Transcleral Therapeutics in Diabetic Retinopathy

糖尿病视网膜病变的经巩膜治疗

• 批准号: 8045379
• 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/8045379
• 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; public health relevance; response; ruboxistaurin; solute

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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, with some beneficial effects in diabetic retinas, the extent of delivery is still very low. 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. Further, this project will identify new drugs for treating diabetic retinopathy.

描述（由申请人提供）：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，这是美国失明的主要原因。跨菌药物输送被认为是视网膜药物输送的新革命。尽管与全身途径相比，跨孢子的递送导致视网膜输送大大更大，但递送程度是边缘的。此外，尚不清楚适合跨孢子递送的药物特性和跨孢子递送的障碍。因此，跨菌药物的递送仍处于起步阶段，它需要开发更好的药物，并增强递送，以有效治疗人类糖尿病的视网膜并发症。我们较早的研究表明，与白化动物相比，在有色动物中，高脂蛋白药物塞来氧化的效率低下的跨孢子视网膜递送。这是由于色素脉络膜层中塞来昔布的无生产性结合所致。持续的药物递送进一步加剧了这些差异，这对于治疗糖尿病性视网膜病至关重要。塞来昔布具有治疗糖尿病性视网膜病的治疗潜力。该项目将检验以下假设：通过降低色素结合的极性前药可以增强经scleral视网膜递送和高度亲脂性药物的功效。由于使用一系列与结构相关的分子可以使我们更容易地识别有利于跨障碍物递送的关键药物特性，因此本研究将评估一系列在包括sclera-choroid-rpe在内的各种障碍物的塞勒克氏蛋白前药的跨孢子渗透性。此外，使用一系列Celecoxib衍生物，这项研究的另一个目的是证明，跨巩膜-Choroid-RPE的体外溶质渗透性与体内药物输送到视网膜相关。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被外推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nimesulide。这些药物具有治疗糖尿病性视网膜病的潜在治疗价值。这种方法将使我们能够验证从一系列塞来昔布前药中学到的原则，并进一步翻译和推广这些概念。这些假设和相关目标将使用以下四个特定目的进行评估：1）确定有益于增强跨孢子药物运输的Celecoxib化学衍生物。 2）确定巩膜 - 壳螺旋体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方面的有用性。 3）确定具有增强跨孢子递送的塞来氧化衍生物是否发挥更大的功效。 4）确定极性前药是否增强了其他三种亲脂性药物的递送和疗效，并在眼后潜在应用。除了药物亲脂性外，这项研究还将将包括组织和黑色素色素结合和前药生物转化速率在内的其他参数与跨孢子药物的递送相关。这项研究将评估封装药物或四种药物的可渗透前药的聚合微标志系统，以便其在糖尿病大鼠中的功效。除了开发治疗糖尿病性视网膜病的治疗价值的跨症药物/前药外，这项研究的重要性是，鉴定出用于增强经骨递送的药物特性可以指导药物设计用于治疗糖尿病性视网膜病变以及其他视网膜疾病。 公共卫生相关性：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，这是美国失明的主要原因。跨菌药物输送被认为是视网膜药物输送的新革命。尽管与全身途径相比，跨孢子的递送导致视网膜输送大大增加，并且对糖尿病视网膜有一些有益的影响，但递送程度仍然很低。这项研究的意义在于，鉴定出用于增强的跨孢子分娩的药物特性可以指导药物设计治疗糖尿病性视网膜病以及其他视网膜疾病。此外，该项目将确定用于治疗糖尿病性视网膜病的新药。