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.

目前还没有批准的药物方法来预防或延缓糖尿病视网膜病变， 在美国是致盲的主要原因。经巩膜给药被认为是视网膜给药的新革命 交付.虽然与经巩膜递送相比，经巩膜递送导致显著更大的视网膜递送， 全身途径，交付的程度是边际。此外，适合于经巩膜递送的药物性质 并且对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其 婴儿期，它需要开发更好的药物与增强交付有效治疗视网膜病变 糖尿病的并发症。我们早期的研究表明， 与白化病动物相比，高亲脂性药物塞来昔布在有色动物中的作用。这是由于非- 塞来昔布在色素脉络膜层中的有效结合。这些差异进一步加剧， 持续的药物输送，这对于治疗糖尿病视网膜病变至关重要。塞来昔布具有治疗 治疗糖尿病视网膜病变该项目将测试经巩膜视网膜递送和 高亲脂性药物可以通过其具有减少的色素结合的极性前药来增强。因为使用 一系列结构相关的分子使我们能够更容易地识别关键的药物特性， 本研究将评估塞来昔布的一系列前药的经巩膜渗透性 穿过包括巩膜-脉络膜-RPE在内的各种屏障。此外，使用一系列塞来昔布衍生物， 本研究的目的是证明巩膜-脉络膜-RPE的体外溶质渗透性与 体内药物输送到视网膜。此外，这项研究将确定塞来昔布前药具有上级疗效。 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模型。 药物，布地奈德，ruboxietin和尼美舒利。这些药物在治疗中具有潜在的治疗价值， 糖尿病视网膜病变这种方法将使我们能够验证从一系列塞来昔布中学到的原理。 前药，并进一步翻译和概括的概念。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）确定塞来昔布的化学衍生物有益于 用于增强经巩膜药物转运。2)为了确定巩膜-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。3)以确定是否 具有增强的经巩膜递送的塞来昔布衍生物发挥更大的功效。4)为了确定极性是否 前药增强了其他三种亲脂性药物的递送和功效， 的眼睛。除了药物亲脂性之外，本研究还将其他参数（包括组织和 黑色素结合和前药生物转化率对经巩膜药物递送的影响。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， 糖尿病大鼠除了开发具有治疗价值的糖尿病药物/前体药物外， 视网膜病变，这项研究的意义是，确定的药物性质，为增强经巩膜 递送可以指导用于治疗糖尿病视网膜病以及其它视网膜疾病的药物设计。