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 (Agm6-M-Oleate), a synthetic non-peptidic cell penetration enhancer (CPE), and/or 5% of mPEG2kDa-DSPE. The zeta potential of liposomes increased, and the mobility in bovine vitreous and colloidal stability decreased with the Agm6-M-Oleate coating concentration. Oppositely, mPEG2kDa-DSPE decreased the zeta potential of liposomes and restored both the diffusivity and the stability in vitreous. Liposomes with 5 mol% Agm6-M-Oleate coating were well tolerated by ARPE-19 retina cells either with or without mPEG2kDa-DSPE, while 10 mol% Agm6-M-Oleate showed cytotoxicity. Agm6-M-Oleate promoted the association of liposomes to ARPE-19 cells with respect to plain liposomes, while mPEG2kDa-DSPE slightly reduced the cell interaction. Dexamethasone hemisuccinate (DH) was remotely loaded into liposomes with a loading capacity of ∼10 wt/wt%. Interestingly, mPEG2kDa-DSPE coating reduced the rate of DH release and enhanced the disposition of Agm6-M-Oleate coated liposomes in the ARPE-19 cell cytosol resulting in a more efficient anti-inflammatory effect. Finally, mPEG2kDa-DSPE enhanced the association of DH-loaded Agm6-M-Oleate coated liposomes to explanted rat retina, which reflected in higher viability of inner and outer nuclear layer cells.

Diffusion and Protein Corona Formation of Lipid-Based Nanoparticles in the Vitreous Humor: Profiling and Pharmacokinetic Considerations.

The vitreous humor is the first barrier encountered by intravitreally injected nanoparticles. Lipid-based nanoparticles in the vitreous are studied by evaluating their diffusion with single-particle tracking technology and by characterizing their protein coronae with surface plasmon resonance and high-resolution proteomics. Single-particle tracking results indicate that the vitreal mobility of the formulations is dependent on their charge. Anionic and neutral formulations are mobile, whereas larger (>200 nm) neutral particles have restricted diffusion, and cationic particles are immobilized in the vitreous. PEGylation increases the mobility of cationic and larger neutral formulations but does not affect anionic and smaller neutral particles. Convection has a significant role in the pharmacokinetics of nanoparticles, whereas diffusion drives the transport of antibodies. Surface plasmon resonance studies determine that the vitreal corona of anionic formulations is sparse. Proteomics data reveals 76 differentially abundant proteins, whose enrichment is specific to either the hard or the soft corona. PEGylation does not affect protein enrichment. This suggests that protein-specific rather than formulation-specific factors are drivers of protein adsorption on nanoparticles in the vitreous. In summary, our findings contribute to understanding the pharmacokinetics of nanoparticles in the vitreous and help advance the development of nanoparticle-based treatments for eye diseases.