Transcleral Therapeutics in Diabetic Retinopathy

目前还没有被批准的药物方法来预防或延缓糖尿病视网膜病变，a 在美国是导致失明的主要原因。经巩膜给药被认为是视网膜药物的新革命 送货。虽然与经巩膜外分娩相比，经巩膜外分娩导致的视网膜分娩显著更多 系统性路线，交付的程度是边际的。此外，适合于经巩膜外给药的药物性质 而且，跨巩膜分娩的障碍也没有得到很好的理解。因此，经巩膜外给药仍在进行中。 婴儿期，它需要开发更好的药物，加强递送，以有效治疗视网膜 人类糖尿病的并发症。我们早期的研究表明，经巩膜视网膜分娩效率低下 与白化动物相比，色素动物中的高度亲脂性药物塞来昔布。这是由于非 塞来昔布在色素脉络膜层的有效结合。这些差异随着 持续给药，这是治疗糖尿病视网膜病变的关键。塞来昔布具有治疗高血压的潜力 治疗糖尿病视网膜病变。该项目将检验经巩膜视网膜分娩的假说和 高亲脂性药物可以通过减少色素结合的极性前药来增强。由于使用了 一系列结构相关的分子使我们能够更容易地识别有益于 跨屏障给药，这项研究将评估塞来昔布一系列前药的经巩膜渗透性 跨越各种障碍，包括巩膜-脉络膜-RPE。此外，使用一系列塞来昔布衍生物，另一种 本研究的目的是证明体外溶质通过巩膜-脉络膜-RPE的渗透性与 通过体内药物输送到视网膜。此外，这项研究还将确定一种疗效更好的塞来昔布前药。 最后，从塞来昔布前药学到的原理将外推到其他三种亲脂性模型。 药物、布地奈德、Ruboxistaurin和尼美舒利。这些药物在治疗上有潜在的治疗价值。 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则。 并进一步翻译和推广这些概念。这些假设和相关目标将是 使用以下四个具体目标进行评估：1)确定对塞来昔布有益的化学衍生物 以加强经巩膜的药物转运。2)确定巩膜-脉络膜-RPE通透性在 预测一系列化学相关的塞来昔布前体药物的体内释放。3)确定是否 塞来昔布衍生物具有增强的经巩膜给药作用，具有更好的疗效。4)确定极点是否 前药增强另外三种脂类药物的传递和疗效，并具有潜在的背部应用 眼睛的。除了药物的亲脂性，这项研究还将关联其他参数，包括组织和 黑色素结合和前药生物转化率经巩膜给药。这项研究将评估 四种药物的药物或透皮前药聚合物微球系统的药效学研究 糖尿病大鼠。除开发治疗糖尿病有治疗价值的跨巩膜药物/前药外 视网膜病变，这项研究的意义是，药物特性被确定为增强的经巩膜 递送可以指导治疗糖尿病视网膜病变和其他视网膜疾病的药物设计。

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.