Release of liposomes from hyaluronic acid-based hybrid systems: effects of liposome surface and size

Mixtures of hyaluronic acid (HA, in the semi-dilute entangled regime) with liposomes (high lipid concentration) exhibit a great interest in drug delivery. Considering the difference of microstructures when varying the liposome surface, we aimed to determine if liposome characteristics (surface and size) also influenced their release from these hybrid systems and to explore the mechanisms involved. Small-angle neutron scattering, cryogenic electron microscopy, zetametry, and dynamic light scattering were used to characterize liposomes. The implemented Transwell® model (two compartments separated by a polycarbonate membrane) showed that both size and surface governed liposome release. At 150 nm, anionic liposomes with or without poly(ethylene glycol) chains (PEG) migrated from HA-liposome mixtures, while cationic and neutral ones did not. Furthermore, increasing the size of PEGylated liposomes up to 200 nm or more strongly hindered their migration. Below 200 nm, the smaller the liposome size, the faster the release. Multiple and complex mechanisms (interactions between HA and liposomes, water exchanges, liposome migration, swelling and erosion, and HA reptation) were involved. Their relative importance depended on liposome characteristics. The Transwell® model is a pertinent tool to assess in vitro the release of liposomes over several weeks and discriminate the formulations, depending on the foreseen therapeutic strategy.