Enhancing ocular uptake of thiol antioxidants with nanodiamonds

用纳米金刚石增强硫醇抗氧化剂的眼部吸收

• 批准号: 9812458
• 负责人: NURAN ERCAL
• 金额: $ 38.75万
• 依托单位: MISSOURI UNIVERSITY OF SCIENCE & TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9812458
• 关键词: Acids; Address; Adsorption; Age; Americas; Animal Model; Animals; Antioxidants; Area; Blindness; Cataract; Cataract Extraction; Chemicals; Chemistry; Complex; Cornea; Crystallins; Destinations; Development; Disease; Dose; Drug Delivery Systems; Ensure; Epithelial; Epithelium; Equilibrium; Eugenol; Excision; Exhibits; Eye; Eyedrops; Formulation; Free Radical Scavenging; Gel; Glutathione; Glutathione Disulfide; Goals; Human; In Vitro; Lens Opacities; Lipid Peroxidation; Liquid substance; Measures; Mechanics; Microscopy; Modeling; Monitor; Mus; Nuclear; Operative Surgical Procedures; Oral; Oxidation-Reduction; Oxidative Stress; Patients; Penetration; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Poloxamers; Property; Public Health; Reporting; Research; Risk; Rodent; Role; Route; Rupture; Site; Sulfhydryl Compounds; Surface; Testing; Time; Tissues; Topical application; Vascular blood supply; World Health Organization; age related; anterior chamber; antioxidant enzyme; base; biomaterial compatibility; carboxylate; common treatment; corneal epithelium; cost; design; effective therapy; enzyme activity; experimental study; eye chamber; eye preservation; functional group; improved; in vitro Model; in vivo; insight; lens; lens transparency; nanodiamond; nanoparticle; novel; novel therapeutics; oxidation; oxidative damage; premature; preservation; prevent; residence; side effect; theranostics; uptake; zeta potential

Project Summary/ Abstract Surgery is the only effective treatment for cataract, the most common cause of blindness worldwide. Although cataract surgery is routine and generally considered safe, it is costly and carries risks of serious complications (e.g., capsular opacification or rupture). Thus, there is a high demand for an effective topical treatment that can prevent this debilitating disease. Cataract is caused by the aggregation of lens proteins, which is associated with accumulated oxidative damage that occurs throughout one’s lifetime. Glutathione (GSH), the most important endogenous redox regulator, is highly concentrated in the lens and protects against oxidative damage. However, levels of GSH in the lens decrease with age, leaving the lens vulnerable to oxidative damage. Antioxidants that can penetrate ocular tissue have the potential to protect the lens proteins and to restore GSH. 2- Mercaptopropionylglycine (MPG), also known as tiopronin, is a thiol antioxidant drug that appears to exhibit anticataract activity. However, its ability to penetrate ocular tissues when administered in eye drop form is limited. To overcome this problem, we will investigate a novel nanodiamond (ND) drug delivery vehicle for ocular administration of MPG. The reasons for ND use are three-fold: (1) NDs can improve ocular uptake of topically administered drugs by providing sustained release on the corneal surface, (2) NDs have been shown to enhance antioxidant activity and suppress photodegradation of the adsorbed molecules, thereby protecting MPG from premature oxidation and inactivation, and (3) NDs are excellent drug delivery platforms: they are non-toxic and chemically stable, while also exhibiting large surface area-to-mass and highly tailorable surface chemistry for optimization of interactions with drugs and tissues at their intended destination. The project’s long-term goal is to develop a topically applied formulation that can halt or significantly delay progression of cataracts. The Specific Aims of this proposed research are (1) to determine the optimal surface chemistry of the novel nanodiamond (ND) drug delivery platform for enhancing corneal penetration of MPG, (2) to determine whether NDs can preserve or promote the antioxidant efficacy of MPG, and (3) to investigate the efficacy of NDs for promoting the anticataract effects of MPG in vivo. We will characterize NDs with various surface chemistries and test their ability to deliver MPG using in vitro models of corneal and lens epithelium. We will also investigate antioxidant properties and photostability of NDs alone and in complexes with MPG in both in vitro models. To accomplish the third aim, we will use the Emory mouse, a model of age-related nuclear cataracts, which will be treated with eye drops containing MPG adsorbed to NDs prior to cataract development. We will evaluate the ability of ND-MPG eye drops to prevent cataracts by monitoring cataract formation via slit- lamp microscopy during treatment. Levels of MPG and its metabolite 2-mercaptopropionic acid (MPA), will be measured in tear fluid and ocular tissues to determine the extent of drug release and penetration. Various markers of oxidative stress including GSH/GSSG ratio, antioxidant enzyme activities, and lipid peroxidation will be measured in the ocular tissues to determine if ND improve antioxidant activity of MPG.

项目概要/摘要 手术是治疗白内障的唯一有效方法，白内障是全世界最常见的致盲原因。虽然 白内障手术是常规手术，通常被认为是安全的，但成本高昂且存在严重并发症的风险 （例如，囊膜混浊或破裂）。因此，迫切需要一种有效的局部治疗方法 预防这种使人衰弱的疾病。白内障是由晶状体蛋白聚集引起的，这与 一生中发生的累积氧化损伤。谷胱甘肽（GSH），最重要的 内源性氧化还原调节剂，高度集中在镜片中，可防止氧化损伤。然而， 晶状体中的谷胱甘肽水平随着年龄的增长而降低，使得晶状体容易受到氧化损伤。抗氧化剂 可以穿透眼组织，具有保护晶状体蛋白和恢复 GSH 的潜力。 2- 巯基丙酰甘氨酸 (MPG)，也称为硫普罗宁，是一种硫醇抗氧化药物，似乎表现出 抗白内障活动。然而，当以滴眼剂形式给药时，其穿透眼组织的能力有限。 为了克服这个问题，我们将研究一种用于眼部的新型纳米金刚石（ND）药物递送载体 MPG 的管理。使用 ND 的原因有三个：(1) ND 可以改善眼部对局部药物的吸收 通过在角膜表面提供持续释放来施用药物，(2) ND 已被证明可以增强 抗氧化活性并抑制吸附分子的光降解，从而保护 MPG 免受 过早氧化和失活，以及 (3) ND 是优秀的药物递送平台：它们无毒且 化学稳定，同时还表现出大的表面积与质量和高度可定制的表面化学 优化与药物和组织在预定目的地的相互作用。 该项目的长期目标是开发一种局部应用的配方，可以阻止或显着延迟 白内障的进展。本研究的具体目标是 (1) 确定最佳表面 用于增强 MPG 角膜渗透性的新型纳米金刚石 (ND) 药物递送平台的化学成分，(2) 确定 ND 是否可以保留或促进 MPG 的抗氧化功效，以及 (3) 研究 NDs 促进 MPG 体内抗白内障作用的功效。我们将用各种不同的方式来描述 ND 的特征 表面化学并使用角膜和晶状体上皮的体外模型测试其传递 MPG 的能力。我们 还将研究 ND 单独使用以及与 MPG 复合的抗氧化特性和光稳定性 体外模型。为了实现第三个目标，我们将使用埃默里小鼠，一种与年龄相关的核模型 白内障，在白内障发生前，使用含有 ND 吸附的 MPG 的滴眼液进行治疗。 我们将通过狭缝监测白内障形成来评估 ND-MPG 滴眼液预防白内障的能力。 治疗期间的灯显微镜检查。 MPG 及其代谢物 2-巯基丙酸 (MPA) 的水平将 测量泪液和眼组织以确定药物释放和渗透的程度。各种各样的 氧化应激标志物包括 GSH/GSSG 比率、抗氧化酶活性和脂质过氧化作用 在眼组织中进行测量，以确定 ND 是否可以提高 MPG 的抗氧化活性。