CONICET | Buscador de Institutos y Recursos Humanos

INTRODUCTION.During the development of different ocular pathologies, such as glaucoma and other retinopathies, oxidative stress becomes the main cause of cellular damage. In addition, in most of these cases, the antioxidant capacity of the cell is insufficient to protect the retinal ganglion cells (RGCs). Therefore, the exogenous administration of antioxidant agents is a promising strategy to inhibit some of the steps involved in the death of retinal cells. Related to this, it was observed that the injection by the intravitreal route of exogenous melatonin (ME) protects retinal ganglion cells from degeneration and apoptosis in different experimental models of retina. Therefore, novel drug delivery systems for topical applications has recently attracted great attention as it constitutes a non-invasive route of administration to deliver antioxidants to the posterior segment of the eye. We propose the development of a nanoparticulate based system able to reach the posterior segment of the eye aiming to exert neuroprotective effect on RGCs, such as polymeric nanocapsules (NC).These nanoparticles (NPs) of EC revealed mucoadhesive properties, permitting a close contact with the cornea surface, thereby facilitating its penetration.OBJETIVE.The objective of the present work was to prepare and characterize NC loaded with ME using ethyl cellulose (EC) as encapsulating polymer. These formulations were evaluated after the topical ophthalmic application in rabbits with previously induced retinal degeneration (RD) model, in terms of physicochemical characteristics, in vitro drug release, transcorneal permeation assay, in vivo study of irritation and antiapoptotic and neuroprotective effects of ME on RGCs.MATERIALS AND METHODS.NCECMEs 1 and 2 mg/mlwere prepared by interfacial deposition of preformed polymers. The formulations were characterized in terms of particle size, electrokinetic potential, pH, osmolarity, loading capacity and encapsulation efficiency.The particle structures of the NCECMEs were observed and analyzedby Field Emission Scanning Electron Microscopy (FE-SEM Σigma, Carl Zeiss).Invitro drug release and transcorneal permeation assaywere performedin a modified Franz diffusion assembly at 35.0 ± 0.5°Ccoupled with UV spectroscopy technique. The neuroprotective effect of ME was evaluated using the induced retinal degeneration (RD) modelcarried out by means of intravitreal administration in the rabbit eyes of a single dose of glutamate (GLUT) and L-Butionine-S, R-Sulfoximine (BSO).RESULTS. . The particle size of the NPs thus obtained (NCECME) ranged from 150 nm to 170 nm. The Polydispersity Index (PDI) was less than 0.120 and the measured electrokinetic potential was approximately -15 mV, with the encapsulation efficiency being approximately 60%. The pH of the aqueous dispersion was around 4-5 and the osmolality properties of the NCECME dispersions were very close to those of tears.In vitro ME release (1 and 2 mg/mL) from NCECMEs was found to be slower than ME solution. However, ex vivo assays demonstrated a higher permeation, attributable to the extended residence time of NCECMEs and ME effect on the membrane at low concentrations, leading to an increase in drug absorption. NCECMEs appeared to be more efficient for RGC protection, compared to ME solutions, against induced RD model, as indicated by damage indicators such as the apoptotic index (AI) and retina integrity.CONCLUSION.These findings add promising new perspectives to the current knowledge concerning the topical administration of neuroprotectors as melatonin for the treatment of retinal degeneration diseases and the use of nanoparticles of ethylcellulose as efficient carriers for drug delivery in the ocular area.Keywords: Melatonin, Oxidative stress, Retinal ganglion cells (RGCs), Neuroprotection, Topical application, Nanocapsules.

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