Study of ATP borate ester effects on cell sensitization to radiation emitted by a nuclear reactor

Abstract

Adenosine triphosphate (ATP) borate ester as a new boron agent for boron neutron capture therapy was tested. It was synthesized via a dehydration reaction induced by heating adenosine triphosphate disodium with boric acid. Next, ATP borate ester pretreatments were assessed to study their effects on cell sensitization from exposure to thermal neutron irradiation emitted by a nuclear reactor. Using cell viability assays (CCK8), survival rates of A549 cells pretreated with or without boron-containing agents, including ATP borate ester and 4-dihydroxyborylphenylalanine (BPA), were measured. One week after feeding an ATP borate ester solution to tumor-bearing nude mice, elemental B content values of tumor muscle and blood were measured using inductively coupled plasma mass spectrometry (ICP-MS). Meanwhile, other tumor tissue samples were placed in a culture medium, subjected to a 3-min neutron irradiation exposure, and then fixed in formalin 24 h later for the terminal-deoxynucleotidyl transferase (TDT)-mediated dUTP nick end labeling (TUNEL) immunohistochemical staining analysis. Results showed that A549 cell irradiation sensitization (irradiation dose of 0.33 Gy) varied with pretreatment. Sensitization values of the ATP borate ester pretreatment group were 1.3–14.1 with boron agent concentrations of 0.3–4.5 mM. Within 1.1–3.4 mM, ATP borate ester showed significantly higher sensitization values than BPA. Meanwhile, TUNEL results demonstrated that apoptosis rates of tumor tissue cells exposed to irradiation after ATP borate ester pretreatment significantly exceeded the corresponding rates for BPA-pretreated cells. In animal experiments, although the distribution ratio of ATP borate ester (tumor tissue/normal muscle, T/N) of 1.2 was not significantly different compared with that of BPA (1.3), the total ATP borate ester concentration in the tumor tissue (0.79 ± 0.05 μg/g) significantly exceeded that of BPA (0.58 ± 0.05 μg/g). Thus, compared with BPA, the greater enrichment of ATP borate ester in tumor tissues permits preferential targeting toward tumor cells for radiation sensitization. Therefore, ATP borate ester is superior to BPA for use in boron neutron capture therapy.