Long-acting fenofibrate-loaded microparticles for treating retinal disorders

Abstract

Age-related macular degeneration (AMD) and Diabetic retinopathy (DR) are the most common forms of retinal disorders and are the leading causes of vision loss. Traditional treatments such as anti-VEGF therapies often require repeated intravitreal injections. Up to 40 % DR/AMD patients do not adequately respond to the anti-VEGF therapies. Therefore, non-VEGF therapies with alternative mechanisms are needed to address these unmet clinical needs. Fenofibrate (an FDA-approved low-cost oral drug) is a peroxisome proliferator-activated receptor-α (PPARα) agonist. We developed large-sized fenofibrate-loaded biodegradable microparticles capable of achieving high drug loading (up to 25 wt%) and sustained in vitro release exceeding six months (larger particles that load more drug and last longer). These long-acting Feno-MP exhibited desired particle size suitable for intravitreal injection (IVT) through fine gauge needles. The lead Feno-MP-F6 maintained sustained drug levels in the retina for at least 6 months following a single intravitreal injection without obvious toxic issues in rats and rabbits. This study investigated a 6-month-long therapeutic effects of a single dose of fenofibrate-loaded microparticles (Feno-MP) via a non-VEGF, PPARα-dependent mechanism in streptozotocin (STZ)-induced diabetic rats (a DR model), Vldlr^-/- mice (a wet-AMD model), and Abca4^-/-/Rdh8^-/- mice (a dry-AMD model). Comprehensive analyses revealed broad therapeutic benefits across all the three disease models. In the STZ-induced DR model, one single IVT dose of Feno-MP restored both photopic and scotopic electroretinogram (ERG) responses, decreased leukostasis, and enhanced blood-retinal barrier function over a period of 6 months. In Vldlr^-/- mice, a wet-AMD model, Feno-MP effectively reduced both subretinal and intraretinal neovascularization and decreased retinal vascular leakage for at least 6 months. In Abca4^-/-/Rdh8^-/- mice, single Feno-MP treatment preserved photoreceptors, increased cone photoreceptors survival and improved mitochondrial function up to 6 months. Our study showed that Feno-MP may become a promising therapy for DR, wet-AMD and even dry-AMD with only 1-2 IVT injections/year. This work represents the approach to repurpose the oral drug fenofibrate for long-lasting intraocular delivery through a sustained release system.

Keywords: Age-related macular degeneration; Diabetic retinopathy; Intravitreal injection; Ocular drug delivery; PLGA; PPARα agonist.