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：铁是必不可少的金属，但是高铁存储由于氧化增加而具有毒性铁催化的活性氧产生的应力。铁存储增加与良好有关既定的心脏和肝脏衰竭，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，尤其是对于遗传上易感铁感染的患者超载。次级铁超负荷发生在几种贫血中（例如，丘脑贫血，骨髓增生综合征，镰状细胞贫血，钻石黑粉刺贫血）由于反复输血而增加，铁的吸收增加反复输血的负载可能是慢性贫血患者发病率和死亡率的主要原因。在美国有三个由FDA批准的螯合剂：脱氟胺（Deferoxamine（Desferral，Novartis; IV/IM/SC注入）， deferasirox（Jadenu，Exjade; Novartis; Oral Tablet）和脱发（Ferriprox，apopharma;口服片剂/解决方案）。自1968年以来，原型铁螯合剂脱氧胺表现出良好的治疗功效，但需要重复注射或连续输注，大大降低了患者的依从性。为了克服这个问题，市场上已经有两个口服螯合剂（2005年的Deferasirox和2011年的脱氟酮）。尽管他们的有效的铁螯合具有改善的患者依从性，口服螯合剂已显示出明显的剂量限制不利影响。例如，deferasirox会引起胃肠道出血，这可能是致命的患者，除了肝和肾脏毒性。这些不利影响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，施加毒性的趋势。此外，临床医生报告说，铁螯合剂的新颖，更方便，更耐受的递送将改善治疗依从性和长期治疗结果。以前，我们已经成功地开发了一种多功能纳米授权剂，该纳米授器从等离子体中捕获铁和肝脏，在非目标组织中没有明显的非特异性摄入循环，然后使身体通过尿液排泄。用这种肾脏可透明纳米授权剂武装，我们旨在开发皮下注射剂水凝胶配方，最多增加了3周的暴露，并使用释放动力学跟踪纵向多模式成像系统。该策略可以减轻铁负担，并降低铁介导的器官毒性，没有明显的螯合相关的不良反应。因此，我们的假设是热敏性注射水凝胶，可长期持续释放铁螯合剂，但短期居住在主要组织/器官中（即铁螯合无积累时的快速清除），可以提高铁螯合的治疗功效，同时最大程度地减少螯合剂引起的毒性，超出电流铁超负荷的标准处理。