Indium(iii) complexes with Schiff base-derived polydentate ligands: chemotherapeutic, radiochemotherapeutic, and radiosensitizer potentials against breast tumor cells†

Abstract

Complexes [In(L1)Cl(H₂O)] (1), [In(L2)Cl(H₂O)]·3H₂O (2), [In(L3)Cl(H₂O)]·H₂O (3), [In(L4)Cl(H₂O)] (4), and [In(L5)Cl(H₂O)] (5) with 2,6-diformylpyridine-bis(benzoylhydrazone) (H₂L1), 2,6-diformylpyridine-bis(para-chloro-benzoylhydrazone) (H₂L2), 2,6-diformylpyridine-bis(para-toluyl-benzoylhydrazone) (H₂L3), 2,6-diacetylpyridine-bis(semicarbazone) (H₂L4), and 2,6-diacetylpyridine-bis(thiosemicarbazone) (H₂L5) were synthesized. The cytotoxic effects of selected compounds were tested on MCF-7 (estrogen-dependent mammary adenocarcinoma), MDA-MB-231 (triple-negative mammary adenocarcinoma), and MRC-5 (healthy human lung fibroblast) cells. H₂L4, H₂L5, and complexes 1, 3, 4, and 5 were cytotoxic against MCF-7 and MDA-MB-231 cells in a dose-dependent way, presenting IC₅₀ values in the micromolar range. 1, 3, 4, and 5 were exposed to neutron activation to produce their ^114mIn(III) analogs *1, *3, *4, and *5. Complex *3 was 13-fold more potent than its non-radioactive counterpart against both tumor cell lineages and complex *5 was 11-fold more potent than complex 5 against MCF-7 cells and 4-fold more potent than complex 5 against MDA-MB-231 cells. Radiotherapy with gamma radiation from a ⁶⁰Co source combined with the treatment with complexes 1, 3, 4, and 5 improved the efficacy of radiotherapeutic doses in the range used for hypo-fractionated radiotherapy. Combined treatment with increasing concentrations of non-radioactive compounds and 1 Gy caused a 2.27- to 4.49-fold increase in the radiation enhancement factor (REF) (REF = % cell death due to combined therapy/% cell death due to radiation monotherapy) against MCF-7 cells. Interestingly, combination therapy was even more beneficial for treating triple-negative MDA-MB-231 tumor cells, with REF ranging from 5.27 to 7.53. The results demonstrate that the indium(III) complexes under study behave as potential multifunctional agents for treating breast cancer, due to their cytotoxic activities, radiosensitizer effects, and the possible ability of the ^114mIn derivatives to be employed in targeted radionuclide therapy.