Influence of eye pigmentation and diabetes on retinal drug delivery

眼色素沉着和糖尿病对视网膜药物输送的影响

• 批准号: 7915552
• 负责人: UDAY B KOMPELLA
• 金额: $ 40.8万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7915552
• 关键词: Abbreviations; Acids; Animal Model; Anti-Inflammatory Agents; Area; Australia; Binding; Blood Vessels; Blood-Retinal Barrier; Bruch' s basal membrane structure; Choroid; Clinical; Development; Diabetes Mellitus; Diabetic Retinopathy; Dinoprostone; Disease; Drug Delivery Systems; Drug Interactions; Encapsulated; Endophthalmitis; European; Extravasation; Exudative age-related macular degeneration; Eye; Fluorescein; Fluorescein-5-isothiocyanate; Fluoresceins; Glutathione Disulfide; Glycolic-Lactic Acid Polyester; High Pressure Liquid Chromatography; Human; Inbred BN Rats; Injection of therapeutic agent; Intramuscular; Intravenous; Investigation; Isothiocyanates; Laboratories; Lead; Melanins; Methylcellulose; Modeling; Norway; Oxidative Stress; Partition Coefficient; Permeability; Pharmaceutical Preparations; Phase III Clinical Trials; Phosphate Buffer; Photochemotherapy; Pigmentation physiologic function; Pigments; Placebos; Prodrugs; Progress Reports; Property; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Rattus; Reduced Glutathione; Research; Retina; Retinal; Retinal Detachment; Route; Running; Saline; Scheme; Sclera; Sprague-Dawley Rats; Streptozocin; Structure of retinal pigment epithelium; Testing; Therapeutic Agents; Thiobarbituric Acid Reactive Substances; Time; Vascular Endothelial Growth Factors; albino rat; anecortave; anecortave acetate; celecoxib; diabetic; diabetic rat; drug efficacy; experience; in vivo; intraperitoneal; liquid chromatography mass spectrometry; macula; poly(lactide); pressure; response; solute

A rate limiting step in the development of therapeutic agents for treating diabetic retinopathy is retinal drug delivery. Although intravitreal injections allow significant drug delivery to the retina, repeated intravitreal injections can lead to endophthalmitis and retinal detachment. Therefore, alternative routes of administration are currently being investigated. Transscleral retinal drug delivery is one such approach. We hypothesized that the eye pigment reduces the extent of transscleral retinal drug delivery in vivo, with the reduction in delivery being greater for drugs with higher melanin binding. Further we hypothesized that diabetes increase transscleral drug delivery to the retina in vivo, due to leakier barriers. The above hypotheses will be assessed at a mechanistic level under two specific aims. Aim 1 will investigate the mechanisms of drug interaction with melanin and determine influence of eye pigmentation on transscleral retinal drug delivery. Aim 2 will correlate leakiness of blood-retinal barriers in diabetic animal models to transscleral retinal drug delivery. This study will investigate widely used model solutes with high and low melanin binding in conjunction with two antiinflammatory agents that are relevant for treating diabetic retinopathy. Both pigmented (Brown Norway) and non-pigmented (Sprague Dawley) rats with and without streptozotocin induced diabetes will be employed in this study. The findings of this study will be useful in developing drugs with enhanced transscleral delivery to the retina in order to treat diabetic retinopathy.

在开发用于治疗糖尿病性视网膜病的治疗剂中的限速步骤是视网膜药物递送。虽然玻璃体内注射允许显著的药物递送至视网膜，但是重复的玻璃体内注射可导致眼内炎和视网膜脱离。因此，目前正在研究其他给药途径。经巩膜视网膜药物递送就是这样一种方法。我们假设，眼睛色素降低了体内经巩膜视网膜药物递送的程度，对于具有较高黑色素结合的药物，递送的减少更大。此外，我们假设，糖尿病增加了体内经巩膜药物输送到视网膜，由于渗漏的障碍。上述假设将在两个具体目标下在机制层面上进行评估。目的1探讨药物与黑色素相互作用的机制，并确定眼部色素沉着对药物经巩膜视网膜给药的影响。目的2将糖尿病动物模型中血-视网膜屏障的渗漏与经巩膜视网膜药物递送相关联。本研究将研究广泛使用的模型溶质与高和低黑色素结合结合与两种治疗糖尿病视网膜病变相关的药物。在本研究中，将使用有和无链脲佐菌素诱导糖尿病的有色（Brown Norway）和非有色（Sprague道利）大鼠。这项研究的结果将有助于开发具有增强的经巩膜递送至视网膜的药物，以治疗糖尿病视网膜病变。