Lanthanide complexes facilitate wound healing by promoting fibroblast viability, migration and M2 macrophage polarization

Abstract

A tridentate ligand LH₃ ((2-hydroxy-3-methoxybenzylidene)-2-(hydroxyimino)propanehydrazide) comprising o-vanillin, hydrazone and oxime donor groups has been employed to prepare a series of tetranuclear Ln(III) complexes. The reaction of ligand LH₃ with Ln(NO₃)₃ [Ln = Sm, Eu, Gd, Tb, Dy, Ho, Er] in MeOH yielded Ln₄(LH)₆(MeOH)₂ (Ln = Sm(1), Eu(2), Gd(3), Tb(4), Ho (6) and Er (7))] whereas the corresponding reaction with Dy(NO₃)₃ afforded Dy₄(LH)₄(LH₂)₂(OH)₂ (5). All complexes were characterized by various analytical techniques including single crystal X-ray diffraction, IR spectroscopy, UV-Vis spectroscopy, and elemental analysis. To investigate the potential of these lanthanide complexes for wound healing applications, their effects on fibroblast viability, migration, and M2 macrophage polarization were evaluated. The cytotoxicity assessment revealed that complexes 2(Eu), 4(Tb), 5(Dy), and 7(Er) significantly enhanced fibroblast viability compared to the negative control (NC). In vitro wound healing assay demonstrated that complexes 2(Eu) and 7(Eu) substantially promoted fibroblast migration compared to the NC. Moreover, complex 2(Eu) exhibited significant anti-inflammatory effects by reducing the phagocytic ability of lipopolysaccharide (LPS)-stimulated macrophage cells and attenuating nitric oxide (NO) production. In conclusion, among the series of complexes tested, complex 2(Eu) displayed the most potent anti-inflammatory effect on macrophage cells, while simultaneously promoting fibroblast viability and migration. This unique combination of properties renders complex 2 (Eu) highly promising for wound healing applications.