Alditols in complex with boronophenylalanine for improving aqueous solubility for boron neutron capture therapy

Abstract

Boron neutron capture therapy (BNCT) aimed at treating brain tumors is deteriorated by the poor aqueous solubility of the BNCT agent, boronophenylalanine (BPA). Solubilizers, such as sorbitol, mannitol and xylitol and their mixing formulas, the storage temperature and time, acid adjusters, and antioxidants, as well as lyophilization conditions were studied. HPLC, ¹H-NMR, and scanning electron microscopy (SEM) were used to investigate the alditol–BPA samples. HPLC results showed that the stability of sorbitol–BPA samples improved when the antioxidant Na₂S₂O₅ was used, 98.25 ± 0.31% vs. 94.37 ± 1.24%, P < 0.05. The osmolality ratio of sorbitol–BPA, 0.83 ± 0.03, was lower than that of saline, 1.0, making it physiologically compatible. SEM results of the lyophilized samples showed a proportion of sorbitol–BPA vs. H₂O in a molar ratio of 1 : 10. Sorbitol was the best solubilizer according to the ¹H-NMR-derived integral ratio in the decreasing order of sorbitol–BPA, mannitol–BPA, fructose–BPA and xylitol–BPA with the values of 12.15 ± 1.30, 6.65 ± 0.61, 6.13 ± 1.90 and 4.77 ± 0.72, P < 0.05, respectively. The antioxidant Na₂S₂O₅ improved the stability of sorbitol–BPA at 25 °C according to the ¹H-integral ratio of 17.60 ± 2.15 vs. 12.67 ± 1.62, P = 0.10. The differences were not statistically significant. From both the HPLC and ¹H-integral results, sorbitol emerges as the optimal solubilizer for PBA for further in vivo studies.