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）：目前没有批准的药理学方法来预防或延迟糖尿病视网膜病变，这是美国失明的主要原因。经巩膜给药被认为是视网膜给药的新革命。虽然与全身途径相比，经巩膜递送已经导致显著更大的视网膜递送，但是递送的程度是边缘的。此外，适合于经巩膜递送的药物性质和经巩膜递送的障碍还没有很好地理解。因此，经巩膜药物递送仍处于起步阶段，并且需要开发具有增强递送的更好的药物以有效治疗人类糖尿病的视网膜并发症。我们早期的研究表明，与白化病动物相比，有色动物中高亲脂性药物塞来昔布的经巩膜视网膜递送效率低下。这是由于塞来昔布在色素脉络膜层中的非生产性结合。持续给药进一步加剧了这些差异，这对治疗糖尿病视网膜病变至关重要。塞来昔布对糖尿病视网膜病变具有潜在的治疗作用。该项目将测试这样的假设，即高度亲脂性药物的经巩膜视网膜递送和功效可以通过其具有减少的色素结合的极性前药来增强。由于使用一系列结构相关的分子使我们能够更容易地确定关键的药物特性，有利于跨越障碍，本研究将评估一系列塞来昔布前药跨越各种障碍，包括巩膜-脉络膜-RPE的跨巩膜渗透性。此外，使用一系列塞来昔布衍生物，本研究的另一个目的是证明跨巩膜-脉络膜-RPE的体外溶质渗透性与体内药物递送至视网膜相关。此外，本研究将确定一种具有上级功效的塞来昔布前药。最后，从塞来昔布前体药物学到的原理将外推到其他三种亲脂性药物模型，布地奈德，ruboxietin和尼美舒利。这些药物对糖尿病视网膜病变具有潜在的治疗价值。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理，并进一步翻译和概括这些概念。这些假设和相关目标将使用以下四个具体目标进行评估：1）确定有利于增强药物跨巩膜转运的塞来昔布化学衍生物。2)确定巩膜-脉络膜-RPE渗透性在预测一系列化学相关的塞来昔布前药的体内递送中的有用性。3)确定塞来昔布衍生物增强的经巩膜递送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可能应用于眼后部的亲脂性药物的递送和疗效。除药物亲脂性外，本研究还将其他参数（包括组织和黑色素结合以及前药生物转化率）与经巩膜给药相关。本研究将评估包封药物或四种药物的可渗透前药的聚合物微粒系统在糖尿病大鼠中的疗效。除了开发在治疗糖尿病视网膜病变中具有治疗价值的经巩膜药物/前药之外，本研究的意义在于，为增强的经巩膜递送而鉴定的药物性质可以指导用于治疗糖尿病视网膜病变以及其他视网膜疾病的药物设计。 公共卫生关系：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，这是美国失明的主要原因。经巩膜给药被认为是视网膜给药的新革命。虽然与全身途径相比，经巩膜递送已经导致显著更大的视网膜递送，在糖尿病视网膜中具有一些有益效果，但递送的程度仍然非常低。这项研究的意义在于，为增强的经巩膜递送确定的药物特性可以指导治疗糖尿病视网膜病变以及其他视网膜疾病的药物设计。此外，该项目将确定治疗糖尿病视网膜病变的新药。