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:
- 金额:$ 73.42万
- 依托单位:
- 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:
- 关键词:Adverse effectsAffectAgranulocytosisAnemiaAnimal ModelAnimalsArthritisBiochemicalBiological AvailabilityBloodBlood TransfusionCardiomyopathiesCaucasiansCessation of lifeChelating AgentsChelation TherapyChemistryChronicClinicalClinical TrialsColumn ChromatographyCommunicationContinuous InfusionCyclic GMPDeferoxamineDiabetes MellitusDialysis procedureDiamond-Blackfan anemiaDiseaseDoseDose LimitingDrug or chemical Tissue DistributionDyslipidemiasDysmyelopoietic SyndromesEngineeringExcisionExcretory functionFDA approvedFamily suidaeFerritinFormulationFreeze DryingFutureGastrointestinal HemorrhageGenetic DiseasesGrantHalf-LifeHeart failureHematopoieticHepaticHereditary hemochromatosisHydrogelsHypertriglyceridemiaHypotensionImpairmentInfectionInflammationInfusion proceduresInjectableInjectionsIntravenousIronIron Chelating AgentsIron ChelationIron OverloadKidneyKineticsLiverLiver CirrhosisLiver FailureLiver FibrosisMarketingMaximum Tolerated DoseMediatingMetabolic syndromeMetalsModelingMorbidity - disease rateMultimodal ImagingMusNational Heart, Lung, and Blood InstituteNatureNeurodegenerative DisordersNutritionalObesityOralOrganOrganic SynthesisOxidative StressOxidative Stress InductionPatientsPatternPersonsPlasmaPolymersPopulationPredispositionProceduresPublicationsRattusReactive Oxygen SpeciesReportingRisk FactorsRisk ReductionRodentSafetySickle Cell AnemiaSiteSolventsSubcutaneous InjectionsTabletsThalassemiaTherapeuticTissuesToxic effectToxicity TestsTransfusionTreatment EfficacyUnited States National Institutes of HealthUrineabsorptioncompliance behaviordesignefficacy evaluationheart damageheart functionimaging systemimmunogenicityimprovedinjection/infusioniron absorptionmilligrammortalitynanonephrotoxicitynovelnovel therapeutic interventionolder patientparenteral administrationprematureprototyperesidenceresponsescale upside effectsmall moleculestandard caresubcutaneoussystemic toxicitytherapy outcometreatment adherenceuptakeurinary
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:铁是人体必需的金属,但高铁含量会增加氧化作用,从而产生毒性
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Hak Soo Choi其他文献
Hak Soo Choi的其他文献
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{{ truncateString('Hak Soo Choi', 18)}}的其他基金
Nanochelation Therapies for Iron Overload Disorders
纳米螯合疗法治疗铁过载疾病
- 批准号:
10318332 - 财政年份:2021
- 资助金额:
$ 73.42万 - 项目类别:
Nanochelation Therapies for Iron Overload Disorders
纳米螯合疗法治疗铁过载疾病
- 批准号:
10437625 - 财政年份:2021
- 资助金额:
$ 73.42万 - 项目类别:
Image-Guided Drug Delivery and Treatment for GIST
图像引导胃肠道间质瘤的药物输送和治疗
- 批准号:
9792375 - 财政年份:2018
- 资助金额:
$ 73.42万 - 项目类别:
Image-Guided Drug Delivery for Pancreatic Neuroendocrine Tumor.
图像引导胰腺神经内分泌肿瘤的药物输送。
- 批准号:
9302133 - 财政年份:2017
- 资助金额:
$ 73.42万 - 项目类别:
Image-Guided Drug Delivery for Pancreatic Neuroendocrine Tumor
图像引导胰腺神经内分泌肿瘤给药
- 批准号:
10167387 - 财政年份:2017
- 资助金额:
$ 73.42万 - 项目类别:
Image-Guided Drug Delivery for Pancreatic Neuroendocrine Tumor.
图像引导胰腺神经内分泌肿瘤的药物输送。
- 批准号:
9566182 - 财政年份:2017
- 资助金额:
$ 73.42万 - 项目类别:
Ultra-Low Background NIR Fluorophores for In Vivo Imaging and Image-Guided Surger
用于体内成像和图像引导手术的超低背景近红外荧光团
- 批准号:
7937599 - 财政年份:2010
- 资助金额:
$ 73.42万 - 项目类别:
Ultra-Low Background NIR Fluorophores for In Vivo Imaging and Image-Guided Surger
用于体内成像和图像引导手术的超低背景近红外荧光团
- 批准号:
8514598 - 财政年份:2010
- 资助金额:
$ 73.42万 - 项目类别:
Ultra-Low Background NIR Fluorophores for In Vivo Imaging and Image-Guided Surger
用于体内成像和图像引导手术的超低背景近红外荧光团
- 批准号:
8112741 - 财政年份:2010
- 资助金额:
$ 73.42万 - 项目类别:
Image-Guided Surgery of Endocrine Glands and Their Tumors using Near-Infrared Flu
使用近红外流感图像引导内分泌腺及其肿瘤手术
- 批准号:
8117244 - 财政年份:2010
- 资助金额:
$ 73.42万 - 项目类别:
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