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

项目摘要/摘要：铁是一种必需的金属，但高铁储存是有毒的，因为增加了氧化 由铁催化的活性氧物种产生的胁迫。铁储备的增加与油井有关- 已确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 综合症和慢性炎症，特别是对遗传易感形成铁的患者 超载。继发性铁超载发生在几种贫血(如地中海贫血、骨髓增生异常综合征、 由于反复输血造成的镰状细胞性贫血、钻石黑粉性贫血以及铁的吸收增加 反复输血的负荷可能是慢性贫血患者发病率和死亡率的主要原因。 美国有三种FDA批准的螯合剂：去铁胺(去铁拉尔，诺华；静脉/肌注/SC注射剂)， Deferasirox(加德努，Exjade；诺华；口服片剂)和去铁酮(Ferriprox，ApoPharma；口服片/溶液)。 自1968年以来，原型铁络合剂去铁胺已显示出良好的治疗效果，但需要反复治疗。 注射或持续输液，这会大大降低患者的依从性。为了克服这个问题， 市场上已经有了两种口服螯合剂(2005年的去铁昔洛克斯和2011年的去铁酮)。尽管 其有效的铁螯合作用改善了患者的依从性，口服螯合剂显示出显著的剂量限制 不良影响。例如，去铁西罗可导致胃肠道出血，这对老年人可能是致命的。 患者，除了肝脏和肾脏的毒性。这些不利影响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的倾向，产生毒性。此外， 临床医生报告说，一种新的、更方便、更耐受性更好的铁络合剂的输送将会改善 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，可以从等离子体中捕获铁 和肝脏，在非靶组织中循环，没有显著的非特异性摄取，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 水凝胶制剂，增加暴露长达3周，并跟踪释放动力学使用 纵向上的多模式成像系统。这一策略可以减轻铁的负担，降低患癌症的风险。 铁介导的器官毒性，没有明显的与螯合剂相关的不良反应。因此，我们的假设是 温度敏感型可注射水凝胶，可提供铁螯合剂的长期持续释放，但短期 在主要组织/器官中滞留(即铁螯合后迅速清除而不积聚)，可 提高铁络合剂的治疗效果，同时将螯合剂的毒性降至最低，超出目前的水平 铁超载的标准治疗。

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.