Pharmacological Approaches to Treat Diabetic Retinopathy

描述（由申请人提供）：糖尿病视网膜病变是一种视网膜微血管病变，是美国致盲的主要原因。目前还没有被批准的药物来预防或延缓糖尿病视网膜病变。越来越多的证据表明，能够抑制血管内皮生长因子（VEGF）的药物将有助于预防或延缓糖尿病视网膜病变。VEGF在糖尿病患者和实验动物模型的玻璃体和视网膜中升高。在实验动物模型中，vegf中和大分子已被证明可以减少视网膜血管渗漏和视网膜新生血管，这是导致糖尿病视网膜病变并发症的两个关键病理变化。首席研究员一直在研究使用小分子药物（如醛糖还原酶抑制剂、皮质类固醇和非类固醇抗炎药）和新的给药方法（植入物、可生物降解颗粒和经巩膜给药到视网膜）来抑制视网膜VEGF表达。目前的建议涉及使用一种新的分子方法（抑制环氧化酶-2，COX-2）和一种新的视网膜药物递送方法（结膜下可生物降解微粒）来抑制视网膜VEGF表达和关键血管变化。文献证据表明，COX-2在包括糖尿病和肿瘤在内的几种炎症条件下上调，抑制COX-2可以减少肿瘤血管生成。在这些肿瘤模型中，COX-2抑制被认为通过抑制VEGF表达来降低上游的VEGF活性。PI发现选择性环氧化酶-2抑制剂塞来昔布（M.Wt: 385）可降低高剂量多次口服后视网膜VEGF表达和血管渗漏。此外，他还观察到，低剂量的结膜下给药可以延长塞来昔布经巩膜途径的视网膜递送时间。基于这些初步结果，本研究将在链脲佐辛鼠模型中验证糖尿病大鼠单次结膜下给药塞来昔布-聚（乳酸-羟基乙酸）（塞来昔布- plga）微粒维持药物传递到视网膜并抑制早期糖尿病变化的假设。这一假设将通过解决两个特定目标来验证：1)确定结膜下给药塞来昔布- plga颗粒是否能维持体内药物释放两个月，并在同侧眼睛中维持较高的视网膜药物水平；2)确定结膜下给药塞来昔布- plga颗粒是否能抑制糖尿病大鼠模型视网膜COX-2活性、VEGF表达和血管渗漏。这些研究的完成将为治疗糖尿病视网膜病变相关血管改变提供新的药理学方法和框架。

DESCRIPTION (provided by applicant): Diabetic retinopathy, a microvascular pathology of the retina, is a leading cause of blindness in the USA. Currently there are no approved pharmacological approaches to prevent or delay diabetic retinopathy. Growing evidence suggests that agents capable of inhibiting vascular endothelial growth factor (VEGF) will be beneficial in preventing or delaying diabetic retinopathy. VEGF is elevated in the vitreous and retinas of diabetic patients and experimental animal models. In experimental animal models, VEGF-neutralizing macromolecules have been shown to reduce retinal vascular leakage and retinal neovascularization, two key pathological changes contributing to the complication of diabetic retinopathy. The principal investigator has been investigating the use of small molecular weight drugs (e.g., aldose reductase inhibitors, corticosteroids, and non-steroid anti-inflammatory drugs) and novel delivery approaches (implants, biodegradable particles, and transcleral drug delivery to the retina) to inhibit retinal VEGF expression. The current proposal addresses the use of a novel molecular approach (inhibition of cycloxygenase-2, COX-2) and a novel retinal drug delivery approach (subconjunctival biodegradable microparticles) to suppress retinal VEGF expression and key vascular changes. Literature evidence suggests that COX-2 is upregulated in several inflammatory conditions including diabetes and neoplasms and that COX-2 inhibition can reduce tumor angiogenesis. In these tumor models, COX-2 inhibition is believed to reduce VEGF activity upstream, by inhibiting VEGF expression. The PI identified that celecoxib (M.Wt: 385), a selective cycloxygenase-2 inhibitor, can reduce retinal VEGF expression and vascular leakage following high dose multiple oral dosing. Also, he observed that the subconjunctival administration of low doses allows prolonged retinal delivery of celecoxib via the transscleral pathway. Based on these preliminary results, this study will test the hypothesis that single subconjunctival administration of celecoxib-poly (lactic-co-glycolic acid) (celecoxib-PLGA) microparticles to diabetic rats sustains drug delivery to the retina and suppresses early diabetic changes in a streptozotocinrat model. This hypothesis will be tested by addressing two specific aims - 1) To determine whether subconjunctivally administered celecoxib-PLGA particles sustain in vivo drug release for two months and maintain higher retinal drug levels in the ipsilateral eye compared to intramuscular administration and 2) To determine whether subconjunctival celecoxib-PLGA particles inhibit retinal COX-2 activity, VEGF expression, and vascular leakage in a diabetic rat model. Completion of these studies will provide a new pharmacological approach and framework for treating vascular changes associated with diabetic retinopathy.