Multidrug resistance modulator interactions with neutral and anionic liposomes: membrane binding affinity and...

Area of Science:

• Biochemistry
• Pharmacology
• Materials Science

Background:

• Multidrug resistance (MDR) in cancer is a significant clinical challenge.
• Cationic lipophilic compounds show potential in reversing MDR.
• Understanding drug-membrane interactions is crucial for optimizing MDR reversal strategies.

Purpose of the Study:

• To investigate the membrane perturbing efficacy and binding affinity of cationic modulators in neutral and anionic liposomes.
• To quantify the effect of negatively charged lipids (phosphatidic acid) on drug-membrane interactions.
• To elucidate the relationship between modulator charge, lipid composition, and membrane permeation.

Main Methods:

• Liposomes with varying phosphatidic acid content (xEPA=0 and 0.1) were prepared.
• Sulfan blue leakage assay was used to measure membrane perturbation induced by five cationic modulators.
• Binding isotherms were determined indirectly via modulator and lipid concentration-dependent leakage rates.
• Lipid concentrations were varied across four levels.

Main Results:

• Inclusion of anionic lipids (phosphatidic acid) generally enhanced the binding of cationic drugs, except when modulator aggregation occurred.
• Modulators with a net electric charge >1.1 showed significantly increased potency in membrane perturbation.
• Phosphatidic acid primarily enhanced membrane permeation through increased membrane perturbation (>50%) and secondarily through binding affinity (<50%).

Conclusions:

• Drug-membrane interactions are complex, influenced by both drug structure/charge and membrane composition.
• Anionic lipids in liposomes can improve the efficacy of cationic modulators in reversing multidrug resistance.
• This study provides insights into optimizing drug delivery systems for enhanced cancer therapy.