Long-Acting, Short-Residing Nanochelators for Iron Overload Therapy

用于铁过载治疗的长效、短效纳米螯合剂

基本信息

批准号：
10585319
负责人：
Hak Soo Choi
金额：
$ 73.42万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10585319
关键词：
Adverse effects Affect Agranulocytosis Anemia Animal Model Animals Arthritis Biochemical Biological Availability Blood Blood Transfusion Cardiomyopathies Caucasians Cessation of life Chelating Agents Chelation Therapy Chemistry Chronic Clinical Clinical Trials Column Chromatography Communication Continuous Infusion Cyclic GMP Deferoxamine Diabetes Mellitus Dialysis procedure Diamond-Blackfan anemia Disease Dose Dose Limiting Drug or chemical Tissue Distribution Dyslipidemias Dysmyelopoietic Syndromes Engineering Excision Excretory function FDA approved Family suidae Ferritin Formulation Freeze Drying Future Gastrointestinal Hemorrhage Genetic Diseases Grant Half-Life Heart failure Hematopoietic Hepatic Hereditary hemochromatosis Hydrogels Hypertriglyceridemia Hypotension Impairment Infection Inflammation Infusion procedures Injectable Injections Intravenous Iron Iron Chelating Agents Iron Chelation Iron Overload Kidney Kinetics Liver Liver Cirrhosis Liver Failure Liver Fibrosis Marketing Maximum Tolerated Dose Mediating Metabolic syndrome Metals Modeling Morbidity - disease rate Multimodal Imaging Mus National Heart, Lung, and Blood Institute Nature Neurodegenerative Disorders Nutritional Obesity Oral Organ Organic Synthesis Oxidative Stress Oxidative Stress Induction Patients Pattern Persons Plasma Polymers Population Predisposition Procedures Publications Rattus Reactive Oxygen Species Reporting Risk Factors Risk Reduction Rodent Safety Sickle Cell Anemia Site Solvents Subcutaneous Injections Tablets Thalassemia Therapeutic Tissues Toxic effect Toxicity Tests Transfusion Treatment Efficacy United States National Institutes of Health Urine absorption compliance behavior design efficacy evaluation heart damage heart function imaging system immunogenicity improved injection/infusion iron absorption milligram mortality nano nephrotoxicity novel novel therapeutic intervention older patient parenteral administration premature prototype residence response scale up side effect small molecule standard care subcutaneous systemic toxicity therapy outcome treatment adherence uptake urinary

项目摘要

Project Summary/Abstract: Iron is an essential metal, but high iron stores are toxic due to increased oxidative stress produced by iron-catalyzed reactive oxygen species. Increased iron stores are associated with well- established risk factors of heart and liver failure, arthritis, dyslipidemia, and diabetes, including obesity, metabolic syndrome, and chronic inflammation, particularly for patients who are genetically susceptible to developing iron overload. Secondary iron overload occurs in several anemias (e.g., thalassemia, myelodysplastic syndrome, sickle cell anemia, Diamond-Blackfan anemia) due to repeated transfusions, and increased absorption of iron loading from repeated transfusions can be major causes of morbidity and mortality in chronic anemia patients. There are three FDA-approved chelators in the U.S.: deferoxamine (Desferral, Novartis; IV/IM/SC injection), deferasirox (Jadenu, Exjade; Novartis; oral tablet), and deferiprone (Ferriprox, ApoPharma; oral tablet/solution). Since 1968, the prototype iron chelator deferoxamine has shown good therapeutic efficacy but requires repeated injections or continuous infusions, which considerably decreases patient compliance. To overcome this issue, two oral chelators have become available in the market (deferasirox in 2005 and deferiprone in 2011). Despite their efficient iron chelation with improved patient compliance, oral chelators have shown significant dose-limiting adverse effects. For example, deferasirox can cause gastrointestinal bleeding, which may be fatal in elderly patients, in addition to hepatic and renal toxicities. These adverse effects occur because these small molecule chelators demonstrate a higher tendency to distribute into non-target tissues, exerting toxicities. Furthermore, clinicians report that a novel, more convenient, and better-tolerated delivery of the iron chelator would improve treatment adherence and long-term therapeutic outcomes. Previously, we have successfully developed a multifunctional nanochelator that captures iron from plasma and liver, circulates without significant nonspecific uptake in non-target tissues, and leaves the body through urinary excretion. Armed with this renal clearable nanochelator, we aim to develop subcutaneous injectable hydrogel formulations with increased exposure for up to 3 weeks and with tracking the release kinetics using multimodal imaging systems longitudinally. This strategy can decrease the iron burden and reduce the risk of iron-mediated organ toxicity, with no overt chelator-related adverse effects. Therefore, our hypothesis is that a thermosensitive injectable hydrogel, which offers a long-term sustained release of iron chelators but a short-term residence in the major tissues/organs (i.e., rapid clearance upon iron chelation without accumulation), can improve the therapeutic efficacy of iron chelation while minimizing chelator-induced toxicity, beyond the current standard treatment of iron overload.

项目摘要/摘要：铁是一种必需金属，但铁含量过高会因氧化增加而有毒由铁催化的活性氧产生的应力。铁储备的增加与健康有关已确定的心力衰竭和肝衰竭、关节炎、血脂异常和糖尿病的危险因素，包括肥胖、代谢综合征和慢性炎症，特别是对于遗传上易产生铁的患者超载。继发性铁超负荷发生在多种贫血中（例如地中海贫血、骨髓增生异常综合征、由于反复输血和铁吸收增加导致的镰状细胞性贫血、戴蒙德-布莱克凡贫血反复输血造成的负荷可能是慢性贫血患者发病和死亡的主要原因。美国 FDA 批准了三种螯合剂：去铁胺（Desferral、诺华；IV/IM/SC 注射剂）、地拉罗司（Jadenu、Exjade；诺华；口服片剂）和去铁酮（Ferriprox、ApoPharma；口服片剂/溶液）。自1968年以来，铁螯合剂去铁胺原型已显示出良好的治疗效果，但需要反复试验注射或连续输注，这大大降低了患者的依从性。为了克服这个问题，两种口服螯合剂已上市（2005 年的地拉罗司和 2011 年的去铁酮）。尽管口服螯合剂具有高效的铁螯合作用和改善的患者依从性，已显示出显着的剂量限制作用不良影响。例如，地拉罗司会导致胃肠道出血，这对老年人来说可能是致命的患者，除了肝和肾毒性外。这些不良反应的发生是因为这些小分子螯合剂表现出更高的分布到非目标组织中的倾向，从而产生毒性。此外，临床医生报告说，一种新颖、更方便、耐受性更好的铁螯合剂递送方法将改善治疗依从性和长期治疗结果。此前，我们已成功开发出一种多功能纳米螯合剂，可从等离子体中捕获铁和肝脏，在非目标组织中循环，没有显着的非特异性摄取，并通过尿液排泄。有了这种肾脏可清除的纳米螯合剂，我们的目标是开发皮下注射剂水凝胶制剂增加暴露时间长达 3 周，并使用跟踪释放动力学纵向多模态成像系统。该策略可以减少铁负担并降低风险铁介导的器官毒性，没有明显的螯合剂相关的副作用。因此，我们的假设是热敏可注射水凝胶，可长期持续释放铁螯合剂，但短期内释放铁螯合剂停留在主要组织/器官中（即铁螯合后快速清除而不积累），可以提高铁螯合的治疗效果，同时最大限度地减少螯合剂引起的毒性，超出目前的水平铁超载的标准治疗。