Co-Delivery Dose-Controllable Implants for Advanced Chronic Eye Disease Treatment

项目摘要/摘要 慢性后眼病，如糖尿病黄斑水肿(DME)、黄斑水肿(ME)由 视网膜静脉阻塞、湿性老年性黄斑变性(湿性AMD)和非传染性后葡萄膜炎 (NU)，与高比率不可逆转的视力损失有关。二甲醚、甲醚和湿气的现行护理标准 AMD是每月玻璃体内注射抗血管内皮生长因子(VEGF)单抗， 贝伐单抗(Bev)，或片段，ranibizumab(RAN)。此外，因为这些疾病是 以炎症和纤维化为特征，每2~6个月玻璃体内注射一次皮质类固醇是 治疗DME、ME和NU的主要药物。近年来，玻璃体腔内抗血管内皮生长因子和皮质类固醇的联合治疗 植入剂(Ozurdex)已经在临床试验中进行了广泛的研究，以期获得更好的治疗效果。 在那些慢性疾病中。然而，多次频繁的玻璃体内注射不仅具有侵入性，而且 给患者带来不便的同时也增加了并发症的风险，如结膜出血，以及 眼压升高(IOP)。尤其是玻璃体内应用糖皮质激素治疗会引起严重的局部 副作用，如白内障和可导致青光眼的异常高眼压。因为眼压峰值是 与药物(地塞米松，地塞米松)在玻璃体/视网膜中的浓度密切相关 OZURDEX，我们假设局部副作用是由于无法调整剂量和突释 以在比预期时间短的时间内高度集中为特征。这项提议的中心假设是 我们的新型剂量可控的地塞米松/RAN联合给药植入物将减少因不可控而产生的副作用 玻璃体内给药后给药剂量，延长治疗效果。我们最近开发了一种 可通过玻璃体内注射和激光通过晶状体触发的可生物降解的光激活植入物 用于安全的剂量控制药物释放。药物剂量可以通过以下方式精确而轻松地控制 变化的激光参数，如功率和持续时间。这项研究的总体目标是提高 治疗慢性眼后部疾病并减少当前糖皮质激素治疗的副作用 方法研制一种剂量可控的共给药植入剂。目标1的重点是完成 剂量可控的地塞米松/RAN植入剂的研制及其释药动力学研究 体外培养。目的2重点确定不同给药方式在减少副作用、青光眼、 利用人眼小梁细胞。目的3将确定在体内的疗效和减少副作用 视网膜血管内植入与传统方法的比较，即Ozurdex和每月注射RAN 渗漏/水肿兔模型。在该项目成功完成后，预期成果包括 确定剂量可控植入物潜在改变慢性疾病护理标准的可行性 眼球后方给药。此外，该项目将支持未来的R01应用，通过生成初步的 数据，并将国际翻译学会提升为翻译科学领域的独立研究员。

PROJECT SUMMARY/ABSTRACT Chronic posterior eye diseases, such as diabetic macular edema (DME), macular edema (ME) caused by retinal vein occlusion, wet age-released macular degeneration (wet AMD) and non-infectious posterior uveitis (NU), are associated with high rates irreversible vision loss. Current standard of care for DME, ME and wet AMD is monthly intravitreal injections of anti-vascular endothelial growth factor (VEGF) monoclonal antibody, Bevacizumab (Bev), or the fragment, Ranibizumab (Ran). In addition, because those diseases are characterized by inflammation and fibrosis, intravitreal corticosteroid implant injections every 2~6 months is the mainstay to treat DME, ME, and NU. Recently, combination therapy of intravitreal anti-VEGF and corticosteroid implant (Ozurdex) injections has been extensively studied in clinical trials to expect better therapeutic efficacy in those chronic diseases. However, multiple frequent intravitreal injections are not only invasive and inconvenient for patients but also increase the risk of complications, such as conjunctival hemorrhage, and increased intraocular pressure (IOP). Especially, the intravitreal corticosteroid treatment causes serious local side effects, such as cataract and abnormally high IOP which can lead to glaucoma. Because the peak IOP is highly associated with the drug (dexamethasone, Dex) concentration in the vitreous/retina released from Ozurdex, we hypothesize that the local side effect is due to the inability to adjust dosage and burst release characterized by high concentration in shorter time than desired. The central hypothesis of this proposal is that our novel dose-controllable co-delivery implant of Dex/Ran would reduce the side effects due to uncontrollable dosage after intravitreal administration, and extend therapeutic efficacy. We recently developed a biodegradable light-activated implant that can be intravitreally injected and triggered by laser through the lens of the eye for dose-controlled drug release safely. The drug dosage can be precisely and easily controlled by varying laser parameters, such as power and duration. The overall goal of this research is to improve the treatment of chronic posterior eye diseases and reduce side effects caused by current corticosteroid treatment methods by developing a dose-controllable co-delivery drug implant. The focus of Aim 1 is to complete the development of a dose-controllable co-delivery Dex/Ran implant and investigate the drug release kinetics in vitro. Aim 2 focuses on defining effect of different drug delivery methods on reducing side effects, glaucoma, utilizing human trabecular meshwork cells. Aim 3 will determine in vivo efficacy and reduced side effects of the implant compared to the traditional methods, i.e. Ozurdex and monthly Ran injections, in a retinal vessel leakage/edema rabbit model. At the successful completion of this project, expected outcomes include identifying feasibility of the dose-controllable implants to potentially change the standard of care for chronic posterior eye drug delivery. In addition, the project will support future R01 application by generating preliminary data and enhance the PI to be an independent researcher in the field of translational science.