(235e) Nanogels for Ocular Drug Delivery to Treat Uveitis

Tacrolimus (FK506) is an immunosuppressive agent that has shown a strong immunosuppressive effect in a variety of animal models of transplantation and experimental autoimmune uveitis and uveoretinitis after systemic adminstration. However, it has limited ocular therapeutic effects due to its poor permeability across ocular biological barriers. The aim of this study is to develop degradable nanogels for enhancing the permeability of FK506 across ocular biological barriers to treat uveitis for a long period of time. In this work, a series of nanogels are synthesized in aqueous medium using UV photopolymerization under stirring. The nanogels are composed of N-isopropylacrylamide (NIPAAm) and 2-hydroxyl methacrylate-lactide-dextran macromer with different crosslinking, hydrophobicity, and charges. FK506 is loaded into the nanogels during the synthesis process. The size and morphology of the nanogels with/without FK506 are studied by dynamic light scattering (DLS) and atomic force microscopy (AFM). FTIR is used to study the interaction between FK506 and nanogels. The release kinetics of FK506 from the nanogels were measured and calculated. Cytotoxicity of the nanogels is evaluated by using human brain microvascular endothelial cells (HBMVEC) and MTT assay. The permeability of the DTAF-labeled nanogels across the cornea and the sclera ex vivo and in vivo is studied by using side-by-side diffusion cells, and New Zealand rabbits, respectively. The administration routes for the in vivo studies include intravitreal and subconjunctival injections and topical instillation. The ocular distributions of the nanogels in the cornea, lens, retina, and vitreous are also assessed 1 day after the administrations. The results demonstrate that the release kinetics of FK506 from the nanogels, the ex vivo and in vivo permeability of the nanogels across the cornea and the sclera, and the ocular pharmacokinetics of the nanogels strongly depend on the corsslinking, hydrophobicity and charge characteristics of the nanogels.