Diabetic retinopathy, a microvascular pathology of the retina, is a leading cause of blindness in the USA. Currently there are no approved pharmacological approaches to prevent or delay diabetic retinopathy. Growing evidence suggests that agents capable of inhibiting vascular endothelial growth factor (VEGF) will be beneficial in preventing or delaying diabetic retinopathy. VEGF is elevated in the vitreous and retinas of diabetic patients and experimental animal models. In experimental animal models, VEGF-neutralizing macromolecules have been shown to reduce retinal vascular leakage and retinal neovascularization, two key pathological changes contributing to the complication of diabetic retinopathy. The principal investigator has been investigating the use of small molecular weight drugs (e.g., aldose reductase inhibitors, corticosteroids, and non-steroid anti-inflammatory drugs) and novel delivery approaches (implants, biodegradable particles, and transcleral drug delivery to the retina) to inhibit retinal VEGF expression. The current proposal addresses the use of a novel molecular approach (inhibition of cycloxygenase-2, COX-2) and a novel retinal drug delivery approach (subconjunctival biodegradable microparticles) to suppress retinal VEGF expression and key vascular changes. Literature evidence suggests that COX-2 is upregulated in several inflammatory conditions including diabetes and neoplasms and that COX-2 inhibition can reduce tumor angiogenesis. In these tumor models, COX-2 inhibition is believed to reduce VEGF activity upstream, by inhibiting VEGF expression. The PI identified that celecoxib (M.Wt: 385), a selective cycloxygenase-2 inhibitor, can reduce retinal VEGF expression and vascular leakage following high dose multiple oral dosing. Also, he observed that the subconjunctival administration of low doses allows prolonged retinal delivery of celecoxib via the transscleral pathway. Based on these preliminary results, this study will test the hypothesis that single subconjunctival administration of celecoxib-poly (lactic-co-glycolic acid) (celecoxib-PLGA) microparticles to diabetic rats sustains drug delivery to the retina and suppresses early diabetic changes in a streptozotocinrat model. This hypothesis will be tested by addressing two specific aims - 1) To determine whether subconjunctivally administered celecoxib-PLGA particles sustain in vivo drug release for two months and maintain higher retinal drug levels in the ipsilateral eye compared to intramuscular administration and 2) To determine whether subconjunctival celecoxib-PLGA particles inhibit retinal COX-2 activity, VEGF expression, and vascular leakage in a diabetic rat model. Completion of these studies will provide a new pharmacological approach and framework for treating vascular changes associated with diabetic retinopathy. ? ?
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