Suprachroidal Drug Delivery for Retina Disorders

视网膜疾病的蛛网膜上给药

• 批准号: 8545512
• 负责人: UDAY B KOMPELLA
• 金额: $ 65.63万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2017-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8545512
• 关键词: Adverse effects; Age related macular degeneration; Angiogenesis Inhibitors; Animal Model; Anterior; Antibodies; Area; Back; Bathing; Biodistribution; Blindness; Cataract; Catheters; Choroid; Choroid Diseases; Choroidal Neovascularization; Clinical; Devices; Diabetic Retinopathy; Dimensions; Disease; Disorder by Site; Drug Administration Routes; Drug Compounding; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug Targeting; Drug usage; Elderly; Electroretinography; Endophthalmitis; Eye; Histopathology; Injection of therapeutic agent; Investigation; Knowledge; Laboratories; Lateral; Lead; Measures; Methods; Modeling; Molecular Weight; Monitor; Needles; Oryctolagus cuniculus; Paper; Pharmaceutical Preparations; Pharmacodynamics; Physiologic Intraocular Pressure; Procedures; Property; Publishing; Research; Research Personnel; Retina; Retinal Detachment; Retinal Diseases; Retinitis Pigmentosa; Route; Safety; Science; Sclera; Site; Solubility; Solutions; Staging; Surface; System; Technology; Testing; Therapeutic; Therapeutic Agents; Tissues; Translations; Uveitis; Vascular Endothelial Growth Factors; Vitreous humor; Work; base; bevacizumab; controlled release; design; drug distribution; drug efficacy; effective therapy; experience; hypodermic needle; improved; in vivo; innovation; innovative technologies; intravitreal injection; lipophilicity; macromolecule; member; minimally invasive; multidisciplinary; novel; patient safety; pressure; public health relevance; small molecule; standard of care; targeted delivery; therapy outcome

Intravitreal injection has become the standard of care for drug delivery to the back of the eye. While this method administers drug to the eye, it does not target drug delivery within the eye to the sites of therapeutic action, specifically in the choroid and retina. This leads to inefficient use of the drug and possible side effects at off-target sites, especially in the anterior segment. Moreover, repeated intravitreal injections are associated with side effects including endophthalmitis, retinal detachment, and cataracts. In this proposal, we seek to target drug delivery to the sites of therapeutic action in choroid and retina by injecting drugs into the suprachoroidal space (SCS) using a microneedle. The SCS is a potential space between sclera and choroid that can be accessed selectively and in a minimally invasive way using a microneedle measuring hundreds of microns long. Drug targeted into the SCS bathes the choroidal surface and adjacent retina, rather than distributing drug throughout the posterior segment, as occurs after intravitreal injection. A few studies, mostly from our laboratories, have demonstrated feasibility of drug delivery to SCS. This multidisciplinary project will provide the first in-depth study of suprachoroidal drug delivery targeted using microneedles and thereby develop novel drug delivery technologies that set the stage for clinical translation. This project will study drug delivery to the SCS to improve treatment of choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD), which is the leading cause of blindness in the elderly. We will study administration of bevacizumab, a macromolecular antibody drug in widespread clinical use for this indication, and pazopanib, a small-molecule, anti-angiogenic drug under investigation to treat CNV. Our preliminary studies indicate that drug administration to the SCS offers superior tissue-specific targeting to the posterior segment and especially to the choroid and adjacent retina. Based on these findings, our long- term objective is to develop minimally invasive, targeted drug delivery methods that are superior to intravitreal injections, in order to enhance drug efficacy, while minimizing drug and injection-related side effects in treating CNV. In this study, we will test the hypothesis that suprachoroidal drug delivery offers a safe route of administration for sustained and effective therapy of posterior segment diseases such as CNV. The project has three specific aims: 1) Design and fabricate a minimally invasive microneedle device and determine its effect on targeted suprachoroidal delivery. 2) Determine the effect of drug physicochemical properties and sustained- release formulations on drug pharmacokinetics and biodistribution in the tissues of the back of the eye after suprachoroidal delivery. 3) Determine the efficacy and safety of suprachoroidal delivery of a small molecule drug and a macromolecule drug for sustained-release treatment of choroidal neovascularization. In addition to improving CNV therapy, the outcomes of this project will provide innovative targeted solutions for treating other posterior segment disorders including diabetic retinopathy, dry AMD, retinitis pigmentosa, and uveitis.

玻璃体内注射已成为向眼睛递送药物的护理标准。同时 方法将药物施用到眼睛，它不会针对眼睛内的药物输送到治疗部位 动作，特别是在脉络膜和视网膜中。这导致药物的使用效率低下，并在 脱离目标的位置，尤其是在前部。此外，重复的玻璃体内注射是相关的 具有副作用，包括内嗜性，视网膜脱离和白内障。 在此提案中，我们试图将药物送入脉络膜和视网膜治疗作用部位 使用微针将药物注射到甲状腺类空间（SC）中。 SC是一个潜在的空间 在巩膜和脉络膜之间，可以使用A 微针长数百微米。靶向SCS的药物沐浴脉络膜表面 和相邻的视网膜，而不是在整个后部分布药物，如玻璃体内后发生 注射。一些研究，主要来自我们的实验室，已经证明了向SCS递送药物的可行性。 这个多学科项目将提供针对使用 微针，从而开发了新型的药物输送技术，为临床翻译奠定了基础。 该项目将研究给SCS的药物输送以改善脉络膜新生血管的治疗（CNV） 与年龄相关的黄斑变性（AMD）相关，这是失明的主要原因 老年。我们将研究贝伐单抗的给药，贝伐单抗是一种大分子抗体药物 用于这种适应症和一种正在研究的小分子的抗血管生成药物Pazopanib来治疗CNV。 我们的初步研究表明，对SCS的药物给药提供了较高的组织特异性靶向 到后段，尤其是脉络膜和相邻视网膜。基于这些发现，我们的长期 术语目标是开发最低侵入性的靶向药物输送方法，优于玻璃体室内 注射，以增强药物疗效，同时最大程度地减少药物和注射相关的副作用 CNV。在这项研究中，我们将检验以下假设，即胸骨类药物提供了安全的途径 治疗后部疾病（例如CNV）的持续有效治疗。该项目有 三个具体目的：1）设计和制造微创微针设备并确定其效果 在靶向上的上递送上。 2）确定药物物理化学特性和持续性的影响 - 释放有关药物药代动力学和生物分布在眼后组织的制剂。 胸骨上的递送。 3）确定小分子的上递送的疗效和安全性 药物和大分子药物，用于持续释放脉络膜新生血管形成。此外 改善CNV疗法，该项目的结果将提供创新的目标解决方案，以治疗其他 后段疾病，包括糖尿病性视网膜病，干燥AMD，色素性视网膜炎和葡萄膜炎。