Interactions of Cationic Diruthenium Trithiolato Complexes with Phospholipid Membranes Studied by NMR Spectroscopy

To apprehend the possible mechanisms involved in the cellular uptake and the membrane interactions of cytotoxic dinuclear p-cymene trithiolato ruthenium(II) complexes, the interactions of the complexes [(η⁶-p-MeC₆H₄Pr)₂Ru₂(R¹)₂(R²)]⁺ (R¹ = R² = SC₆H₄-m-Pr:1; R¹ = SC₆H₄-p-OMe, R² = SC₆H₄-p-OH:2; R¹ = SCH₂C₆H₄-p-OMe, R² = SC₆H₄-p-OH:3) with 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) vesicles and 1,2-dihexanoyl-sn-glycero-3-phosphocholine (DHPC) micelles were studied using nuclear magnetic resonance (NMR) spectroscopy. ¹H NMR, nuclear Overhauser effect (NOE), diffusion ordered spectroscopy (DOSY), and T₁ and T₂ relaxation data provided information on interactions between the complexes and the model membranes and on the submolecular localization of the complexes at the membrane interface. The results suggest that (a) the interaction takes place without new covalent adduct formation, (b) the cationic diruthenium complexes interact with DOPC head groups most likely involving electrostatic interactions while remaining structurally unchanged, (c) the changes indicating interactions are more pronounced for the most lipophilic complex 1, and (d) the diruthenium complexes remain at the exterior vesicle surface and are unlikely inserted between the phospholipid chains. The complexes also interact with micellar/free DHPC and seem to induce micellization or aggregation in solutions below critical micelle concentration (CMC). Our study suggests high affinity of the Ru complexes for the membrane surface that likely plays a key role in cellular uptake and possibly also in redistribution in mitochondria.