A calorimetric evaluation of the interaction of amphiphilic prodrugs of idebenone with a biomembrane model

Lipoamino acids (LAA) are useful promoieties to modify physicochemical properties of drugs, namely lipophilicity and amphiphilicity. The resulting membrane-like character of drug–LAA conjugates can increase the absorption profile of drugs through cell membranes and biological barriers. To show the role of amphiphilicity with respect to lipophilicity in the interaction of drugs with biomembranes, in the present study we evaluated the mode of such an interaction of lipophilic conjugates of LAA with the antioxidant drug idebenone (IDE). DSC analysis and transfer kinetic studies were carried out using dimyristoylphosphatidylcholine (DMPC) multilamellar liposomes (MLVs) as a model. For comparison, two esters of IDE with alkanoic acids were synthesized and included in the analysis. The experimental results indicate that based on their different structure, IDE–LAA conjugates interacted at different levels with respect to pure IDE with DMPC bilayers. In particular, a progressive penetration inside the vesicles was observed upon incubation of IDE–LAA compounds with empty liposomes. The enhanced amphiphilicity of the drug due to the LAA moieties caused more complex interactions with DMPC bilayers, compared to those registered with the native drug or IDE alkanoate esters.

Graphical abstractThe lipophilic antioxidant drug idebenone was converted into amphiphilic prodrugs by means of conjugation with short-chain 2-alkylamino acids. DSC analysis and transfer kinetic studies were performed to evaluate their mode and entity of interaction with a biomembrane model (DMPC liposomes).Figure optionsDownload full-size imageDownload as PowerPoint slide