Sustained release of fenofibrate for the treatment of diabetic retinopathy

项目摘要 糖尿病视网膜病变（diabetic retinopathy，DR）是工作年龄段严重视力丧失的最常见原因 世界人口。然而，临床研究表明，大约40%的DR患者没有 对抗VEGF药物有充分反应。对于这40%的DR患者没有药物治疗。此外，委员会认为， 反复推注这些抗VEGF药物与注射相关副作用的风险相关， 这对患者和医疗保健系统都是一个巨大的负担。非诺贝特一种过氧化物酶体增殖剂- 活化受体α（PPARα）激动剂，是第一个低成本和安全的口服药物， 对糖尿病患者视网膜新生血管和糖尿病性黄斑水肿的疗效。然而，口头 非诺贝特具有短的半衰期和差的视网膜吸收。眼部非诺贝特给药是必要的， 玻璃体内注射（IVT）非诺贝特游离药物显示药物的半衰期短， 眼睛和频繁的非诺贝特IVT注射需要维持效果。我们提出一种新药 提供持续眼内非诺贝特靶向非VEGF、PPARα途径的递送策略， 减轻DR患者的治疗负担。最近，我们开发了小尺寸的200 nm可生物降解 含有6%非诺贝特（Feno-NP）的纳米颗粒，其在体外实验中显示药物释放至少8周。 IVT注射后的眼睛，并且没有可检测到的眼睛毒性。我们的初步结果进一步 证明单次IVT注射Feno-NP对链脲佐菌素（STZ）诱导的DR有效。 T1 D大鼠模型8周。在这里，我们的目标是开发和优化新的更持久的大尺寸非诺贝特- 载药微粒（Feno-MP），具有更高的药物载量（≥20%），具有致密的PEG涂层， 单次IVT注射安全有效治疗DR ≥ 6个月。如果成功，这种方法将 显著改善DR患者护理。在目标1中，我们将优化和表征可重复的大尺寸 释放非诺贝特≥6个月的Feno-MP制剂，确定最大耐受剂量，以及 评估眼部药代动力学（PK）。然后将测试两种最有前途的Feno-MP制剂， 对STZ诱导的糖尿病大鼠（T1 D）中视网膜血管渗漏和炎症的剂量依赖性功效 模型）和目标2中的db/db小鼠（T2 D模型）。最后，我们将进行详细的安全性和眼部PK研究， 在目的3中，在家兔中使用一种先导Feno-MP制剂，以促进未来的开发和潜在的临床应用 翻译.

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.