Molecular Mechanism of Ultrasound-Induced Structural Defects in Liposomes: A Nonequilibrium Molecular Dynamics Simulation Study

The use of ultrasound in combination with liposomes is a promising approach to improve drug delivery. To achieve an optimal drug release rate, it is important to understand how ultrasound induces pathways on the liposome surface where drugs can be released from the liposome. To this end, we carry out large-scale ultrasound-induced molecular dynamics simulations for three single lipid component liposomes formed from the commonly used phospholipids: 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoylphosphatidylcholine (DPPC), or phosphatidylcholine (POPC). The results show that ultrasound induces the detachment of two leaflets of the DOPC surface, suggesting that the drug release pathway may be through the low lipid packing areas on the stretched surface. In contrast, ultrasound induces pore formation on the surface of DPPC and DOPC, where drugs could escape from the liposomes. While the leaflet detachment and transient pore formation are the mechanisms of DOPC and DPPC, respectively, in both liquid-ordered and liquid-disordered phases, the leaflet detachment mechanism is switched to the transient pore formation mechanism on going from the liquid-ordered phase to the liquid-disordered phase in the POPC liposome. By adding 30% mol cholesterol, the leaflet detachment mechanism is observed in all liposomes. We found that the molecular origin that determines a mechanism is the competition between the intraleaflet and interleaflet interacting energy of lipids. The connection to experimental and theoretical modeling is discussed in some detail.