Sustained release of fenofibrate for the treatment of diabetic retinopathy

非诺贝特缓释剂治疗糖尿病视网膜病变

基本信息

批准号：
10684823
负责人：
Jian-Xing Ma
金额：
$ 53.8万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684823
关键词：
Acute Address Agonist Animal Model Animals Blindness Blood Vessels Bolus Infusion Chronic Chronic Disease Clinical Clinical Research Clinical Treatment Clinical Trials Data Development Diabetic Retinopathy Dose Drug Delivery Systems Drug Kinetics Drug Targeting Dyslipidemias Endophthalmitis Extravasation Eye Fenofibrate Formulation Future Genes Half-Life Healthcare Systems Human In Vitro Inflammation Injections Insulin-Dependent Diabetes Mellitus Intercellular adhesion molecule 1 Interleukin-6 Ischemia Kidney Failure Knock-out Lead Leukostasis Lipids Maximum Tolerated Dose Medical Methods Mitochondria Modeling Monitor Morphology Non-Insulin-Dependent Diabetes Mellitus Oral Oral Administration Oryctolagus cuniculus PPAR alpha Particle Size Pathway interactions Patient Care Patients Pharmaceutical Preparations Pharmacotherapy Prevention Rattus Regulation Reporting Reproducibility Retina Retinal Neovascularization Risk Safety Streptozocin Testing Therapeutic Effect Toxic effect Treatment Efficacy Type 2 diabetic Vascular Endothelial Growth Factors Virulence Factors Vision absorption aging population angiogenesis clinical practice clinical translation compliance behavior cost db/db mouse diabetic diabetic patient diabetic rat drug standard efficacy testing improved in vivo inhibitor interest intravitreal injection lipid metabolism macular edema meter nanoparticle neovascularization new therapeutic target novel therapeutics oxidation particle preclinical development proliferative diabetic retinopathy randomized placebo-controlled clinical trial retinal toxicity safety study side effect

项目摘要

PROJECT SUMMARY Diabetic retinopathy (DR) is the most common cause of severe vision loss in the working-age population in the world. However, clinical studies have shown that approximately 40% DR patients do not adequately respond to anti-VEGF drugs. There is no drug treatment for those 40% DR patients. Furthermore, repeated bolus injections of these anti-VEGF agents are associated with risks of injection-associated side effects, and are a big burden to patients and the healthcare system. 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. Recently, we developed small-sized 200nm biodegradable nanoparticles containing 6% fenofibrate (Feno-NP) that demonstrated drug release for at least 8 weeks in the eye following an IVT injection, and have no detectable ocular toxicities. Our preliminary results further demonstrated that a single IVT injection of Feno-NP was effective on DR in the streptozotocin (STZ)-induced T1D rat model for 8 weeks. Here, our aim is to develop and optimize new longer-lasting large-sized fenofibrate- loaded microparticles (Feno-MP) 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. If successful, this approach would significantly improve DR patient care. In Aim 1, we will optimize and characterize reproducible large-sized Feno-MP formulations that release fenofibrate for ≥6 months, determine the maximum tolerated dose, and assess ocular pharmacokinetics (PK). The two most promising Feno-MP formulations 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. Finally, we will carry out detailed safety and ocular PK studies of one lead Feno-MP formulation in rabbits in Aim 3 to facilitate future development and potential clinical translation.

项目摘要糖尿病性视网膜病（DR）是造成工作年龄严重视力丧失的最常见原因世界上的人口。但是，临床研究表明，大约40％的DR患者没有对抗VEGF药物做出了充分的反应。这40％的DR患者没有药物治疗。此外，这些抗VEGF药物的重复注射剂与注射相关侧的风险有关效果，对患者和医疗保健系统造成了很大的烧伤。 fenofrate，一种过氧化物组增殖物 - 活化受体-α（PPARα）激动剂是临床证明的第一种低成本和安全的口服药物糖尿病患者中残留的新生血管化和糖尿病黄斑水肿的功效。但是，口头非诺贝特的半衰期短，残留滥用差。需要眼睛的佛经元授权输送博士的治疗非诺贝特无抗药物的玻璃体内注射（IVT）表现出短短的半衰期需要眼睛，并且经常需要注射非诺贝特以维持效果。我们建议一种新药提供持续的眼内非诺贝特的输送策略，以靶向非VEGF，PPARα途径和减少DR患者的治疗燃烧。最近，我们开发了小型200Nm生物降解含有6％fenobibrate（Feno-NP）的纳米颗粒，在该药物中释放了至少8周的药物注射IVT后眼睛，没有可检测的眼毒性。我们的初步结果证明Feno-NP的单个IVT注射对链蛋白酶（STZ）诱导的DR有效 T1D大鼠模型8周。在这里，我们的目的是开发和优化新的持久的大型大型纤维纤维 - 加载的微粒（FENO-MP），具有较高的药物负荷（≥20％），并具有致密的PEG涂层，并且可以单个IVT注射，安全有效地治疗DR，≥6个月。如果成功，这种方法将显着改善DR患者护理。在AIM 1中，我们将优化和表征可重复的大型 Feno-MP公式释放非诺贝型≥6个月，确定最大耐受剂量，并评估眼部药代动力学（PK）。然后将测试两个最有希望的Feno-MP公式剂量依赖性效率对STZ诱导的糖尿病大鼠的永久性血管泄漏和炎症（T1D） AIM 2中的模型）和DB/DB小鼠（T2D模型）。最后，我们将对 AIM 3中兔子中的一个铅feno-MP公式，以促进未来的发展和潜在的临床翻译。