Is lipophilicity the main factor determining the effective drug penetration through lipid membranes? Combined GIXD and PM-IRRAS studies on the example of anthracyclines

Abstract

Cell membranes constitute the first barrier for the drugs on their way to the cell. Therefore, their penetration determines the effectivity of the treatment and is defined by the drug-lipid interactions. A systematic, comprehensive study to assess the impact of different aspects influencing the effective penetration of model lipid membranes by the drugs including lipophilicity, charge, ability to form dimers as well as stearic hindrance was performed. Four anthracyclines differing in the structure and with lipophilicity increasing in the following order: doxorubicin (DOx) < pirarubicin (THP) < daunorubicin (DNR) < idarubicin (IDA) were chosen to assess their impact on 1,2-dimyristoyl-sn-glycero-3-phospho-L-serine (DMPS) monolayers mimicking cancer cell membranes. The investigation performed at the air–water interface involved the application of multiple surface-sensitive techniques to assess the drug interactions with both polar heads of the phospholipid and the penetration of the acyl chain region. The obtained results allowed us to state that although electrostatic interactions and lipophilicity of the drug are one of the key factors, the ability to form dimers as well as stearic hinderance may strongly prevent from the effective penetration of the phospholipid monolayers even for drugs with higher lipophilicity and therefore have to be also taken into account in the development of new therapeutic agents.