Wanachat Chaiyasan

Mucoadhesive Chitosan–Dextran Sulfate Nanoparticles for Sustained Drug Delivery to the Ocular Surface

PURPOSE To characterize nanoparticles produced by self-assembly of oppositely charged polymers, cationic chitosan (CS), and anionic dextran sulfate (DS), for drug delivery to the ocular surface. The goal is to overcome the short residence time of topical drugs through their sustained release from mucoadhesive nanoparticles. METHODS Chitosan-dextran sulfate nanoparticles (CDNs) were produced by mixing CS and DS; polyethylene glycol-400 was used as a surface stabilizing agent. Fourier transform infrared spectroscopy (FTIR) spectra of CS, DS, and CDNs were determined in the wavenumber range of 4,000-700 cm(-1) to assess the ionic interactions in the formation of CDNs. The physicochemical properties, entrapment efficacy, and dissolution profile of CDNs were investigated using Rhodamine B (RhB) and Nile Red (NR) as drug analogs. The mucoadhesiveness of the CDNs was assessed by imaging the retention of the fluorescein isothiocyanate-labeled CDNs on the cornea ex vivo, which was subjected to shear stress by a steady stream of saline solution. RESULTS CDNs were obtained by the polyelectrolyte complexation technique. The FTIR spectra of CDNs showed spectral shifts in the amine and sulfate regions, confirming an involvement of electrostatic interactions between cationic CS and anionic DS. The CDNs were spherical in shape and segregated. They possessed a particle size of ~400 nm with a polydispersity index of 0.3 and exhibited a zeta potential of ~40 mV. A high entrapment efficacy of up to 80% was observed with both RhB and NR. In the dissolution experiments, NR was released from CDNs within 60 min, but RhB was not released. This indicates that the release of drugs could depend on their molecular interactions with the particle. Exposure of CDNs to lysozyme, which is found in tears, had no effect on the mean particle size or the surface charge. Instillation of NR, RhB, and FITC in the presence of saline irrigation resulted in their rapid disappearance (<5 min) from the corneal surface. In contrast, fluorescent CDNs showed retention on the cornea even after 60 min. CONCLUSIONS Cationic and biocompatible mucoadhesive CDNs have been developed for sustained drug delivery to the ocular surface. The CDNs were stable to lysozyme and showed prolonged adherence to the corneal surface.

Penetration of mucoadhesive chitosan-dextran sulfate nanoparticles into the porcine cornea

Topical application of drugs to the eyes suffers from poor bioavailability at the ocular surface and in the anterior chamber. This is due to rapid clearance of the drug because of tear secretion and outflow. This study has investigated mucoadhesive and penetration characteristics of chitosan-dextran sulfate nanoparticles (CDNs), prepared by polyelectrolyte complexation technique, following topical administration to the ocular surface. Topical FITC-labeled CDNs (FCDNs; mean size of 400nm and a surface charge of +48mV) were retained on the porcine ocular surface for more than 4h. Topical FCDNs were partially endocytosed into porcine corneal epithelial cells via a clathrin-dependent pathway. After 6h of topical FCDNs, particles accumulated in the corneal epithelium but not found in the corneal stroma. When epithelium was removed, FCDNs penetrated the stroma. Thus, CDNs are potentially useful for drug/gene delivery to the ocular surface and to stroma when epithelium is damaged.