Transcleral Therapeutics in Diabetic Retinopathy

描述（由申请人提供）：目前没有批准的药物方法来预防或延缓糖尿病视网膜病变，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。虽然经巩膜给药导致视网膜给药比全身途径大得多，但给药的程度是微乎其微的。此外，适合经巩膜给药的药物性质和经巩膜给药的障碍还不清楚。因此，经巩膜给药仍处于起步阶段，需要开发更好的药物，增强给药能力，以有效治疗人类糖尿病视网膜并发症。我们早期的研究表明，与白化动物相比，在色素沉着动物中，高亲脂性药物塞来昔布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的非生产性结合。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。本项目将验证高亲脂性药物通过其减少色素结合的极性前药可以增强经巩膜视网膜传递和疗效的假设。由于使用一系列结构相关分子使我们能够更容易地识别有利于跨屏障递送的关键药物特性，因此本研究将评估塞来昔布一系列前药通过各种屏障（包括巩膜-脉络膜- rpe）的经巩膜通透性。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体外溶质通透性通过巩膜-脉络膜- rpe与体内药物递送到视网膜相关。同时，本研究将确定一种具有优越疗效的塞来昔布前药。最后，从塞来昔布前药中学到的原理将被外推到其他三种模型亲脂性药物，布地奈德、鲁博西托林和尼美舒利。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通过以下四个具体目标进行评估：1)确定有利于加强经巩膜药物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塞来昔布前药体内递送中的作用。3)确定经巩膜给药增强的塞来昔布衍生物是否更有效。4)确定极性前药是否能增强其他三种可能应用于眼后的亲脂性药物的传递和疗效。除了药物亲脂性外，本研究还将组织和黑色素结合以及药物前生物转化率等其他参数与经巩膜给药相关联。本研究将评估四种药物包封或可渗透前药的聚合物微颗粒系统对糖尿病大鼠的疗效。除了开发具有治疗糖尿病视网膜病变治疗价值的经巩膜药物/前药外，本研究的意义还在于，确定的增强经巩膜给药的药物特性可以指导治疗糖尿病视网膜病变及其他视网膜疾病的药物设计。

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.