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

• 批准号: 10521702
• 负责人: Jian-Xing Ma
• 金额: $ 55.18万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 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/10521702
• 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; Oral; Oral Administration; Oryctolagus cuniculus; PPAR alpha; Particle Size; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Pharmacotherapy; Placebo Control; Prevention; Randomized Clinical Trials; 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; mouse model; nanoparticle; neovascularization; new therapeutic target; novel therapeutics; oxidation; particle; preclinical development; proliferative diabetic retinopathy; safety study; side effect; type I diabetic

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.

项目总结 糖尿病视网膜病变(DR)是导致工作年龄严重视力丧失的最常见原因 世界上最大的人口。然而，临床研究表明，大约40%的DR患者没有 对抗血管内皮生长因子药物有充分的反应。这40%的DR患者没有药物治疗。此外， 重复注射这些抗血管内皮生长因子药物与注射相关侧的风险相关 影响，对患者和医疗系统来说是一个巨大的负担。非诺贝特，一种过氧化物酶增殖剂- 活化的受体-α(PPARα)激动剂是第一个经过临床验证的治疗DR的低成本、安全的口服药物 对糖尿病患者视网膜新生血管和糖尿病黄斑水肿的疗效。然而，口头的 非诺贝特的半衰期短，视网膜吸收差。眼部注射非诺贝特是必要的 非诺贝特非诺贝特玻璃体内注射(IVT)的治疗显示该药在 为了维持这种效果，需要经常静脉注射非诺贝特来维持这种效果。我们提出了一种新药 提供持续眼内非诺贝特靶向非血管内皮生长因子，PPARα途径和 减轻DR患者的治疗负担。最近，我们开发了小型200 nm可生物降解材料 含有6%非诺贝特的纳米粒(FeNO-NP)显示药物在体内至少释放了8周 静脉注射后的眼睛，没有可检测到的眼部毒性。我们的初步结果进一步 单次静脉注射FeNO-NP对链脲佐菌素(STZ)诱导的糖尿病视网膜病变有效 T1D模型大鼠8周。在这里，我们的目标是开发和优化新的更持久的大剂量非诺贝特- 载药量较高的微粒(FeNO-MP)(≥20%)，具有致密的聚乙二醇涂层，并且可以 一次静脉注射安全有效地治疗≥6个月的DR。如果成功，这种方法将 显著改善DR患者的护理。在目标1中，我们将优化和表征可复制的大尺寸 释放非诺贝特6个月的FeNO-MP制剂，确定最大耐受量，以及 评价眼部药代动力学(PK)。然后将对两种最有希望的FeNO-MP配方进行测试 STZ诱导的糖尿病大鼠(T1D)视网膜血管渗漏和炎症反应的剂量效应 模型)和db/db小鼠(T2D模型)。最后，我们将进行详细的安全性和眼部PK研究 目标3中兔体内的一种先导FeNO-MP配方，以促进未来的发展和潜在的临床应用 翻译。