Therapeutic Effects of Fenofibrate Nano-Emulsion Eye Drops on Retinal Vascular Leakage and Neovascularization

SIMPLE SUMMARY: Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are the leading causes of blindness and lack non-invasive drug treatments. Macular edema and neovascularization are the key pathogenic features responsible for vision loss in AMD and DR. Clinical studies showed that fenofibrate, a PPARα agonist, has robust therapeutic effects on macular edema and retinal neovascularization after oral administration. However, the efficacy of oral fenofibrate remains to be improved, due to limited amounts of the drug delivered to the retina after systemic administration. To increase the drug availability in the retina, this study developed a novel nano-emulsion fenofibrate eye drop. Topical administration of the fenofibrate eye drop delivered significantly higher drug concentrations to the retina/vitreous, relative to the systemic administration. The fenofibrate eye drop alleviated retinal inflammation and vascular leakage in both DR and AMD models. Further, the fenofibrate eye drop also alleviated laser-induced choroidal neovascularization. These findings suggest that topical administration of the nano-emulsion-based eye drop of a PPARα agonist has potential to become a non-invasive therapeutic strategy for long-term treatment of DR and AMD. ABSTRACT: Macular edema caused by retinal vascular leakage and ocular neovascularization are the leading causes of severe vision loss in diabetic retinopathy (DR) and age-related macular degeneration (AMD) patients. Oral administration of fenofibrate, a PPARα agonist, has shown therapeutic effects on macular edema and retinal neovascularization in diabetic patients. To improve the drug delivery to the retina and its efficacy, we have developed a nano-emulsion-based fenofibrate eye drop formulation that delivered significantly higher amounts of the drug to the retina compared to the systemic administration, as measured by liquid chromatography–mass spectrometer (LC-MS). The fenofibrate eye drop decreased leukocytes adherent to retinal vasculature and attenuated overexpression of multiple inflammatory factors in the retina of very low-density lipoprotein receptor knockout (Vldlr(−/−)) mice, a model manifesting AMD phenotypes, and streptozotocin-induced diabetic rats. The fenofibrate eye drop also reduced retinal vascular leakage in these models. The laser-induced choroidal neovascularization was also alleviated by the fenofibrate eye drop. There were no detectable ocular toxicities associated with the fenofibrate eye drop treatment. These findings suggest that fenofibrate can be delivered efficiently to the retina through topical administration of the nano-emulsion eye drop, which has therapeutic potential for macular edema and neovascularization.