Multidrug resistance modulator interactions with neutral and anionic liposomes: membrane binding affinity and
Madeleine Castaing1, Alain Loiseau, Guillermo Mulliert
1GERCTOP-UMR 6178, 27 Boulevard Jean Moulin, Faculté de Pharmacie, 13385 Marseille Cedex 05, France. gerctop@pharmacie.univ-mrs.fr
Abstract:
A variety of cationic lipophilic compounds (modulators) have been found to reverse the multidrug resistance of cancer cells. In order to determine the membrane perturbing efficacy and the binding affinity of such drugs in neutral and anionic liposomes, the leakage of Sulfan blue induced by five modulators bearing different electric charges was quantified using liposomes with and without phosphatidic acid (xEPA=0 and 0.1), at four lipid concentrations. The binding isotherms were drawn up using the indirect method based on the dependency of the leakage rate on the modulator and the lipid concentrations. Upon inclusion of negatively charged lipids in the liposomes: (i) the binding of cationic drugs was favoured, except in a case where modulator aggregation occurred in the lipid phase; (ii) the drugs with a net electric charge greater than 1.1 displayed a greater enhancement in their potency to produce membrane perturbation; and (iii) the EPA effect on membrane permeation was due mainly to that on membrane perturbation (>or=50%) and, to a lesser extent, to that on the binding affinity (
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