. In vitro pretreatments of F98 glioma and B16 melanoma cells with L-DOPA, followed by exposure to BPA increased boron uptake, as determined by inductively coupled plasma-optical emission spectroscopy (ICP-OES). Based on this, in vivo studies were initiated in F98 glioma bearing rats. Initially, the L-DOPA dosing paradigm was evaluated. Maximum tumor boron uptake was observed following i.p. administration of L-DOPA (50 mg/kg) followed 24 h later by BPA (31.8±8.9 vs. 17.2±6.3 µg/g for BPA alone). Next, the effect of L-DOPA pre-loading as a function of the route of administration of BPA was evaluated in F98 glioma bearing rats. The greatest increase in uptake was seen following i.v. administration of BPA, while in contrast no significant increase was seen following intracarotid (i.c.) administration (38.6±12.4 vs. 34.2±10.9). Cellular localization of the F98 glioma, as determined by secondary ion mass spectrometry (SIMS) boron imaging revealed equivalent tumor boron concentrations following L-DOPA pre-loading. In vivo studies in B16 melanoma bearing mice showed equivalent tumor boron values in treated and untreated mice, suggesting that the effects of L-DOPA pre-loading may depend both on the histologic type of tumor and its anatomic site. - Highlights: • Effects of L-DOPA pre-loading on the uptake of BPA were studied using the F98 glioma and B16 melanoma models. • In vitro studies using both cell lines revealed that pre-loading resulted in increased uptake of BPA. • Enhanced uptake of BPA was seen following i.v. administration to F98 glioma bearing rats (31.8 vs. 17.2 µg/g). • The effects of L-DOPA pre-loading may depend both on the histologic type of tumor and its anatomic site

[en] Unnatural cyclic amino acids (UNAAs) 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) were evaluted 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 (ICP-OES) at 2.5 h 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 could be potentially 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. - Highlights: • Unnatural cyclic amino acids (UNAAs) are a new class of boron delivery agents for neutron capture therapy. • ABCPC and ABCHC attained higher tumor/blood ratios vs. BPA in B16 melanoma bearing mice. • The tumor/brain ratio of cis-ABCPC was superior to BPA (6 vs. 3.3) suggesting that further studies are warranted