Sustained release of fenofibrate for the treatment of diabetic retinopathy

PROJECT SUMMARY This application is for an NEI Diversity Supplement to a basic research (R01EY033477, Sustained release of fenofibrate for the treatment of diabetic retinopathy) funded by National Eye Institute, with the primary goal of training Julio Ocana-Ortiz, BS, a member of disadvantaged group, under the mentorship and guidance of Qingguo Xu, PhD and Jian-xing Ma, MD, PhD. Diabetic retinopathy (DR) is the most common cause of severe vision loss in the working-age population in the world. Fenofibrate, a peroxisome proliferator- activated receptor-α (PPARα) agonist, is the first low-cost and safe oral drug for DR with clinically proven efficacy against retinal neovascularization and diabetic macular edema in diabetic patients. However, oral fenofibrate has a short half-life and poor retinal absorption. An ocular fenofibrate delivery is needed for the treatment of DR. Intravitreal injection (IVT) of fenofibrate free drug demonstrated a short half-life of the drug in the eye, and frequent IVT injections of fenofibrate are needed to sustain the effect. We propose a new drug delivery strategy for providing sustained intraocular fenofibrate to target a non-VEGF, PPARα pathway and reducing the treatment burden from DR patients. In the parent R01 grant, our aim is to develop and optimize new longer-lasting large-sized fenofibrate-loaded microparticles via conventional homogenization method (Feno-MP (HM)) that have higher drug loadings (≥20%) with dense PEG coating, and can safely and effectively treat DR, for ≥ 6 months with a single IVT injection. Unlike the polydisperse Feno-MP (HM) prepared using homogenization method (HM), membrane emulsification method generated Feno-MP with uniform size distribution, which can exhibit more controllable drug loading and drug release (particle size can greatly influence drug loading and drug release profiles). By controlling the membrane pore size, uniform sized Feno- MP at 1.5 µm, 8 µm and 16 µm diameters were formulated via the membrane emulsion method and they exhibit high drug loading and controlled drug release profiles in vitro. Thus, in this supplement we propose to prepare the uniform-sized Feno-MP via the membrane emulsification method, and determine the maximum tolerated dose, and assess ocular pharmacokinetics (PK) in rats in Aim 1. The most promising uniform sized Feno-MP will then be tested for dose dependent efficacy on retinal vascular leakage and inflammation in STZ- induced diabetic rats (T1D model) and db/db mice (T2D model) in Aim 2. Julio will be trained in the areas of microparticle formulation development and characterization, in vitro drug release testing, ocular PK, animal models of DR, and in vivo efficacy studies including the retinal vascular leakage and inflammation. As a PhD student from a disadvantaged background, Julio will receive career development mentoring in ocular drug delivery, PK, DR pathophysiology, will publish first-author abstracts and manuscript, and will form key preliminary data for future NIH F31, K99/R00 applications under this supplement.