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.

项目总结 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是复杂的。 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 由于糖尿病等健康状况与炎症、氧化应激和 山梨醇的积累，以及蛋白质或脂肪分子与糖分子的共价键导致 晚期糖基化终末产物(AGE)形成增加，可对细胞造成重大损害 还有纸巾。使用传统药物来对抗这些影响的努力往往会导致严重的副作用。 超过了带来的好处。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 姜黄素的理化和药理性质我们制备了可生物降解的姜黄素纳米系统 聚乳酸-乙交酯(PLGA)包裹姜黄素(NCUR)。当给予NCUR时，这些被动吸收 每天8 mg/kg姜黄素延缓糖尿病大鼠白内障的效果明显优于普通姜黄素。 不受血糖降低的影响。尽管被动nCUR的性能得到了增强，但显著的剂量 在肠道中仍未被吸收，这表明有可能通过活性纳米系统进一步改进。 第一次，我们提出了一种非竞争性的主动运输策略来改善药物在 通过开发在竞争性配体世界中没有等价物的载体系统来建立生物障碍。我们 转铁蛋白受体(TFR)介导的跨肠屏障和眼部血运的假说 屏障(BOB)将显著增强纳米系统的运输，使全身抗炎 治疗变成了现实。 在这项建议中，我们会继续研究非竞争性主动药物输送策略，以及 了解全身性抗炎治疗如何预防或延缓糖尿病性白内障 手术后发炎。为了验证这一假设，我们提出了以下具体目标：目标#1.建立 TFR促进PLGA-GA NS跨IB和BOB转运的有效性。目标2. 在合适的大鼠模型中建立由于主动运输而产生的期望或不期望的影响的大小。目标 #3.我们将在更像男人的模型中验证这一交付策略的性能。在本研究结束时，我们将 有有效的全身性抗炎治疗，以预防或延缓糖尿病白内障和治疗后遗症 外科炎症。