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药物递送至眼后部的护理标准。虽然这 虽然该方法将药物施用到眼睛，但其不将眼睛内的药物递送靶向到治疗性眼内痛的部位。 作用，特别是在脉络膜和视网膜。这导致药物的低效使用和可能的副作用， 脱靶部位，尤其是眼前节。此外，反复玻璃体内注射与 其副作用包括眼内炎、视网膜脱落和白内障。 在这个提议中，我们寻求通过以下方式将药物递送靶向到脉络膜和视网膜中的治疗作用部位： 使用微针将药物注射到脉络膜上腔（SCS）中。南海是一个潜在的空间 在巩膜和脉络膜之间，可以选择性地并以微创方式使用 数百微米长的微型针。靶向SCS的药物冲洗脉络膜表面 和邻近的视网膜，而不是将药物分布在整个后段，如玻璃体内注射后发生的那样。 注射一些研究，主要来自我们的实验室，已经证明了药物输送到SCS的可行性。 这个多学科项目将提供第一个深入研究脉络膜上的药物输送靶向使用 微针，从而开发新的药物输送技术，为临床转化奠定基础。 该项目将研究药物输送到SCS以改善脉络膜新生血管（CNV）的治疗 与年龄相关性黄斑变性（AMD）有关，这是失明的主要原因， 老人我们将研究贝伐单抗，一种大分子抗体药物，在广泛的临床应用中的给药情况。 用于该适应症，以及帕唑帕尼，一种正在研究中的治疗CNV的小分子抗血管生成药物。 我们的初步研究表明，药物管理的SCS提供了优越的上级组织特异性靶向 到后段，特别是到脉络膜和邻近的视网膜。基于这些发现，我们的长期- 长期目标是开发上级玻璃体内给药的微创靶向药物递送方法， 注射，以提高药物疗效，同时尽量减少药物和注射相关的副作用，在治疗 CNV.在这项研究中，我们将检验脉络膜上腔给药提供了一种安全的给药途径的假设。 用于持续和有效治疗后段疾病如CNV的给药。该项目 三个具体目标：1）设计和制造微创微针装置并确定其效果 靶向脉络膜上腔给药2)测定药物的理化性质和持续作用- 释放制剂对眼后部组织中药物药代动力学和生物分布的影响 脉络膜上腔分娩3)确定脉络膜上递送小分子的有效性和安全性 用于脉络膜新生血管的缓释治疗。除了 改善CNV治疗，该项目的成果将为治疗其他 后段疾病，包括糖尿病性视网膜病、干性AMD、色素性视网膜炎和葡萄膜炎。