Tailoring surface properties of liposomes for dexamethasone intraocular administration

Diseases of the posterior eye segment are often characterized by intraocular inflammation, which causes, in the long term, severe impairment of eye functions and, ultimately, vision loss. Aimed at enhancing the delivery of anti-inflammatory drugs to the posterior eye segment upon intravitreal administration, we developed liposomes with an engineered surface to control their diffusivity in the vitreous and retina association. Hydrogenated soybean phosphatidylcholine (HSPC)/cholesterol liposomes were coated with (agmatinyl)(6)-maltotriosyl-acetamido-N-(octadec-9-en-1-yl)hexanamide (Agm(6)-M-Oleate), a synthetic non-peptidic cell penetration enhancer (CPE), and/or 5% of mPEG(2kDa)-DSPE. The zeta potential of liposomes increased, and the mobility in bovine vitreous and colloidal stability decreased with the Agm(6)-M-Oleate coating concentration. Oppositely, mPEG(2kDa)-DSPE decreased the zeta potential of liposomes and restored both the diffusivity and the stability in vitreous. Liposomes with 5 mol% Agm(6)-M-Oleate coating were well tolerated by ARPE-19 retina cells either with or without mPEG(2kDa)-DSPE, while 10 mol% Agm(6)-M-Oleate showed cytotoxicity. Agm(6)-M-Oleate promoted the association of liposomes to ARPE-19 cells with respect to plain liposomes, while mPEG(2kDa)-DSPE slightly reduced the cell interaction. Dexamethasone hemisuccinate (DH) was remotely loaded into liposomes with a loading capacity of similar to 10 wt/wt%. Interestingly, mPEG(2kDa)-DSPE coating reduced the rate of DH release and enhanced the disposition of Agm(6)-M-Oleate coated liposomes in the ARPE-19 cell cytosol resulting in a more efficient anti-inflammatory effect. Finally, mPEG(2kDa)-DSPE enhanced the association of DH-loaded Agm(6)-M-Oleate coated liposomes to explanted rat retina, which reflected in higher viability of inner and outer nuclear layer cells.