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.

项目概要/摘要 铁过载，最典型的是遗传性血色素沉着症（原发性/遗传性铁过载）和 输血性血红蛋白病（继发性/获得性铁超负荷）是多种疾病的明确危险因素 严重疾病，包括心力衰竭、肝硬化、关节炎、糖尿病和神经退行性疾病。 螯合剂在临床上用于减少铁负荷，但螯合剂的使用受到许多重要因素的限制。 副作用，包括低血压、心动过速、粒细胞缺乏症、中性粒细胞减少症、眼/听觉毒性、丧失 必需营养素、肌肉骨骼关节疼痛、胃肠道出血、肝纤维化和肾功能衰竭。 考虑到数以千万计的人受到各种类型的铁过载疾病的影响，迫切需要 需要一种新的治疗策略，通过控制命运来最大限度地减少螯合剂的不良副作用 这项研究的指导性假设是铁螯合剂涂在尺寸上。 表面改性纳米颗粒（“纳米螯合剂”）将从身体各个部位收集多余的铁， 铁-螯合剂-纳米颗粒复合物将通过两个主要排泄途径被专门清除：进入 根据大小，通过肾脏排泄进入膀胱，通过胆汁排泄进入胆囊/肠道 本研究的具体目标集中在 1) 开发。 多功能螯合剂涂层的尿液靶向纳米颗粒（UNP）可有效收集循环和不稳定的纳米颗粒 铁并通过尿液排泄处理铁-UNP复合物，2) 工程表面改性、螯合剂涂层 胆汁靶向纳米颗粒 (BNP) 仅通过胆汁分泌途径处理多余的铁，3) 表征已开发的铁纳米螯合剂的体内药代动力学和药效学 使用临床相关的铁过载小鼠和大鼠模型进行处置，以及 4) 评估治疗效果 纳米螯合剂改善铁超载相关生理并发症的功效 总体而言，该策略提供了一种安全有效的方法，提高了铁的获益/风险比。 螯合剂通过组合来支持对多种铁超载疾病的治疗效果 纳米技术和铁超载的转基因动物模型此外，“靶向清除”的想法。 可以测试是否有助于消除其他有毒物质，例如重金属和药物 通过解决这些问题，我们希望找到新的治疗方法。 并改善临床结果。