Electrochemical, spectroelectrochemical and molecular dynamics investigation of doxorubicin interactions with nucleolipid-containing floating lipid bilayer on gold electrodes.

Floating lipid bilayers (fBLMs) of 1,2-dipalmitoyl-sn-glycero-3-cytidine diphosphate: 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DG-CDP: DPPC) (7:3) assembled on β-D-thioglucose-modified Au electrodes were used as biomimetic systems to investigate, at the molecular level, the interaction of doxorubicin (DOX) with nucleolipid-containing membranes under electrochemical control. Pseudocapacitance and electrochemical impedance spectroscopy (EIS) reveal that the presence of DOX decreases membrane capacitance and increases defect resistance, indicating reduced ionic permeability. ATR-SEIRAS measurements show that DOX does not alter the acyl chain organization but interacts with the lipid polar heads, predominantly with cytidine moieties of nucleolipid units, adopting a preferential orientation at the membrane interface and showing negligible dependence on electrode potential. Complementary molecular dynamics simulations confirm that DOX is adsorbed at the polar region of the membrane and that DOX permeation across the non-polar region of the bilayer is hindered by a significant energy barrier, which decreases with temperature. Overall, these results provide mechanistic insight into DOX-membrane interactions in nucleolipid-containing model membranes, highlighting features that may contribute to limited drug release in related nanocarrier systems.