Behavior of Doxorubicin Lipophilic Conjugates in Liposomal Lipid Bilayers

Abstract

Preparation of liposomal formulations containing water-soluble drugs in the form of lipophilic prodrugs in their lipid bilayer is of considerable interest. Previously, we synthesized doxorubicin dioleoyl glyceride and oleoyl conjugates intended for incorporation into fluid-phase liposomal bilayers. In this work, we studied the behavior of lipid conjugates in bilayers prepared from palmitoyl oleoyl phosphatidylcholine and dimyristoyl phosphatidylcholine using methods of fluorescence spectroscopy and molecular modeling. The conjugates were shown to have limited mobility in lipid bilayers, which can be explained by the formation of hydrogen bonds between the doxorubicin aglycone and the lipid phosphate groups. In the liposome membrane, lipophilic conjugates also tend to form clusters through interaction of doxorubicin moieties. Oleoyl chains stretch in parallel to the acyl residues of phospholipids. Due to the formation of a larger number of hydrogen bonds, the oleoyl conjugates interacted with the bilayer more effectively than the dioleoyl glyceride counterparts. These properties of doxorubicin conjugates can affect both the possibility of their incorporation into the lipid bilayer (from the therapeutic effect point of view) and intracellular release of the antibiotic drug by means of enzymolysis.