Transcleral Therapeutics in Diabetic Retinopathy

描述(申请人提供)：目前还没有被批准的药理学方法来预防或延缓糖尿病视网膜病变，糖尿病视网膜病变是美国的主要致盲原因。经巩膜外给药被认为是视网膜药物给药的一次新革命。虽然与全身途径相比，经巩膜外分娩导致了更多的视网膜分娩，但分娩的程度是边缘的。此外，适合于经巩膜给药的药物特性和经巩膜给药的障碍还没有被很好地了解。因此，经巩膜外给药仍处于初级阶段，需要开发更好的药物，加强给药，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，与白化动物相比，色素动物的经巩膜视网膜传递高度亲脂性药物塞来昔布的效率低下。这是由于塞来昔布在有色脉络膜层中的非生产性结合所致。这些差异随着持续给药而进一步加剧，这对治疗糖尿病视网膜病变至关重要。塞来昔布在治疗糖尿病视网膜病变方面具有治疗潜力。该项目将验证这样一种假设，即高度亲脂药物的极性前体药物的色素结合减少，可以增强其经巩膜视网膜的传输和疗效。由于一系列结构相关分子的使用使我们能够更容易地确定关键的药物性质，有利于跨屏障给药，本研究将评估塞来昔布一系列前体药物的跨巩膜渗透性，包括巩膜-脉络膜-RPE。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体外溶质通过巩膜-脉络膜-RPE的渗透性与体内药物进入视网膜的相关性。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，从塞来昔布前体药物中学到的原理将被外推到其他三种亲脂性药物，布地奈德、Ruboxistaurin和尼美舒利。这些药物在治疗糖尿病视网膜病变方面具有潜在的治疗价值。这一办法将使我们能够验证从一系列塞来昔布前体药物中学到的原则，并进一步翻译和推广这些概念。这些假设和相关目标将通过以下四个具体目标进行评估：1)确定有利于促进药物经巩膜转运的塞来昔布化学衍生物。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体内给药中的作用。3)确定塞来昔布衍生物经巩膜外给药是否有更好的疗效。4)确定极性前体药物是否增强了其他三种可能在眼后部应用的亲脂性药物的释放和疗效。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以及前药生物转化率与经巩膜给药。这项研究将评估包裹药物或四种药物的渗透性前药的聚合物微粒系统对糖尿病大鼠的疗效。除了开发治疗糖尿病视网膜病变的具有治疗价值的药物/前药外，本研究的意义在于，被确定为增强经巩膜给药的药物性质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。 公共卫生相关性：目前还没有被批准的药理学方法来预防或延缓糖尿病视网膜病变，糖尿病视网膜病变是美国失明的主要原因。经巩膜外给药被认为是视网膜药物给药的一次新革命。虽然与全身途径相比，经巩膜外分娩带来了更多的视网膜输送，对糖尿病视网膜也有一些有益的影响，但分娩的程度仍然很低。这项研究的意义在于，被确定为增强经巩膜给药的药物性质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。此外，该项目将确定治疗糖尿病视网膜病变的新药。

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.