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Nano‐sensing and nano‐therapy targeting central players in iron homeostasis

Advanced Review

Linyuan Wu, Yan Li, Ning Gu

Published Online: Sep 06 2020

DOI: 10.1002/wnan.1667

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Abstract Iron plays vital roles in many life activities and it is strictly controlled via elaborate metabolic system. Growing evidence has suggested that the dysfunctional iron homeostasis is implicated to many refractory diseases including cancers and neurodegenerations. Systemic and cellular iron are regulated through different pathways but are meanwhile interconnecting with each other via a few key regulators, whose abnormal expressions are often found to be the root causes of many iron disorders. Nano‐sensing techniques have enabled the detection and monitoring of such central players, which provide rich information for the iron homeostasis profile through multiplexing and flexible designs. In addition to general sensing, nanoprobes are capable of target imaging and precise local access, which are particularly beneficial for revealing the conditions of intra‐/extracellular environments. Nanomaterials have also been applied in some therapies, targeting the aberrant iron metabolism. Various iron uptake pathways have been utilized for target drug delivery and iron level manipulation, while abnormal iron content is notably useful in tumor killing. With brief introduction to the significance of iron homeostasis, this review includes recent works regarding the nanotechnology that has been applied in iron‐related diagnostic and therapeutic applications. This article is categorized under: Diagnostic Tools > Biosensing Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Diagnostic Tools > in vivo Nanodiagnostics and Imaging

Major iron flow in systemic iron regulation. Iron in plasma is mostly bound to transferrin (Tf) and travels along with the circulation. Major part of iron in Tf is extracted and consumed in bone marrow to produced new erythrocytes, while the aged ones are recycled by macrophages, sending iron back to the pool. Iron can also be stored in hepatocytes and get released according to different circumstances. Iron losses are compensated by duodenal iron adsorption from foods and medicines, which maintain the overall systemic iron balance. Iron export from cell to plasma relies on ferroportin (Fpn), which is negatively controlled by hepcidin, a peptide secreted from hepatocytes

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Strategic directions for iron‐based cancer therapies with their existing and possible forms. The induced ferroptosis and apoptosis can work in synergy with greater tumor killing efficacy, while the treatment specificity is also improved through the iron uptake pathways. More combinations could be considered (marked in gray which has not been reported so far) in perspective of iron regulation, such as how to specifically target the microenvironment between tumor cells and TAMs, and how to enhance the cancer therapy by introducing ferroptosis from the inside, meanwhile arousing immune responses from the outside

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Iron related nano‐therapies for cancers: target drug delivery using nanomaterials and iron uptake pathways; cell ferroptosis induction through additional iron dosing and intracellular interventions of the ferroptosis regulation systems; oriented macrophage polarization by iron oxide nanoparticles

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Iron chelation and iron supplement therapies with nanomaterials. (a) Iron chelation therapy has been applied in some neurodegenerative diseases. Nanomaterials with modifications can promote drug penetration through the blood brain barrier (BBB), which brings better efficiency for iron chelators to reduce iron and reactive oxygen species (ROS) damage in the lesion parts. (b) Iron supplement utilizing iron‐base nanoparticles mainly takes effect through the macrophages endocytosis and further bioavailable iron (Tf‐Fe2) release, which is more efficient compares to many traditional iron supplement therapies

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Local detection of key regulators in iron homeostasis targeting their specific traits. (a) The alternations on the magnetic spin relaxation of NV in diamond were visualized into fluorescence signals for ferritin detection (Reprinted with permission from Ziem et al. (2013). Copyright 2013 American Chemical Society); (b) Iron binding properties of ferritin were utilized for ferric iron and apoferritin detection (Reprinted with permission from Han et al. (2016). Copyright 2016 Elsevier); (c) Ferrous iron was measured by electrodes in nanopipette modified with iron binding proteins (Reprinted with permission from Bulbul et al. (2018). Copyright 2018 American Chemical Society); (d) Fluorescence can be restored through ferric ion‐catalyzed destruction of the quenching encapsulation of fluorescent NPs (Reprinted with permission from W. Zhang et al. (2019). Copyright 2019 Elsevier); Tumor cell imaging through (e) TfR‐mediated endocytosis (Reprinted with permission from Y. Wang et al. (2013). Copyright 2013 Elsevier) and (f) TfR surface binding with catalytic SIONPs and coloration effect (Reprinted with permission from Weerathunge et al. (2019). Copyright 2019 American Chemical Society)

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Cellular iron metabolic pathways and iron homeostasis. Apart from the cancer‐specific pathway through lipocalin 2 (Lcn‐2) for acquiring iron, iron is usually uptake by the cell in free form, or bound with transferrin (Tf), heme alone or heme in hemoglobin. Depending on their corresponding receptors and internalization process, iron is released into the LIB mostly as ferrous state for later distribution. Available iron is partially stored in the iron‐sequestering protein ferritin for later use, while the rest is transported into mitochondria and involved in producing substantial elements such as heme and iron‐sulfur clusters. Iron‐loaded heme can exit mitochondria via 1b isoform of FLVCR (feline leukemia virus subgroup C cellular receptor) and later get secreted from cell through another isoform FLVCR1a. Excessive iron in LIB is sent out of the cell through ferroportin (Fpn) mediated efflux, with the exported iron soon be oxidized into ferric state and put back to the circulation by binding to transferrin

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General nano‐sensing platforms for detecting key players in iron homeostasis. The specific target capturing is mainly based on antigen–antibody interaction (a–e) and engineered MIP binding (f–h). Modified with corresponding antibodies, protein detections were implemented on (a) ELISA with AuNPs, (b) photonic crystals with IONPs, (c) dual‐mode fluorometric/colorimetric sensing with AuNPs and carbon dots, (d) LSPR detection in microfluid device with AuNPs, and (e) semiconductor sensing on a nanostructured FET device with a poly‐Si nanowire. Protein recognition through MIP was applied in (f) SPR sensing, (g) fluorescent detection with magnetic NPs, and (h) electrochemical measurement

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Hepcidin‐mediated iron regulation as host defense and interplays with macrophage and inflammatory effect under different systemic iron status. (a) When systemic iron is at balance, the pathogens will stimulate inflammation and hepcidin expression to sequester iron from pathogens. When there is iron overload, the effect is further promoted which blunts the response to pathogens. (b) When iron is deficient, the hepcidin expression is inhibited. Since the need of erythropoiesis outplays the host defense mechanism, chronic inflammation is often accompanied with iron deficiency anemia

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