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Subconjunctival Nano- and Microparticles Sustain Retinal Delivery of Budesonide, a Corticosteroid Capable of Inhibiting VEGF Expression

¹From the Departments of Pharmaceutical Sciences and ²Ophthalmology, University of Nebraska Medical Center, Omaha, Nebraska.

PURPOSE. The purpose of this study was to determine whether budesonide inhibits expression of vascular endothelial growth factor (VEGF) in a retinal pigment epithelial cell line (ARPE-19) and to determine whether subconjunctivally administered budesonide nano- and microparticles sustain retinal drug levels.

METHODS. The effect of budesonide (100 pM to 10 µM) on VEGF secretion, expression of VEGF mRNA, and cytotoxicity were determined in ARPE-19 cells by ELISA, RT-PCR, and a cell-viability assay, respectively. To determine the involvement of glucocorticoid receptor in the observed effects of budesonide, secretion and mRNA expression studies were also performed in the presence of a glucocorticoid receptor antagonist (RU486). DL-Polylactide (PLA) nano- and microparticles containing budesonide were prepared by a solvent evaporation technique, and the particles were characterized for size, morphology, encapsulation efficiency, and in vitro release. Budesonide-PLA nano- and microparticles were administered subconjunctivally to one eye of Sprague-Dawley rats and drug levels in the retina, vitreous, lens, and cornea of both eyes were determined at the end of 1, 7, and 14 days.

RESULTS. At concentrations devoid of cytotoxicity, budesonide inhibited VEGF secretion as well as mRNA expression in ARPE-19 cells in a dose-dependent manner. RU486 treatment prevented budesonide-mediated inhibition of VEGF secretion and VEGF mRNA expression. Budesonide-PLA nano- (345 nm) and microparticles (3.6 µm), with an encapsulation efficiency of 65% and 99%, respectively, sustained budesonide release in vitro. After subconjunctival administration, both budesonide-PLA nano- and microparticles produced sustained budesonide levels in the retina and other ocular tissues.

CONCLUSIONS. Budesonide is capable of inhibiting VEGF expression through glucocorticoid receptor activity. Subconjunctivally administered budesonide-PLA nano- and microparticles sustain retinal drug delivery.

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