Improving the anticancer efficacy of azole-platinum(II) complexes through a Pluronic® micelle formulation strategy.

Four new azole-platinum(II) complexes with the general formulas cis-[PtCl2(L1)2] (1), cis-[PtCl2(L2)2] (2), trans-[PtCl2(L1)(DMSO)] (3), and trans-[PtCl2(L2)(DMSO)] (4), where L1 is 1-(benzofuran-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethenone, L2 is (benzofuran-2-yl)-2-(1H-imidazol-1-yl)ethenone, and DMSO is dimethyl sulfoxide, were synthesized and fully characterized. The compositions of the coordination spheres were established using spectroscopic methods (1H, 13C, 15N, 195Pt NMR; IR; X-ray). Complexes (1) and (2) adopted cis geometries, featuring two triazole ligands L1 in (1) or two imidazole ligands L2 in (2), each coordinated through the nitrogen donor atom N4″, along with two chloride ions. In contrast, complexes (3) and (4) exhibited trans configurations and contained one azole ligand (L1 or L2), each coordinated via a nitrogen donor N4″ atom, an S-donor DMSO molecule, and two chloride ions. All complexes displayed moderate lipophilicity (logP = 0.92-1.12) and markedly reduced reactivity toward glutathione compared with cisplatin, reflecting the steric shielding provided by the azole ligands. Despite these favorable physicochemical features, only complex (1) demonstrated notable intrinsic in vitro cytotoxicity. It showed activity against a lung cancer cell line (A549) and four bladder cancer cell lines (T24, HT1376, 5637, and HB-CLS-1), with IC50 values ranging from 5.00 to 8.50 µM. Comparable toxicity was observed toward normal SV-HUC-1 urothelial cells (IC50 = 8.54 µM). Notably, complex (1) induced only minor alterations in the cell-cycle profile, suggesting a mechanism of action distinct from those of classical DNA-targeting platinum drugs. To improve its therapeutic performance, complex (1) was encapsulated in polymeric micelles formed by PEO-PPO-PEO triblock copolymers. This nanoformulation resulted in a striking increase in anticancer activity, yielding submicromolar IC50 values (0.13-0.94 µM). The corresponding toxicity toward normal SV-HUC-1 cells ranged from IC50 = 0.17 to 0.75 µM. The substantial increase in potency suggests that micellar delivery enhances intracellular accumulation while protecting the complex from premature deactivation. These results suggest that triazole-based platinum(II) complexes, particularly when combined with polymeric nanocarriers, may represent a promising system for further investigation in the development of platinum-based chemotherapeutic drugs.