(T1430-07-41) Fenofibrate Microparticles for Long Lasting Therapy of Posterior Eye Disease

Purpose: Fenofibrate is a peroxisome proliferator-activated receptor α (PPARα) agonist with proven therapeutic effects on age related macular degeneration (AMD) [1,2,3]. However, the therapeutic effects of fenofibrate via systemic administration are limited due to inefficient drug delivery to the retina. In this study, we aim to explore the long-lasting therapeutic effects of fenofibrate-loaded microparticles with high drug loading and sustained drug release on age-related macular degeneration (AMD). The efficacy of the lead Feno-MP was evaluated in a murine model of AMD over 6 months with a single intravitreal (IVT) injection.

Methods: Feno-MP was formulated using solvent evaporation emulsification method. Fenofibrate microparticles were optimized using different molecular weights of poly(lactic-co-glycolic acid (PLGA) polymers. The lead fenofibrate loaded PLGA_54k/PLGA_45k-PEG_5k microparticle (Feno-MP) was fully characterized on particle size, surface charge, particle morphology, drug loading, in vitro drug release, and ocular pharmacokinetics. The efficacy of one single IVT injection of  Feno-MP (30 µg Fenofibrate) and blank microparticles (Blank-MP) (125 µg MP) in 1 µL aqueous suspension was evaluated in very low-density lipoprotein receptor gene knockout (Vldlr ^-/- ) mice. Six months post injection, therapeutic effects were evaluated using electroretinography (ERG), peanut agglutinin lectin staining of cone photoreceptors , neovascular lesions, retinal neovascularization and vascular leakage area.

Results: A single IVT injection of Feno-MP provides sustained release of fenofibrate under in-vitro conditions and in the vitreo-retina tissues for 6 months. Single IVT injection of Feno-MP prevented the decline of cone ERG response in Vldlr ^-/- mice (n =5, p < 0.01). The photopic a-wave amplitudes in the Feno-MP group were 16.28%,30.87% and 20.34% higher than those of the Blank-MP group at 1,3- and 5-months post-injection, respectively. In addition, the decreased density of cone photoreceptors in both the central and peripheral retinas were alleviated by Feno-MP treatment (n = 5, p< 0.05). Feno-MP treated mice exhibited significantly fewer retinal leakage spots and decreased leakage spot area relative to the Blank-MP (n = 4, p< 0.05) as shown by FFA. With isolectin-stained flat-mounted RPE/choroid and retina, the number of subretinal neovascularization (SRNV) was decreased from 15.2±0.41 per eye in the Blank-MP group to 10.1 ±1.47 in the Feno-MP group (n = 5, p< 0.01), and the number of intraretinal neovascularization (IRNV) was significantly decreased from 25.6±2.29 per eye in the Blank-MP group to 15.2±1.24 per eye in the Feno-MP group (n = 5, p< 0.01).

Conclusion: A single IVT injection of Feno-MP protected retinal photoreceptor cells, ameliorated vascular leakage and retinal neovascularization in Vldlr ^-/- mice for 6 months, suggesting their sustained therapeutic potential for AMD.

References: 1. Qiu F, Meng T, Chen Q, Zhou K, Shao Y, Matlock G, Ma X, Wu W, Du Y, Wang X, Deng G, Ma JX, Xu Q. Fenofibrate-Loaded Biodegradable Nanoparticles for the Treatment of Experimental Diabetic Retinopathy and Neovascular Age-Related Macular Degeneration. Mol Pharm. 2019 May 6;16(5):1958-1970.
2. Ma J, Qiu F, Meng T, Xu Q, PPARα agonist compositions and methods of use, Granted Patent #, US 11369575B2, June 28, 2022.
3. Chen Y, Hu Y, Lin M, et al. Therapeutic effects of PPARα agonists on diabetic retinopathy in type 1 diabetes models. Diabetes. 2013;62(1):261-272

Acknowledgements: This project was supported by National Institutes of Health R01EY033477 and VCU commercialization fund.