Which Liposomes to Bypass Multidrug Resistance? A Study of Doxorubicin-Loaded Vesicles

Abstract

Liposomes used as antitumoral drug carriers have recently been designated as potential tools to overcome multidrug resistance. In order to understand better the mechanism of such an effect, we have investigated the capacity of liposomes exhibiting a pH gradient to trap efficiently the antitumoral drug doxorubicin in conditions of high dilution such as those used for cell cultures treatment. A simple calculation described the transmembrane pH gradient and the thermodynamic equilibrium of the neutral form, on both sides of the membrane. It showed that liposomes, even efficiently loaded with doxorubicin in response to the pH gradient will lose most of their content upon dilution because of the neutral form physicochemical gradient. Using fluorescence properties of the drug, we found that liposomes made of egg yolk phosphatidylcholine (EPC), phosphatidyl serine (PS) and cholesterol in the ratio 10:1:4 rather closely fitted the situation predicted by the calculation and that the equilibrium state after dilution was reached within one hour. We also showed using liposomes made of dipalmitoyl phosphatidyl choline (DPPC) and cholesterol in the ratio 11:4 that the drastic leakage could be overcome by changing the physical state of the liposome membrane at 37°C.

Referring to the drug release characteristics of other colloidal systems having demonstrated significant capacitiy to oververcome doxorubicin resistance, we concluded that liposomes made of lipids in gel (Lβ or Lβ') state at 37°C could be interesting tools in MDR bypass because they very efficiently retain their content under high dilution conditions.