Neutron activation of In(iii) complexes with thiosemicarbazones leads to the production of potential radiopharmaceuticals for the treatment of breast cancer

Abstract

In(III) complexes [In(2Ac4oClPh)₂]NO₃ (1) and [In(2Ac4pFPh)₂]NO₃·1.5H₂O (2) were obtained with N(4)-ortho-chlorophenyl-2-acetylpyridine thiosemicarbazone (H2Ac4oClPh) and N(4)-para-fluorophenyl-2-acetylpyridine thiosemicarbazone (H2Ac4pFPh). Neutron activation of complexes (1) and (2), and of previously prepared [In(2Ac4oClPh)Cl₂(MeOH)] (3) and [In(2Ac4pFPh)Cl₂(MeOH)] (4) resulted in the formation of ^114mIn/^115mIn analogues (*1–*4). The cytotoxic activities of the compounds under study were investigated on MCF-7 breast cancer cells as well as against non-malignant MRC-5 fibroblast cells. Upon coordination to In(III) the cytotoxicity against MCF-7 cells significantly increased in complexes (1–4), suggesting that complexation was a good strategy to improve the cytotoxic effect. While both non-radioactive and radioactive In(III) salts were inactive against MCF-7 cells, the radioactive complexes (*1–*4) proved to be 10² to 10⁴ times more potent than the non-radioactive analogues (1–4). For the non-radioactive In(III) complexes (1–4) the selectivity indexes (SI), defined as IC_50 MRC-5/IC_50 MCF-7, were SI = 0.07–0.36, while high values of SI were found for the radioactive In(III) analogues (*1–*4), SI = 46–4716, indicating that irradiation represented an interesting strategy for increasing the selectivity. Since cytotoxicity was evaluated following 48 h of treatment and 72 h after neutron activation, the observed cytotoxic effects were attributed mainly to ^114mIn, the contribution of the ^115mIn (t_1/2 = 4.5 h) isomer being considered irrelevant. Complexes (*1–*4) induced higher levels of intracellular ROS in MCF-7 cells in comparison to the parent compounds. The results suggest that ^114mIn complexes with thiosemicarbazones might show potential for application as radiopharmaceuticals for the treatment of breast cancer.