Retinal delivery of an aldose reductase inhibitor and a VEGF antisense oligonucleotide

Delivery of drugs to the retina is a challenge because of several barriers the drug has to cross before reaching the retina. Diabetic retinopathy is a retinal vascular disease affecting several retinal cells including retinal pigment epithelial cells. In this research project we investigated means to enhance the retinal pigment epithelial cellular delivery of BAPSG, an aldose reductase inhibitor (ARI) and a VEGF antisense oligonucleotide, potential agents for the treatment of diabetic retinopathy. The results of this project demonstrated that MRP, an anionic efflux protein, is expressed in RPE cells and the cellular accumulation of BAPSG, an organic anion, can be enhanced by co-treatment with MRP inhibitors. RPE cells form blood-retinal barrier and restrict the movement of molecules from systemic circulation to the retina. Since the accumulation of BAPSG into these cells was enhanced by co-treatment with MRP inhibitors, it is a likely approach to enhance the retinal delivery of BAPSG. Antisense oligonucleotides are charged macromolecules that exhibit low cellular uptake and efficacy in plain solution form. In this study, we investigated a nanoparticulate approach to enhance the activity of a VEGF antisense oligonucleotide. The in vitro activity of VEGF antisense oligonucleotide was increased when exposed as a nanoparticle formulation compared to a solution form, possibly due to enhanced delivery of the antisense oligonucleotide with the nanoparticle formulation.; Since diabetic retinopathy requires chronic therapy and because toxicity of ARIs can possibly be reduced using a sustained release delivery system, we also developed an injectable implant of BAPSG and investigated its performance in a galactose-fed rat model for diabetic retinopathy. After administering this implant in a galactose-fed diabetic rat, the implant sustained drug release in the plasma, with 44% of the drug released by the end of 18 days. The implant reduced galactitol levels, reduced glutathione depletion, and inhibited VEGF expression in the retinas of a galactose-fed rat, suggesting its in vivo efficacy in ameliorating biochemical changes associated with diabetes.