Mechanism of cytotoxicity and cellular uptake of lipophilic inert dinuclear polypyridylruthenium(II) complexes

The accumulation, uptake mechanism, cytotoxicity, cellular localisation of-and mode of cell death induced by-dinuclear ruthenium(II) complexes ΔΔ/ΛΛ-[{Ru(phen) ₂ } ₂ {μ-bb _n }] ⁴⁺ (Rubb _n ), where phen is 1,10-phenanthroline, bb _n is bis[4(4'-methyl-2,2'-bipyridyl)]-1,n-alkane (n=2, 5, 7, 10, 12 or 16), and the corresponding mononuclear complexes containing the bb _n ligands, were studied in L1210 murine leukaemia cells. Cytotoxicity increased with linker chain length, and the ΔΔ-Rubb ₁₆ complex displayed the highest cytotoxicity of the series, with an IC ₅₀ value of 5μM, similar to that of carboplatin in the L1210 murine leukaemia cell line. Confocal microscopy and flow cytometry studies indicated that the complexes accumulate in the mitochondria of L1210 cells, with the magnitude of cellular uptake and accumulation increasing with linking chain length in the bb _n bridge of the metal complex. ΔΔ-Rubb ₁₆ entered the L1210 cells by passive diffusion (with a minor contribution from protein-mediated active transport), inducing cell death via apoptosis. Additionally, metal-complex uptake in leukaemia cells was approximately 16-times that observed in healthy Bcells highlighting that the bb _n series of complexes may have potential as selective anticancer drugs. Quick on the uptake! Inert dinuclear polypyridylruthenium complexes with ligand bridges containing long alkyl chains exhibit high cellular uptake in L1210 cells, selectively accumulating in the mitochondria and inducing cell death by apoptosis. These novel complexes have potential applications as cancer therapeutics.