Pharmacological Approaches to Treat Diabetic Retinopathy

描述（由申请人提供）：糖尿病视网膜病变是视网膜的一种微血管病变，是美国致盲的主要原因。目前还没有批准的药物方法来预防或延迟糖尿病视网膜病变。越来越多的证据表明，能够抑制血管内皮生长因子（VEGF）的药物将有利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形成，这是导致糖尿病视网膜病变并发症的两种关键病理变化。主要研究者一直在研究小分子量药物的使用（例如，醛糖还原酶抑制剂、皮质类固醇和非类固醇抗炎药）和新的递送方法（植入物、可生物降解的颗粒和经巩膜药物递送至视网膜）来抑制视网膜VEGF表达。目前的建议解决了使用一种新的分子方法（抑制环氧合酶-2，考克斯-2）和一种新的视网膜药物递送方法（结膜下可生物降解的微粒），以抑制视网膜VEGF的表达和关键的血管变化。文献证据表明，考克斯-2在包括糖尿病和肿瘤在内的几种炎性疾病中上调，并且考克斯-2抑制可以减少肿瘤血管生成。在这些肿瘤模型中，据信考克斯-2抑制通过抑制VEGF表达而降低上游VEGF活性。PI发现，塞来昔布（M.Wt：385）是一种选择性环氧合酶-2抑制剂，可减少高剂量多次口服给药后视网膜VEGF表达和血管渗漏。此外，他观察到低剂量的结膜下给药允许通过经巩膜途径延长塞来昔布的视网膜递送。基于这些初步结果，本研究将检验以下假设：在链脲佐菌素大鼠模型中，单次结膜下给予糖尿病大鼠塞来昔布-聚（乳酸-共-乙醇酸）（塞来昔布-PLGA）微粒可维持药物向视网膜的递送并抑制早期糖尿病变化。将通过解决两个特定目的来检验该假设- 1）确定结膜下给予塞来昔布-PLGA颗粒是否维持体内药物释放两个月，并与肌内给药相比在同侧眼中维持更高的视网膜药物水平，和2）确定结膜下塞来昔布-PLGA颗粒是否抑制糖尿病大鼠模型中视网膜考克斯-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的血管变化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.