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Jesus Alvarez-Trabado, Antonio López-García, Alejandro Sánchez, Yolanda Diebold; Sorbitan ester nanoparticles (SENS) as topical ocular cyclosporine delivery systems. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4116.
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© ARVO (1962-2015); The Authors (2016-present)
Cyclosporine-loaded sorbitan ester nanoparticles (SENS) were developed as a topical ocular delivery system. Our aim was to optimize the formulation by response surface methodology and to in vitro analyze its biocompatibility and cell uptake mechanisms in corneal epithelial cells.
Formulations of cyclosporine-loaded sorbitan ester nanoparticles (SENS) were prepared according the experimental matrix generated by a 3-factor, 3-level Box-Behnken statistical design. Particle size, zeta potential, encapsulation efficiency, and final drug loading were the dependent variables to optimize. The ratio of the nanoparticle components (Sorbitan monooleate (span 80), vitamin E TPGS, CTAB) and the cyclosporine were the independent variables under study. According to the statistical design outcomes, a cationic optimized formulation (SENS-O) was selected for further studies. Additionally, an anionic formulation was prepared by coating the SENS-O with hyaluronic acid (SENS-O-HA). Human corneal epithelial (HCE) cells were used to in vitro study the biocompatibility and cellular uptake of both nanosystems. The biocompatibility was evaluated using the XTT cytotoxicity test and the alamarBlue cell proliferation assay. Different cell uptake mechanisms were studied analyzing different internalization pathways.
Both SENS-O and SENS-O-HA showed adequate physicochemical properties for topical ocular administration. Encapsulation efficiency and drug loading were 83.95% and 15.98%, respectively. In vitro studies with HCE cells revealed a good biocompatibility profile of both formulations, with cell viability percentage close to 80% up to 4 mg/mL of nanoparticles (equivalent to a final cyclosporine concentration of 0.1%). Both nanosystems were taken up by an active transport mechanism. The predominant internalization pathway was caveolin-dependent endocytosis; however, an additional CD44 HA receptor-dependent uptake mechanism for SENS-O-HA was identified.
We have successfully developed and optimized a novel type of patented SENS for topical ocular drug delivery. Taking into account the in vitro results, cyclosporine-loaded SENS can be considered as a safe and promising formulation for the management of inflammatory ocular surface diseases.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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