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N. P. Cheruvu, P. K. Malik, S. Sundaram, U. B. Kompella; Highly Permeable Prodrug of Celecoxib and Its Encapsulation in PLGA Nanoparticles for Enhanced Transscleral Drug Delivery to the Retina. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3195.
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To determine the sclera and sclera-choroid-RPE permeability and in vivo transscleral delivery of a novel prodrug of celecoxib and to further compare the transscleral retinal drug delivery from periocular PLGA nanoparticles containing celecoxib or its prodrug.
In vitro transport studies for celecoxib and its prodrug were performed for 6 hours using freshly excised bovine sclera and sclera-choroid-RPE. The cytotoxicity of the prodrug was assessed in ARPE-19 cells. Sprague Dawley rats were used to study the in vivo distribution of celecoxib and prodrug following periocular injection of plain drug or prodrug. Further, drug delivery from periocular PLGA nanoparticles containing drug or prodrug was also assessed. At 15 min following plain formulation and 7 days after nanopartilce dosing, the animals were euthanized, the eyes were enucleated and frozen, and the concentrations of celecoxib and the prodrug in the isolated retina were estimated using a HPLC assay.
Prodrug did not exert any cytotoxicity in ARPE-19 cells. The prodrug exhibited 4-fold higher scleral permeability and 40-fold higher sclera-choroid-RPE permeability compared to celecoxib. Periocular injection of the plain prodrug resulted in 7-fold higher effective (drug plus prodrug) retinal drug delivery compared to dosing with plain drug. Prodrug encapsulated PLGA nanoparticles resulted in 2-fold higher levels of celecoxib in the retina compared to celecoxib PLGA nanoparticles at the end of 1 week.
Chemical modifications to the drug are useful in enhancing transscleral drug delivery in vitro and in vivo. Encapsulation of permeable prodrug, in particulate systems enhances transscleral retinal drug delivery, while sustaining the same.
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