Doxorubicin Interaction with Lipid Monolayers Leads to Decreased Membrane Stiffness when Experiencing...

Area of Science:

• Biophysics
• Materials Science
• Pharmacology

Background:

• Cell membranes are crucial for cellular functions and drug interactions.
• Understanding drug interactions with membrane lipids is key to explaining drug efficacy and toxicity.
• Artificial membrane models provide a simplified system to study these interactions.

Purpose of the Study:

• To investigate the molecular mechanism of doxorubicin's interaction with key mammalian cell membrane lipids.
• To explore how doxorubicin affects the biophysical properties of lipid monolayers, focusing on cardiotoxicity.

Main Methods:

• Construction of artificial Langmuir single-lipid monolayers using dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylserine (DPPS), and sphingomyelin.
• Surface pressure measurements using a Langmuir trough to determine collapse pressure, minimum area per molecule, and maximum compression modulus (Cs^-1).
• Compression/expansion isotherm experiments to estimate viscoelastic properties and assess doxorubicin's effects on lipid monolayers.

Main Results:

• Doxorubicin intercalates into DPPS, sphingomyelin, and DPPE lipid monolayers, but not DPPC.
• Significant changes in the compression modulus (Cs^-1) were observed, with up to a 34% increase for DPPS.
• Doxorubicin reduced the dynamic viscoelasticity of DPPE and DPPS membranes by 43% and 23%, respectively, and decreased membrane stiffness.

Conclusions:

• Doxorubicin's intercalation into specific membrane lipids (DPPS, DPPE, sphingomyelin) causes structural distortion, reducing membrane stiffness and compressibility.
• These observed biophysical alterations in lipid monolayers offer a potential molecular explanation for doxorubicin's mechanism of action in cancer cells.
• The findings provide insights into doxorubicin's cardiotoxicity by highlighting its disruptive effects on membrane properties.