Pharmacological Approaches to Treat Diabetic Retinopathy

描述(申请人提供)：糖尿病视网膜病变，视网膜的一种微血管病变，在美国是导致失明的主要原因。目前还没有被批准的药理学方法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。糖尿病患者和实验动物模型的玻璃体和视网膜中的血管内皮生长因子水平升高。在实验动物模型中，血管内皮生长因子中和大分子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。这位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)和新的给药途径(植入物、可生物降解颗粒和经巩膜给药)来抑制视网膜血管内皮生长因子的表达。目前的提案涉及使用一种新的分子方法(抑制环氧合酶-2，COX-2)和一种新的视网膜药物释放方法(结膜下可生物降解的微粒)来抑制视网膜血管内皮生长因子的表达和关键的血管变化。文献证据表明，COX-2在包括糖尿病和肿瘤在内的多种炎症条件下表达上调，抑制COX-2可以减少肿瘤血管生成。在这些肿瘤模型中，环氧合酶-2的抑制被认为是通过抑制血管内皮生长因子的表达来降低上游的血管内皮生长因子活性。PI证明，选择性环氧合酶-2抑制剂塞来昔布(M.Wt：385)可以减少大剂量多次口服后视网膜血管内皮生长因子的表达和血管渗漏。此外，他还观察到，低剂量的结膜下给药允许塞来昔布通过巩膜途径延长视网膜给药时间。基于这些初步结果，这项研究将检验这样一种假设：在链脲佐菌素大鼠模型中，给糖尿病大鼠单一结膜下注射塞来昔布-聚(乳酸-乙醇酸)(塞来昔布-PLGA)微粒可以维持药物向视网膜的输送，并抑制早期糖尿病的变化。这一假说将通过解决两个具体目标来验证-1)确定结膜下注射塞来昔布-PLGA微粒是否能维持体内药物释放两个月，并保持同侧眼睛比肌肉注射更高的视网膜药物浓度；2)确定结膜下注射塞来昔布-PLGA微粒是否能抑制糖尿病大鼠模型的视网膜COX-2活性、血管内皮生长因子的表达和血管渗漏。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.