Nanochelation Therapies for Iron Overload Disorders

纳米螯合疗法治疗铁过载疾病

• 批准号: 10318332
• 负责人: Hak Soo Choi
• 金额: $ 64.36万
• 依托单位: UNIVERSITY OF MASSACHUSETTS LOWELL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318332
• 关键词: Nanochelation; Therapies; Iron; Overload; Disorders

PROJECT SUMMARY/ABSTRACT Iron overload, best represented by hereditary hemochromatosis (primary/genetic iron overload) and transfusional hemoglobinopathy (secondary/acquired iron overload), is a well-defined risk factor for several critical diseases, including heart failure, liver cirrhosis, arthritis, diabetes and neurodegenerative diseases. Iron chelators are clinically used to reduce iron burden, but the use of chelators is limited by a number of significant side effects, including hypotension, tachycardia, agranulocytosis, neutropenia, ocular/auditory toxicities, loss of essential nutrients, musculoskeletal-joint pains, gastrointestinal bleeding, hepatic fibrosis and renal failure. Considering tens of millions of people affected by various types of iron overload disorders, there are urgent needs for a new therapeutic strategy to minimize unwanted adverse effects of chelators by controlling the fate of iron-chelator complex in the body. The hypothesis guiding this study is that iron chelators coated onto size- and surface-modified nanoparticles (“nanochelators”) will collect excess iron from various body compartments, and the iron-chelator-nanoparticle complexes will be exclusively cleared by two major excretion pathways: into the urinary bladder by renal excretion and into the gallbladder/gut by biliary excretion depending on the size and surface properties of nanoparticles. The specific aims of this study are focused on 1) developing multifunctional chelator-coated urine-targeted nanoparticles (UNPs) to effectively harvest circulating and labile iron and dispose the iron-UNP complex by urinary excretion, 2) engineering surface-modified, chelator-coated bile-targeted nanoparticles (BNPs) to dispose excess iron exclusively by the biliary secretion pathway, 3) characterizing the in vivo pharmacokinetics and pharmacodynamics of developed nanochelators in iron disposal using clinically-relevant mouse and rat models of iron overload, and 4) evaluating the therapeutic efficacy of nanochelators in the amelioration of physiological complications associated with iron overload disorders. Overall, this strategy provides a safe and effective method with increased benefit/risk ratios of iron chelators to support therapeutic benefits over numerous iron overload disorders by a combination of nanotechnology and transgenic animal models of iron overload. Furthermore, the idea of “targeted clearance” can be tested for the facilitated elimination of other toxic substances, such as heavy metals and drugs of abuse, from the body. By addressing these questions, we hope to both identify novel therapeutic approaches and improve clinical outcomes.

项目摘要/摘要 铁超负荷，以遗传性血色素症（主要/遗传铁超载）和 输血血红蛋白病（次级/获得的铁超载），是几个定义的危险因素 关键疾病，包括心力衰竭，肝硬化，关节炎，糖尿病和神经退行性疾病。铁 螯合剂在临床上用于减少铁伯嫩，但螯合剂的使用受到许多重要的限制 副作用，包括低血压，心动过速，农业细胞增多症，中性粒细胞减少，眼/听觉毒性，丧失 必需的营养素，肌肉骨骼接头疼痛，胃肠道出血，肝纤维化和肾衰竭。 考虑到受各种铁超载障碍影响的数以千万万的人，紧急 需要一种新的理论策略，以最大程度地减少螯合剂的不良不利影响 体内的铁旋转剂配合物。指导这项研究的假设是涂在尺寸上的铁螯合剂 和表面修饰的纳米颗粒（“纳米插剂”）将从各种身体室中收集超过铁， 并将仅通过两个主要排泄途径清除铁旋剂 - 纳米颗粒复合物：进入 肾脏排泄的膀胱，并通过胆道排泄量进入胆囊/肠道 纳米颗粒的表面特性。这项研究的具体目的侧重于1） 多功能螯合剂涂层的尿液靶向纳米颗粒（UNP）有效收获循环和不稳定 铁并通过尿液排泄来处理铁 - unp复合物，2）工程表面修饰的螯合剂涂层 针对胆汁的纳米颗粒（BNP），仅由胆道分泌途径处置多余的铁，3） 表征铁中发达的纳米胆素的体内药代动力学和药效学 使用与临床相关的小鼠和铁超载的大鼠模型处置，4）评估治疗性 纳米体的功效在与铁超负荷相关的生理并发症改善方面的功效 疾病。总体而言，该策略提供了一种安全有效的方法，并增加了铁的收益/风险比率 螯合剂通过结合 铁超载的纳米技术和转基因动物模型。此外，“有针对性的清理”的想法 可以测试是否准备消除其他有毒物质，例如重金属和药物 虐待，身体。通过解决这些问题，我们希望既可以识别新颖的治疗方法 并改善临床结果。