THE INTERACTION OF DAUNOMYCIN WITH MODEL MEMBRANES - EFFECT OF THE LIPID PHYSICAL STATE AND THE LIPID-COMPOSITION

The sensitivity of the keto and carbonyl infrared bands of daunomycin (DNM) to hydrogen bonding with the solvent, has been used to study the effect of the physical state and lipid composition of the bilayer on drug location. Our results show that penetration of daunomycin into dihexadecylphosphatidylcholine (Hxd2GroPCho) or dipalmitoylphosphatidylcholine bilayers, is dependent on the molecular packing of the lipid. DNM incorporates into the bilayer once the interdigitation of the gel phase of Hxd2GroPCho has been removed, above the pretransition temperature. Melting of the hydrocarbon chains of both lipids, at the main transition temperature, allows a similar and deeper drug penetration into the bilayers. Experiments using liposomes with different lipid compositions suggest that the relative concentration of certain lipids may modulate the location of DNM within the bilayer. Cholesterol, in a concentration-dependent manner, inhibits incorporation of anthracycline into apolar regions of the bilayer, while the presence of the negatively charged lipid dihexadecylphosphatidic acid is able to prevent the inhibitory effect of the steroid, allowing deeper penetration of the drug. Due to the importance of drug-membrane interactions in anthracycline cytotoxicity, the relevance of the observed differences in daunomycin location, caused by physical and/or chemical changes in the biological membranes, is discussed.