Transscleral Drug Delivery for Retinal Disorders

描述（由申请人提供）：埃默里大学眼科与乔治亚理工学院、内布拉斯加州大学和宾夕法尼亚大学开展多学科合作。这种合作是为了改善药物输送到眼后段。在视网膜疾病的治疗中，将药物输送到这个靶点是一个重大的挑战。全球药物治疗的方法包括全身给药、滴眼液、眶内注射。药物稀释、眼部感染、眼内炎和手术损伤如视网膜脱离都可能发生。鉴于这些缺点，我们假设经巩膜入路更适合后段给药。我们建议开发新的经巩膜给药方法，使用纳米颗粒、微针、纤维蛋白密封剂、细胞电泳和电泳。我们将a)检查经巩膜药物运输的生理学，b)建立分析方法来确定低分子量药物和大分子在后段不同区域的分布，以及c)在实验动物模型中展示给药和治疗效果。被测试的药物在基础科学实验、临床前研究或临床研究中已知对视网膜疾病有影响。这个项目需要来自不同学科的研究者之间的合作研究，包括眼科、工程学和制药科学。里程碑：理论模型将在第一年完成；这些将在实验后每年重新评估。体外给药系统已经建立，在第一年将产生用于模型改进的数据集，并在第一年和第二年为体内研究建立起始参数。毒性研究将在第二年和第三年完成。药代动力学和药效学数据将在第三至第五年收集。在第4年和第5年获得疗效数据。通过完成这些临床前试验，我们将发现和开发新的途径，有效地将药物输送到眼睛。这些输送技术应该比目前的技术更安全、更有效。

DESCRIPTION (provided by applicant): The Ophthalmology Department at Emory University leads a multidisciplinary collaboration with the Georgia Institute of Technology, University of Nebraska, and University of Pennsylvania. This collaboration was formed to improve drug delivery to the posterior segment of the eye. Drug delivery to this target is a significant challenge in the treatment of retinal disorders. Methods for drug treatment of the globe include systemic administration, eye drops, and injection into the orbit. Drug dilution, ocular infection, endophthalmitis, and surgical damage such as retinal detachment can occur with these techniques. Given these drawbacks, we hypothesize that transscleral approaches are better for posterior segment drug delivery. We propose to develop novel transscleral drug delivery approaches that use nanoparticles, microneedles, fibrin sealant, ontophoresis, and electoporation. We will a) examine the physiology of transscleral drug transport, b) establish analytical methods to determine the distribution of low molecular weight drugs as well as macromolecules to the various regions of the posterior segment, and c) demonstrate delivery and therapeutic effectiveness in experimental animal models. The drugs to be tested are known to affect retinal diseases in basic science experiments, pre-clinical studies, or clinical studies. This project entails collaborative research among investigators from various disciplines including ophthalmology, engineering, and pharmaceutical sciences. Milestones: Theoretical models will be completed during the first year; these will be post-experimentally reassessed annually. Drug delivery systems are established in vitro already, and during the first year will produce data sets for model refinement and establish starting parameters for in vivo studies in the first and second years. Toxicity studies will be completed during the second and third years. Pharmacokinetic and pharmacodynamic data will be collected during the third through fifth years. In the fourth and fifth years efficacy data are obtained. By accomplishing these pre-clinical tests, we will discover and develop new routes for efficacious delivery of drugs to the eye. These delivery techniques should be safer and more effective than the state of the art. Ultimately, these results will guide us in enhancing drug treatments in ophthalmic practice.