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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要目前，手术干预是白内障的唯一治愈方法，尽管患者可能会复杂糖尿病。患有糖尿病患者的最常见术后并发症之一是持续性炎症（葡萄膜炎），可能引起明显的角膜水肿，后肌和进展糖尿病性视网膜病或新生血管瘤。有大量证据表明次生白内障形成由于健康状况（例如糖尿病），炎症，氧化应激和山梨糖醇的积累，以及蛋白质或脂质分子与糖分子的共价键高级糖基化最终产物（年龄）形成的增加，可能对细胞造成重大损害和组织。使用传统药物对抗这些作用的努力通常会导致严重的副作用超过利益。另一方面，天然化合物（例如姜黄素）提供了承诺，但由于缺乏合适的剂型和差的生物利用度，因此进展受到阻碍。为了克服劣等姜黄素的物理化学和药理属性我们已经准备了可生物降解的纳米系统囊化姜黄素（NCUR）（NCUR）。这些被动地吸收了NCUR 在延迟啮齿动物的糖尿病性白内障方面，8 mg/kg/天比普通姜黄素更有效，独立于葡萄糖还原。尽管被动NCUR的性能提高，但大量剂量在肠道中仍然没有吸收，表明通过活动纳米系统进一步改进的潜力。我们首次提出了一种非竞争性的主动运输策略，以改善跨越药物的运输通过开发在竞争性配体领域没有等效的载体系统来建立生物障碍。我们假设转铁蛋白受体（TFR）介导的肠壁（IB）和血管的传递障碍物（BOB）将显着增强纳米系统的运输治疗是一种现实。在此提案中，我们将继续研究非竞争激烈的活动药物输送策略和了解系统性抗炎疗法将如何预防或延迟糖尿病性白内障并管理手术后炎症。为了检验这一假设，我们提出以下特定目的：目标＃1。建立 TFR在大鼠模型中促进PLGA-GA NS跨IB和BOB的运输方面的有效性。目标＃2。由于主动转运而在合适的大鼠模型中建立所需或不希望效应的大小。目的＃3。我们将以更类似人的模型来验证这种交付策略的性能。在这项研究结束时，我们将进行有效的全身性抗炎疗法，以预防或延迟糖尿病性白内障并治疗手术炎症。