Systemic anti-inflammatory therapy to prevent or delay diabetic cataracts and treat post-surgical inflammation

全身抗炎治疗可预防或延缓糖尿病性白内障并治疗术后炎症

• 批准号: 9752567
• 负责人: Ravikumar N Majeti
• 金额: $ 37.13万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752567
• 关键词: Active Biological Transport; Active Sites; Acute; Advanced Glycosylation End Products; Animals; Anti-inflammatory; Behavior; Binding; Biochemical Pathway; Biological; Biological Availability; Blood; Blood - brain barrier anatomy; Blood Circulation; Brain; Caco-2 Cells; Canis familiaris; Cataract; Cataract Extraction; Cell Death; Cells; Clinical; Clinical Trials; Corneal edema; Crystallins; Curcumin; Development; Diabetes Mellitus; Diabetic Retinopathy; Disease; Disease Progression; Dosage Forms; Dose; Drug Delivery Systems; Drug Targeting; Drug Transport; Effectiveness; Encapsulated; Eye diseases; Fc Receptor; Galactose; Glucose; Goals; Health; Human; Immune response; Incidence; Inferior; Infiltration; Inflammation; Intestines; Kinetics; Ligands; Lipids; Mediating; Modeling; Monitor; Neovascular Glaucoma; Operative Surgical Procedures; Oral; Outcome; Oxidative Stress; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Pharmacology; Plasma; Polymers; Postoperative Complications; Postoperative Period; Property; Proteins; Rattus; Regimen; Risk; Rodent; Safety; Sorbitol; Surface; System; TFRC gene; Testing; Therapeutic; Therapeutic Index; Time; Tissues; Transferrin; Translations; Uveitis; Vision; base; combat; covalent bond; density; diabetes management; diabetic; diabetic cataract; diabetic rat; dosage; gambogic acid; hydrophilicity; improved; in vivo; innovation; macrophage; man; nanoparticle; nanosystems; novel; poly(lactide); polyol; prevent; receptor; side effect; small molecule; sugar; treatment strategy

PROJECT SUMMARY Currently, surgical intervention is the only cure for cataracts, though this can be complicated in patients with diabetes. One of the most common postoperative complications in patients suffering from diabetes is persistent inflammation (uveitis) that can cause significant corneal edema, posterior synechia, and progression of diabetic retinopathy or neovascular glaucoma. There is substantial evidence that secondary cataract formation due to health conditions such as diabetes are associated with increased inflammation, oxidative stress, and sorbitol accumulation, along with covalent bonding of a protein or lipid molecule with a sugar molecule causing an increase in advanced glycosylation end products (AGE) formation that can cause significant damage to cells and tissues. The efforts to combat these effects using traditional drugs often leads to severe side effects outweighing the benefits. On the other hand natural compounds such as curcumin offer promise, but their progress is hampered due to lack of suitable dosage forms and poor bioavailability. In order to overcome inferior physicochemical and pharmacological attributes of curcumin we have prepared biodegradable nanosystems of polylactide-co-glycolide (PLGA) encapsulating curcumin (nCUR). These passively absorbed nCUR when given 8 mg/kg/day were significantly more effective than plain curcumin in delaying diabetic cataract in rodents, independent of glucose reduction. Despite the enhanced performance of passive nCUR, a significant dose remained unabsorbed in the intestine, indicating potential for further improvement through active-nanosystems. For the first time, we present a non-competitive active transport strategy to improve drug transport across biological barriers by developing carrier systems that have no equivalent in the world of competitive ligands. We hypothesize that transferrin receptor (TfR) mediated delivery across the intestinal barriers (IB) and blood ocular barriers (BOB) would significantly enhance the transport of the nanosystems making systemic anti-inflammatory therapy a reality. In this proposal, we will continue our studies on non-competitive active drug delivery strategy and understand how the systemic anti-inflammatory therapy will prevent or delay diabetic cataracts and manage post-surgical inflammation. To test this hypothesis, we propose the following specific aims: AIM #1. Establish the effectiveness of TfR in facilitating the transport of PLGA-GA NS across the IB and BOB in rat model. AIM #2. Establish the magnitude of desired or undesired effects in suitable rat models as a result of active transport. AIM #3. We will verify performance of this delivery strategy in a more man-like model. At the end of this study, we will have an effective systemic anti-inflammatory therapy to prevent or delay diabetic cataracts and treat post- surgical inflammation.

项目概要 目前，手术干预是治疗白内障的唯一方法，尽管这对患者来说可能很复杂 患有糖尿病。糖尿病患者最常见的术后并发症之一是 持续性炎症（葡萄膜炎），可导致严重的角膜水肿、后粘连和进展 糖尿病视网膜病变或新生血管性青光眼。有大量证据表明继发性白内障的形成 由于糖尿病等健康状况与炎症、氧化应激增加和 山梨醇积累，以及蛋白质或脂质分子与糖分子的共价键合，导致 高级糖基化终产物 (AGE) 形成增加，可能对细胞造成严重损害 和纸巾。使用传统药物对抗这些影响的努力通常会导致严重的副作用 超过了好处。另一方面，姜黄素等天然化合物提供了希望，但它们的 由于缺乏合适的剂型和生物利用度差，进展受到阻碍。为了克服劣势 根据姜黄素的理化和药理学特性，我们制备了可生物降解的纳米系统 聚丙交酯-乙交酯 (PLGA) 封装姜黄素 (nCUR)。这些被动吸收的 nCUR 给予时 8 毫克/公斤/天在延缓啮齿动物糖尿病性白内障方面比普通姜黄素显着更有效， independent of glucose reduction.尽管被动 nCUR 的性能增强，但显着的剂量 在肠道中仍未被吸收，表明通过活性纳米系统进一步改善的潜力。 我们首次提出一种非竞争性主动转运策略来改善跨区域药物转运 通过开发在竞争性配体领域中无可比拟的载体系统来打破生物屏障。我们 假设转铁蛋白受体 (TfR) 介导跨肠屏障 (IB) 和血眼传递 屏障（BOB）将显着增强纳米系统的运输，从而实现全身抗炎 治疗成为现实。 在本提案中，我们将继续研究非竞争性主动给药策略和 了解全身抗炎治疗如何预防或延缓糖尿病性白内障并进行治疗 手术后炎症。为了检验这一假设，我们提出以下具体目标：AIM #1。建立 在大鼠模型中，TfR 促进 PLGA-GA NS 跨 IB 和 BOB 转运的有效性。目标#2。 确定适当的大鼠模型中主动转运所产生的所需或不良影响的程度。目的 ＃3。我们将在一个更像人的模型中验证这种交付策略的性能。在本研究结束时，我们将 进行有效的全身抗炎治疗，以预防或延缓糖尿病性白内障的发生并治疗糖尿病后白内障 手术炎症。