Molecular Dynamics simulations of Doxorubicin in sphingomyelin-based lipid membranes

TL;DR

This study uses molecular dynamics simulations to analyze how Doxorubicin interacts with and penetrates sphingomyelin-based lipid membranes, revealing how membrane composition influences drug partitioning and penetration.

Contribution

It provides atomic-level insights into Doxorubicin's membrane interactions, highlighting the impact of lipid composition on drug penetration and partitioning in sphingomyelin-based membranes.

Findings

Doxorubicin penetration is easier into less tightly packed membranes.

Partitioning of Doxorubicin depends on lipid composition.

Membrane packing influences drug-membrane interaction efficiency.

Abstract

Doxorubicin (DOX) is one of the most efficient antitumor drugs employed in numerous cancer therapies. Its incorporation into lipid-based nanocarriers, such as liposomes, improves the drug targeting into tumor cells and reduces drug side effects. The carriers' lipid composition is expected to affect the interactions of DOX and its partitioning into liposomal membranes. To get a rational insight into this aspect and determine promising lipid compositions, we use numerical simulations, which provide unique information on DOX-membrane interactions at the atomic level of resolution. In particular, we combine classical molecular dynamics simulations and free energy calculations to elucidate the mechanism of penetration of a protonated Doxorubicin molecule (DOX+) into potential liposome membranes, here modeled as lipid bilayers based on mixtures of phosphatidylcholine (PC), sphingomyelin (SM) and cholesterol lipid molecules, of different compositions and lipid phases. Moreover, we analyze DOX+ partitioning into relevant regions of SM-based lipid bilayer systems using a combination of free energy methods. Our results show that DOX+ penetration and partitioning are facilitated into less tightly packed SM-based membranes and are dependent on lipid composition. This work paves the way to further investigations of optimal formulations for lipid-based carriers, such as those associated with pH-responsive membranes.