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

• 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
• 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

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：铁是一种必需的金属，但由于氧化性增加，高铁储存是有毒的。 由铁催化的活性氧物质产生的压力。铁含量的增加与 已确定的心脏和肝脏衰竭、关节炎、血脂异常和糖尿病的风险因素，包括肥胖、代谢性 综合征和慢性炎症，特别是对于遗传上易受铁生成影响的患者 超载。继发性铁超负荷发生在几种贫血中（例如，地中海贫血，骨髓增生异常综合征， 镰状细胞性贫血，Diamond-Blackfan贫血），由于反复输血和铁吸收增加 反复输血的负荷可能是慢性贫血患者发病和死亡的主要原因。 在美国有三种FDA批准的螯合剂：去铁胺（Desferral，Novartis; IV/IM/SC注射）， 地拉罗司（Jadenu，Exjade; Novartis;口服片剂）和去铁酮（奥贝安可，ApoPharma;口服片剂/溶液）。 自1968年以来，原型铁螯合剂去铁胺已显示出良好的治疗效果，但需要重复 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， 市场上有两种口服螯合剂（2005年的地拉罗司和2011年的去铁酮）。尽管 口服螯合剂的有效的铁螯合作用和改善的患者依从性显示出显著的剂量限制性， 不良影响例如，地拉罗司可引起胃肠道出血，这对老年人可能是致命的。 患者，除了肝和肾毒性。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靶组织中的倾向，从而产生毒性。此外，委员会认为， 临床医生报告说，一种新的、更方便的和耐受性更好的铁螯合剂的递送将改善 治疗依从性和长期治疗结果。 此前，我们已经成功开发了一种多功能纳米螯合剂，可以从血浆中捕获铁 和肝脏，在非靶组织中循环而没有显著的非特异性摄取，并通过 尿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 增加暴露长达3周的水凝胶制剂，并使用 多模态成像系统纵向。这种策略可以减少铁负荷，降低 铁介导的器官毒性，没有明显的螯合剂相关的不良反应。因此，我们的假设是 温敏性可注射水凝胶，其提供铁螯合剂的长期持续释放，但提供铁螯合剂的短期释放。 在主要组织/器官中的驻留（即，铁螯合后快速清除而无蓄积），可 提高铁螯合的治疗效果，同时最大限度地减少螯合剂诱导的毒性， 铁超载的标准治疗