Transcleral Therapeutics in Diabetic Retinopathy

糖尿病视网膜病变的经巩膜治疗

• 批准号: 8244512
• 负责人: UDAY B KOMPELLA
• 金额: $ 39.63万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8244512
• 关键词: Abbreviations; Acids; Animals; Area; Australia; Back; Binding; Blindness; Blood-Retinal Barrier; Bruch' s basal membrane structure; Budesonide; Chemicals; Choroid; Clinical; Complications of Diabetes Mellitus; Development; Diabetic Retinopathy; Dinoprostone; Disease; Drug Delivery Systems; Drug Design; Drug Transport; Encapsulated; European; Exudative age-related macular degeneration; Eye; Fluorescein; Fluorescein-5-isothiocyanate; Glutathione Disulfide; Glycolic-Lactic Acid Polyester; High Pressure Liquid Chromatography; Human; In Vitro; Inbred BN Rats; Intramuscular; Intravenous; Investigation; Isothiocyanates; Laboratories; Lead; Learning; Melanins; Methylcellulose; Modeling; Nimesulide; Norway; Particulate; Partition Coefficient; Permeability; Pharmaceutical Preparations; Phase III Clinical Trials; Phosphate Buffer; Photochemotherapy; Pigments; Placebos; Prodrugs; Progress Reports; Property; Prostaglandin-Endoperoxide Synthase; Rattus; Reduced Glutathione; Research; Retina; Retinal; Retinal Diseases; Route; Saline; Scheme; Sclera; Series; Sprague-Dawley Rats; Streptozocin; Structure of retinal pigment epithelium; System; Testing; Therapeutic; Thiobarbituric Acid Reactive Substances; Time; Tissues; Translating; Vascular Endothelial Growth Factors; albino rat; anecortave; anecortave acetate; celecoxib; diabetic; diabetic rat; drug efficacy; effective therapy; experience; in vivo; infancy; intraperitoneal; lipophilicity; liquid chromatography mass spectrometry; macula; poly(lactide); pressure; prevent; response; ruboxistaurin; solute

Currently there are no approved pharmacological approaches to prevent or delay diabetic retinopathy, a leading cause of blindness in the USA. Transscleral drug delivery is considered a new revolution in retinal drug delivery. While transscleral delivery has resulted in substantially greater retinal delivery compared to the systemic route, the extent of delivery is marginal. Further, the drug properties suitable for transscleral delivery and the barriers to transscleral delivery are not well understood. Thus, transscleral drug delivery is still in its infancy and it requires the development of better drugs with enhanced delivery for effective treatment of retinal complications of diabetes in humans. Our earlier studies indicated inefficient transscleral retinal delivery of a highly lipophilic drug, celecoxib, in pigmented animals compared to albino animals. This is due to non- productive binding of celecoxib in the pigmented choroid layer. These differences are further aggravated with sustained drug delivery, which is critical for treating diabetic retinopathy. Celecoxib has therapeutic potential in treating diabetic retinopathy. This project will test the hypothesis that transscleral retinal delivery and efficacy of highly lipophilic drugs can be enhanced by their polar prodrugs with reduced pigment binding. Since the use of a series of structurally related molecules allows us to more readily identify critical drug properties beneficial in delivery across barriers, this study will assess transscleral permeability for a series of prodrugs of celecoxib across various barriers including sclera-choroid-RPE. Further, using a series of celecoxib derivatives, another purpose of this study is to demonstrate that in vitro solute permeability across sclera-choroid-RPE correlates with in vivo drug delivery to the retina. Also, this study will identify a celecoxib prodrug with superior efficacy. Finally, the principles learned from celecoxib prodrugs will be extrapolated to three other model lipophilic drugs, budesonide, ruboxistaurin, and nimesulide. These drugs are of potential therapeutic value in treating diabetic retinopathy. This approach would allow us to validate the principles learned from a series of celecoxib prodrugs and to further translate and generalize the concepts. These hypotheses and related objectives will be assessed using the following four specific aims: 1) To determine the celecoxib chemical derivatives beneficial for enhancing transscleral drug transport. 2) To determine the usefulness of sclera-choroid-RPE permeability in predicting in vivo delivery of a series of chemically related celecoxib prodrugs. 3) To determine whether celecoxib derivatives with enhanced transscleral delivery exert greater efficacy. 4) To determine whether polar prodrugs enhance the delivery and efficacy of three other lipophilic drugs with potential application in the back of the eye. In addition to drug lipophilicity, this study will correlate other parameters including tissue and melanin pigment binding and prodrug bioconversion rates to transscleral drug delivery. This study will assess polymeric microparticulate systems encapsulating drug or permeable prodrugs of four drugs for their efficacy in diabetic rats. Besides developing transscleral drugs/prodrugs of therapeutic value in treating diabetic retinopathy, the significance of this study is that the drug properties identified for enhanced transscleral delivery can guide drug design for treating diabetic retinopathy as well as other retinal disorders.

目前尚无批准的药理方法来预防或延迟糖尿病性视网膜病， 美国失明的主要原因。跨菌药物输送被认为是视网膜药物的新革命 送货。虽然与跨孢子的传递相比，跨孢子的传递导致了视网膜的交付大大更大 全身途径，交付的程度是边缘的。此外，适用于跨孢子递送的药物特性 并且跨史散布的障碍尚不清楚。因此，跨孢子药的输送仍在 婴儿期，需要增强递送的更好药物以有效治疗视网膜 人类糖尿病的并发症。我们较早的研究表明，A 与白化动物相比，在色素动物中高度亲脂性药物，塞来氧化。这是由于非 色素脉络膜层中塞来昔布的生产性结合。这些差异进一步加剧了 持续药物递送，这对于治疗糖尿病性视网膜病至关重要。塞来昔布具有治疗潜力 治疗糖尿病性视网膜病。该项目将检验以下假设 高亲脂性药物可以通过降低色素结合来增强其极性前药。由于使用 一系列与结构相关的分子使我们能够更容易地识别有益的关键药物特性 跨障碍物的交付，这项研究将评估一系列塞来氧化前药的跨尺度渗透性 在包括巩膜螺旋体内的各种障碍物中。此外，使用一系列塞来昔布衍生物，另一种 这项研究的目的是证明跨硬化螺旋体rpe的体外溶质渗透性相关 体内药物输送到视网膜。此外，这项研究将确定具有较高功效的塞来氧化前药。 最后，从塞来氧化前药中学到的原则将推断到其他三种模型的亲脂性。 药物，布德索尼，鲁布克斯龙蛋白和氮硫化物。这些药物在治疗中具有潜在的治疗价值 糖尿病性视网膜病。这种方法将使我们能够验证从一系列Celecoxib中学到的原则 前药并进一步翻译和概括这些概念。这些假设和相关目标将是 使用以下四个特定目的评估：1）确定塞来氧化化学衍生物有益 用于增强跨孢子药的运输。 2）确定巩膜 - 螺布渗透性在 预测一系列化学相关的塞来氧化前药的体内递送。 3）确定是否 塞来氧化衍生物具有增强的跨孢子递送发挥更大的功效。 4）确定是否极性 前药增强了其他三种亲脂性药物的递送和功效 眼睛。除了药物亲脂性外，这项研究还将与包括组织和包括组织在内的其他参数相关 黑色素色素结合和前药生物转化速率与跨孢子药物的递送。这项研究将评估 聚合微标志系统封装了四种药物的药物或可渗透的前药，以便其在 糖尿病大鼠。除了开发治疗糖尿病的治疗价值的跨症药物/前药外 视网膜病变，这项研究的重要性是，鉴定出用于增强的跨孢子的药物特性 分娩可以指导药物设计用于治疗糖尿病性视网膜病以及其他视网膜疾病。