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A.C. Amrite, N.P. S. Cheruvu, D.S. Dhanda, U.B. Kompella; Single Periocular Administration of Celecoxib–PLGA Microparticles Reduces Retinal PGE2 Secretion, VEGF Expression, and Vascular Leakage in Diabetic Rats . Invest. Ophthalmol. Vis. Sci. 2005;46(13):449.
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Purpose: We previously demonstrated that COX–2 is elevated in diabetic rat retinas; celecoxib (a COX–2 inhibitor) delivery to the retina is greater following periocular administration compared to systemic administration; and that microparticles are retained in the periocular space at the end of 2 months. The objective of this study was to determine the efficacy of celecoxib–poly(lactide–co–glycolide)(PLGA) microparticles in a diabetic rat model. Methods: Celecoxib–PLGA microparticles were prepared using a modified solvent evaporation technique. The particles were sterilized with 25 KGy of γ–irradiation. Diabetes was induced in male Sprague Dawley rats using intraperitoneal streptozotocin (60 mg/kg). The animals were divided into 5 groups: 1) normal, 2) diabetic, 3) normal + celecoxib microparticles, 4) diabetic + celecoxib microparticles, and 5) diabetic + placebo particles. After ensuring hyperglycemia, phosphate buffer saline (PBS) containing celecoxib–PLGA microparticles (750 µg of celecoxib), placebo microparticles, or PBS was administered to one eye by periocular (posterior subconjunctival) injection under anesthesia. Two months post–administration, the animals were sacrificed and the retinal PGE2 secretion, VEGF protein, and vascular leakage (measured as vitreous:plasma protein ratio) were estimated. Results: Microparticles (diameter – 1.14 ± 0.02 µm; 14.93 ± 0.21% of celecoxib) sustained in vitro drug release for 2–months. Sterilization did not affect the drug release. Diabetes elevated PGE2 secretion 3–fold, VEGF protein from 297 ± 86 to 498 ± 121 pg/mg protein, and vitreous:plasma protein ratio from 0.35 ± 0.07 to 1.09 ± 0.21. In diabetic rats, celecoxib–PLGA microparticles significantly reduced PGE2 secretion, VEGF concentration, and vascular leakage by 40, 50, and 40%, respectively. Neither the placebo treated eyes nor the contralateral eyes in celecoxib–PLGA microparticle treated rats showed significant effects. Celecoxib–PLGA microparticles did not exert any effects in normal rats. Conclusions: Single periocular administration of celecoxib–PLGA microparticles reduced diabetes induced retinal PGE2 secretion, retinal VEGF, and vascular leakage for at least two months. Since VEGF and PGE2 are implicated in the pathogenesis diabetic retinopathy, celecoxib–PLGA microparticles are of therapeutic value in diabetic retinopathy.
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