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

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.