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: 10608566
• 负责人: Ravikumar N Majeti
• 金额: $ 8.54万
• 依托单位: UNIVERSITY OF ALABAMA IN TUSCALOOSA
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10608566
• 关键词: Active Biological Transport; Active Sites; Acute; Advanced Glycosylation End Products; Animals; Anti-Inflammatory Agents; 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; 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; cell injury; combat; covalent bond; density; diabetes management; diabetic; diabetic cataract; diabetic rat; dosage; efficacious treatment; gambogic acid; hydrophilicity; improved; in vivo; innovation; intestinal barrier; 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.

项目摘要 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），可导致显著的角膜水肿、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 由于健康状况，如糖尿病，与增加的炎症，氧化应激， 山梨醇积累，沿着蛋白质或脂质分子与糖分子的共价键合， 晚期糖基化终产物（AGE）形成增加，可对细胞造成重大损害 和纸巾。使用传统药物对抗这些影响的努力往往导致严重的副作用 超过了收益另一方面，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。为了克服自卑 姜黄素的物理化学和药理学属性，我们已经制备了可生物降解的纳米系统， 包封姜黄素的聚丙交酯-共-乙交酯（PLGA）（nCUR）。当给予这些被动吸收的nCUR时 8 mg/kg/天的姜黄素在延缓啮齿动物糖尿病性白内障方面比普通姜黄素显著更有效， 独立于葡萄糖减少。尽管被动nCUR的性能增强， 在肠道中保持未吸收，表明通过活性纳米系统进一步改善的潜力。 我们首次提出了一种非竞争性主动转运策略，以改善药物跨膜转运。 生物屏障，通过开发载体系统，在竞争性配体的世界中没有等价物。我们 假设转铁蛋白受体（TfR）介导的传递通过肠屏障（IB）和血眼屏障（Blood Ocular屏障）， 屏障（BOB）将显着增强纳米系统的运输，使全身抗炎 治疗成为现实 在这项建议中，我们将继续研究非竞争性主动给药策略， 了解全身抗炎治疗如何预防或延迟糖尿病性白内障， 术后炎症为了验证这一假设，我们提出了以下具体目标：目标#1。建立 在大鼠模型中TfR促进PLGA-GA NS穿过IB和BOB转运的有效性。目标#2。 在适当的大鼠模型中确定主动转运导致的预期或非预期效应的程度。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 有一个有效的全身抗炎治疗，以预防或延迟糖尿病性白内障和治疗后， 外科炎症

项目成果

Paclitaxel and Urolithin A Prevent Histamine-Induced Neurovascular Breakdown Alike, in an Ex Vivo Rat Eye Model.

• DOI: 10.1021/acschemneuro.1c00692
• 发表时间: 2022-07-20
• 期刊: ACS CHEMICAL NEUROSCIENCE
• 影响因子: 5
• 作者: Uppada, Srijayaprakash;Zou, Dianxiong;Scott, Erin M.;Ko, Gladys;Pflugfelder, Stephen;Kumar, M. N. V. Ravi;Ganugula, Raghu
• 通讯作者: Ganugula, Raghu