Bilosomal Encapsulation of Binuclear Phosphino Ru(II)–Cu(II) Compounds Enhances Their Selectivity and Activity toward Lung and Prostate Cancers

This study reports
the synthesis, characterization, and biological
evaluation of four novel heteronuclear Ru(II)–Cu(II) complexes
with phosphine–fluoroquinolone conjugates. Structural analysis
using X-ray diffraction, density functional theory calculations, and
various spectroscopic techniques confirmed the stability and coordination
geometries. The cytotoxicity was evaluated in vitro across multiple
cancer cell lines (lung, breast, pancreatic, prostate) and noncancerous
cells. In vivo toxicity was also assessed using a zebrafish (Danio rerio) larvae model. The results demonstrated
that Ru(II)–Cu(II) complexes exhibit greater anticancer activity
compared with cisplatin while almost being nontoxic toward control
cells in vitro. Mechanistic studies revealed that their action involves
nuclei accumulation, reactive oxygen species generation, lipid peroxidation,
and mitochondrial membrane depolarization. The expression ratio of
Bax to Bcl-2 mRNA correlates with apoptotic cell death. Additionally,
encapsulation of the one Ru(II)–Cu(II) complex in bilosomes
significantly improved its stability, selectivity, and therapeutic
efficacy in three-dimensional (3D) cancer spheroid models.