Clustering of Spin-labeled Drug Fenofibrate in a Lipid Raft-mimicking Bilayer

Abstract Lipid rafts are domains in biological membranes of relatively ordered (Lo) phase distributed in a relatively disordered (Ld) phase; sterols are an important component of lipid rafts. Fenofibrate is a hypolipidemic drug used to improve lipid profiles, particularly triglyceride and high-density lipoprotein-cholesterol levels. Interaction of fenofibrate with lipid rafts may be of particular interest. Here, spin-labeled analogue of fenofibrate (Feno-SL) in a raft-mimicking lipid bilayer was studied using EPR spectroscopy. The bilayers were formed by a mixture of dioleoyl-glycero-phosphocholine (DOPC), dipalmitoyl-glycero-phosphocholine (DPPC) and cholesterol (Chol). It is found that room-temperature EPR spectra depend only slightly on the presence of Chol, whereas for the frozen state at 200 K EPR spectra demonstrate a pronounced dependence on Chol content. The obtained results are explained by magnetic dipole and spin-exchange interactions occurring at low temperatures in dense clusters of Feno-SL molecules, which are assumed to be present in bilayers. The threshold Chol content at which clustering appears is close to its known value for a given lipid composition required for the formation of lipid rafts at physiological temperatures which suggests that the structure of lipid rafts during membrane freezing differs from the structure of their environment. The observed clustering highlights the important issue of drug accumulation and toxicity in domain-containing biological membranes.