Understanding the molecular insights of marketed liposomal drugs using molecular dynamics simulations of reduced scale coarse-grained models.

The complexity of the internal structure of liposome remains insufficiently understood, posing challenges to the rational design and development of liposomal formulations. In this study, we employed coarse-grained molecular dynamics simulation to investigate the structural details of the commercially available nine liposomal formulations, with five passive loading systems (Arikayce Kit®, Visudyne®, Ambisome®, Mepact®, and Exparel®) and four active loading systems (Doxil®, Myocet®, Onivyde®, and Vyxeos®). In five passive loading liposome systems, protonation of drug molecules significantly reduces their binding to phospholipid membranes and even drastically alters the morphology and vesicle size in multivesicular liposomes. However, the orientation of drug molecules in lipid membranes is independent of protonation, with hydrophobic part inward and hydrophilic part outward. In four active loading systems, the presence of ions within the liposome cavity promotes the self-aggregation of drugs, thereby enhancing drug retention and release profiles. This study provided valuable molecular insights for marketed liposomes formulation.