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Nanochelation Therapies for Iron Overload Disorders

纳米螯合疗法治疗铁过载疾病

基本信息

批准号：
10437625
负责人：
Hak Soo Choi
金额：
$ 54.3万
依托单位：
UNIVERSITY OF MASSACHUSETTS LOWELL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10437625
关键词：
Acute Address Adverse effects Affect Agranulocytosis Anemia Animal Model Animals Area Arthralgia Arthritis Auditory Bile fluid Biliary Biodistribution Biological Availability Biological Markers Bladder Blood Circulation Blood Transfusion Caucasians Chelating Agents Chronic Clinical Complex Contrast Media Deferoxamine Diabetes Mellitus Disease Dose Drug Kinetics Drug or chemical Tissue Distribution Dysmyelopoietic Syndromes Engineering Excision Excretory function Family suidae Feces Ferritin Gallbladder Gastrointestinal Hemorrhage Genetic Genetic Diseases Harvest Healthcare Heart failure Heavy Metals Hematopoietic Hemoglobinopathies Hepatotoxicity Hereditary hemochromatosis Hydrogels Hypotension Image Impairment Implant Injections Iron Iron Chelating Agents Iron Chelation Iron Overload Kidney Kidney Failure Kinetics Life Liver Liver Cirrhosis Liver Fibrosis Lysine Mediating Metabolism Metals Methods Modeling Monitor Mus Musculoskeletal Nanotechnology Neurodegenerative Disorders Neutropenia Nutrient Nutritional Organ Outcome Oxidative Stress Pathway interactions Patients Pharmacodynamics Physiological Physiology Plasma Poison Population Rattus Reporting Risk Risk Factors Rodent Safety Sickle Cell Anemia Site Surface Surface Properties Systemic Therapy Tachycardia Testing Thalassemia Therapeutic Time Tissues Toxic effect Toxicity Tests Transgenic Animals Travel Treatment Efficacy Urine Venous blood sampling absorption base biomaterial compatibility carboxylate chelation clinically relevant cohort design drug of abuse flexibility heart damage heart function improved in vivo iron chelation therapy nanoparticle nephrotoxicity novel therapeutic intervention pharmacokinetics and pharmacodynamics predictive modeling response risk benefit ratio side effect targeted delivery targeted imaging urinary

项目摘要

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/摘要铁超载，最好的表现为遗传性血色素沉着症(原发/遗传性铁超载)和输血性血红蛋白病(继发性/获得性铁超载)是一种明确定义的危险因素严重疾病，包括心力衰竭、肝硬变、关节炎、糖尿病和神经退行性疾病。铁螯合剂在临床上用来减少铁负荷，但它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、眼/听毒性、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超负荷紊乱的影响，有迫切的需要一种新的治疗策略，通过控制命运将螯合剂的不良反应降至最低体内的铁-螯合剂复合体。指导这项研究的假设是，包覆在浆料上的铁络合剂- 而表面修饰的纳米颗粒(“纳米螯合剂”)将从不同的身体隔间收集多余的铁，铁-螯合剂-纳米颗粒复合体将通过两条主要的排泄途径被完全清除：进入膀胱通过肾脏排泄，通过胆汁排泄进入胆囊/肠道，具体取决于大小以及纳米颗粒的表面性质。这项研究的具体目的集中在1)发展多功能螯合剂包裹尿靶向纳米粒(UNPS)有效采集循环和不稳定的铁并通过尿液排泄来处理铁-UNP复合体，2)工程表面改性，螯合剂涂层胆汁靶向纳米颗粒(BNPS)通过胆汁分泌途径来处理多余的铁，3) 铁纳米螯合剂的体内药代动力学和药效学研究使用临床相关的铁超载小鼠和大鼠模型进行处理，以及4)评估治疗纳米螯合剂改善铁超载相关生理性并发症的疗效精神错乱。总体而言，这一战略提供了一种安全有效的方法，提高了铁的收益/风险比螯合剂支持多种铁过载障碍的治疗效果，其组合纳米技术和铁超载的转基因动物模型。此外，“定向清除”的想法可以进行测试，以便于消除其他有毒物质，如重金属和虐待，来自身体。通过解决这些问题，我们希望既能找到新的治疗方法并改善临床结果。