Liposomes as a Model for the Biological Membrane: Studies on Daunorubicin Bilayer Interaction

Carla Matos,Carla Moutinho,Paulo Lobão

doi:10.1007/s00232-011-9414-2

Abstract

In this study the interaction of the antitumoral drug daunorubicin with egg phosphatidylcholine (EPC) liposomes, used as a cell membrane model, was quantified by determination of the partition coefficient (K(p)). The liposome/aqueous-phase K(p) of daunorubicin was determined by derivative spectrophotometry and measurement of the zeta-potential. Mathematical models were used to fit the experimental data, enabling determination of K(p). In the partition of daunorubicin within the membrane both superficial electrostatic and inner hydrophobic interactions seem to be involved. The results are affected by the two types of interaction since spectrophotometry measures mainly hydrophobic interactions, while zeta-potential is affected by both interpenetration of amphiphilic charged molecules in the bilayer and superficial electrostatic interaction. Moreover, the degree of the partition of daunorubicin with the membrane changes with the drug concentration, due mainly to saturation factors. Derivative spectrophotometry and zeta-potential variation results, together with the broad range of concentrations studied, revealed the different types of interactions involved. The mathematical formalism applied also allowed quantification of the number of lipid molecules associated with one drug molecule.

Highlights

Biological membranes act as a physiological barrier for a drug in its path to reach the site of action
The results are affected by the two types of interaction since spectrophotometry measures mainly hydrophobic interactions, while zeta-potential is affected by both interpenetration of amphiphilic charged molecules in the bilayer and superficial electrostatic interaction
We studied the interaction of the antitumoral drug daunorubicin with the membrane of unilamellar liposomes composed of phosphatidylcholine

Summary

Introduction

Biological membranes act as a physiological barrier for a drug in its path to reach the site of action. The diffusion (through the phospholipidic cell membrane) is a key step in the absorption and distribution of a drug as well as, its action in the organism. Even in cases where a specific transporter is involved, the drug’s ability to interact with the membrane is often highly correlated with the velocity or extent of the transportation. This ability depends on the drug’s hydrophilic/lipophilic equilibrium, which can be quantitatively expressed as a partition coefficient. The n-octanol/water partition coefficient (KO/W) has been correlated with the hydrophobicity of drugs since the studies of Hansch and coworkers in the 1970s (Leo et al 1971; Hansch and Dunn 1972). The n-octanol/water system, is only an approximation of the actual environment found in the interface between the cellular membranes and extracellular/intracellular fluids since it is an isotropic environment

Results

Discussion

Conclusion