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WIREs Nanomed Nanobiotechnol
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Ultrasmall superparamagnetic iron oxide nanoparticles: A next generation contrast agent for magnetic resonance imaging

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Abstract As a research hotspot, the development of magnetic resonance imaging (MRI) contrast agents has attracted great attention over the past decades for improving the accuracy of diagnosis. Ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles with core diameter smaller than 5.0 nm are expected to become a next generation of contrast agents owing to their excellent MRI performance, long blood circulation time upon proper surface modification, renal clearance capacity, and remarkable biosafety profile. On top of these merits, USPIO nanoparticles are used for developing not only T1 contrast agents, but also T2/T1 switchable contrast agents via assembly/disassembly approaches. In recent years, as a new type of contrast agents, USPIO nanoparticles have shown considerable applications in the diagnosis of various diseases such as vascular pathological changes and inflammations apart from malignant tumors. In this review, we are focusing on the state‐of‐the‐art developments and the latest applications of USPIO nanoparticles as MRI contrast agents to discuss their advantages and future prospects. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging
(a) Field‐dependent magnetization curves of differently‐sized USPIO nanoparticles at 300 K; (b) illustration of the spin canting effect of USPIO particles with different diameters; (c) T1‐weighted MRI of MCF‐7 cell pellets after 24 h incubation with 3.0 nm and 12 nm iron oxide nanoparticles, respectively (Reprinted with permission from Kim et al., 2011, Copyright 2011, American Chemical Society); (d) particle size dependencies of r1 value and r2/r1 ratio; (e) the corresponding T1 MR signal intensities of USPIO nanoparticles against Fe concentration (Reprinted with permission from Shen, Chen, et al., 2017, Copyright 2017, American Chemical Society); (f) chemical structures of the anchoring groups of three PEG‐based ligands and the corresponding TEM images of 3.6 nm nanoparticle (S) and 10.9 nm nanoparticle (L) stabilized by these three PEG ligands, respectively; and (g) T1/T2‐weighted MR images of solutions containing these two differently sized PEGylated particles (Reprinted with permission from Zeng, Jia, et al., 2014, Copyright 2014, Wiley). MCF‐7, human breast cancer cells; MRI, magnetic resonance imaging; PEG, polyethylene glycol; TEM, transmission electron microscope; USPIO, ultrasmall superparamagnetic iron oxide
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(a) Schematic illustration of the preparation of USPIO‐scFv conjugates; (b) T1‐weighted and T2‐weighted MRI of carotid arteries with USPIO‐scFv nanoprobe (top) and the mother USPIO as control (bottom) (Reprinted with permission from Ta et al., 2017, Copyright 2017, Elsevier); (c) schematic illustration of T1/T2 MRI for inflammation based on the light‐triggered USPIO nanoprobes; (d) T1‐weighted MRI of normal arthritis (top) and folate inhibited arthritis models (bottom); (e) T1‐weighted (top) and T2‐weighted (bottom) MRI, and the corresponding quantified data of arthritis area acquired before and after laser irradiation (Reprinted with permission from X. Li, Lu, et al., 2019, Copyright 2019, Wiley). MRI, magnetic resonance imaging; USPIO, ultrasmall superparamagnetic iron oxide
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(a) Schematic diagram of a responsive nanoprobe based on GSH‐induced aggregation of USPIO nanoparticles for T1/T2‐weighted MRI of intracranial tumors; (b) TEM image of USPIO particle clusters formed in the presence of GSH; (c) GSH concentration dependent ΔR1 and ΔR2 of GSH‐responsive USPIO nanoparticles in vitro; (d) T1‐weighted (top) and T2‐weighted (bottom) MRI of brain glioma acquired at different time points after the intravenous injections of GSH‐responsive and nonresponsive probes, respectively, together with the quantified T1 and T2 signal placed right‐hand side (Reprinted with permission from Zhang et al., 2021, Copyright 2021, Wiley). GSH, glutathione; MRI, magnetic resonance imaging; TEM, transmission electron microscope; USPIO, ultrasmall superparamagnetic iron oxide
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(a) Illustration of the mechanism of HCC imaging using pH‐responsive USPIO nanoparticles for T1/T2 MRI; (b) in vivo T1‐weighted MRI of acid responsive USPIO‐based assembly (top) and nonresponsive USPIO‐based assembly (bottom) (Reprinted with permission from J. Lu et al., 2018, Copyright 2018, American Chemical Society); (c,d) three‐dimensional model reconstruction to show the distribution of oligosaccharide‐coated 3.5 nm USPIO nanoparticles and 20 nm SPIO nanoparticles in tumor; and (e) the analysis on the distance between nanoparticles and blood vessels; (f) in vivo MRI of tumors with the aid of USPIO nanoparticles as contrast agents (Reprinted with permission from L. Wang, Huang, et al., 2017, Copyright 2017, American Chemical Society). HCC, hepatocellular carcinoma; MRI, magnetic resonance imaging; USPIO, ultrasmall superparamagnetic iron oxide
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(a) T1‐weighted MRI and (b) quantificational analysis of the temporal SNR of tumors after intravenous injection of 4.8 nm Gd‐embedded ZDS‐coated USPIO nanoparticles (Reprinted with permission from Zhou et al., 2013, Copyright 2013, American Chemical Society); (c) T1‐weighted and T2‐weighted MRI and (d) the temporal evolution of R1 and R2 values of tumors after intravenous injection of HX‐PEG‐coated 3.6 nm USPIO nanoparticles (Reprinted with permission from Zeng, Jing, et al., 2014, Copyright 2014, Wiley). Gd, gadolinium; HX, hydroxamate; MRI, magnetic resonance imaging; PEG, polyethylene glycol; SNR, signal‐to‐noise ratio; USPIO, ultrasmall superparamagnetic iron oxide; ZDS, zwitterionic dopamine sulfonate
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(a) Blood circulation behaviors of USPIO‐PEG nanoparticles and l‐Cys modified USPIO‐PEG nanoparticles (Reprinted with permission from D. Ma et al., 2017, Copyright 2017, The Royal Society of Chemistry); (b) iron contents in tumor tissues harvested from mice receiving intravenous injections of differently‐sized iron oxide nanoparticles, respectively (Reprinted with permission from L. Wang, Huang, et al., 2017, Copyright 2017, American Chemical Society); (c) the scanning time‐dependent spatial resolution of MRI (Reprinted with permission from Shin et al., 2021, Copyright 2021, Springer Nature); (d) the renal clearance curves of iron oxide nanoparticles with different hydrodynamic sizes (Reprinted with permission from Xie, Wang, et al., 2020, Copyright 2020, American Chemical Society); (e) biodistribution of ZDS‐coated USPIO particles labeled with 59Fe in mice (Reprinted with permission from Wei et al., 2017, Copyright 2017, National Academy of Sciences). l‐Cys, l‐cysteine; MRI, magnetic resonance imaging; PEG, polyethylene glycol; USPIO, ultrasmall superparamagnetic iron oxide; ZDS, zwitterionic dopamine sulfonate
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(a) High‐resolution TEM image of PEGylated USPIO nanoparticles; (b–d) USPIO‐enhanced arterial MRA of the whole body (b,c) and upper body (d) of a beagle dog; (e) USPIO‐enhanced MRA of the upper body of a macaque (Reprinted with permission from Y. Lu et al., 2017, Copyright 2017, Springer Nature); (f) negatively stained TEM image of USPIO; (g–j) T1‐weighted MRI of brain vessels (g), peripheral vessels (h), and coronary vessels (i) of rodents and lower‐extremity vessels of rabbits (j), respectively (Reprinted with permission from Shin et al., 2021, Copyright 2021, Springer Nature). MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; PEG, polyethylene glycol; TEM, transmission electron microscope; USPIO, ultrasmall superparamagnetic iron oxide
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(a) The biological effects of USPIO‐, Gd‐ and Mn‐based T1 MRI contrast agents delivered through intravenous injection (Reprinted with permission from R. Chen et al., 2015, Copyright 2015, American Chemical Society); (b) toxicological risk assessments of USPIO‐ and Gd‐based T1 MRI contrast agents in renal failure rats (Reprinted with permission from Weng et al., 2019, Copyright 2019, American Chemical Society). Gd, gadolinium; Mn, manganese; MRI, magnetic resonance imaging; PEG, polyethylene glycol; USPIO, ultrasmall superparamagnetic iron oxide
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