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WIREs Nanomed Nanobiotechnol
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Functional nanoparticles for magnetic resonance imaging

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Nanoparticle‐based magnetic resonance imaging (MRI) contrast agents have received much attention over the past decade. By virtue of a high payload of magnetic moieties, enhanced accumulation at disease sites, and a large surface area for additional modification with targeting ligands, nanoparticle‐based contrast agents offer promising new platforms to further enhance the high resolution and sensitivity of MRI for various biomedical applications. T 2* superparamagnetic iron oxide nanoparticles (SPIONs) first demonstrated superior improvement on MRI sensitivity. The prevailing SPION attracted growing interest in the development of refined nanoscale versions of MRI contrast agents. Afterwards, T 1‐based contrast agents were developed, and became the most studied subject in MRI due to the positive contrast they provide that avoids the susceptibility associated with MRI signal reduction. Recently, chemical exchange saturation transfer (CEST) contrast agents have emerged and rapidly gained popularity. The unique aspect of CEST contrast agents is that their contrast can be selectively turned ‘on’ and ‘off’ by radiofrequency saturation. Their performance can be further enhanced by incorporating a large number of exchangeable protons into well‐defined nanostructures. Besides activatable CEST contrast agents, there is growing interest in developing nanoparticle‐based activatable MRI contrast agents responsive to stimuli (pH, enzyme, etc.), which improves sensitivity and specificity. In this review, we summarize the recent development of various types of nanoparticle‐based MRI contrast agents, and have focused our discussions on the key advantages of introducing nanoparticles in MRI. WIREs Nanomed Nanobiotechnol 2016, 8:814–841. doi: 10.1002/wnan.1400 This article is categorized under: Diagnostic Tools > Biosensing Diagnostic Tools > Diagnostic Nanodevices Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Illustration of Gd‐based nanoparticles, including dendrimer nanoclusters, liposomal‐Gd agents, and quantum dots. (a) Schematic illustration of PAMAM (G‐3)–[Gd‐C‐DOTA]−1 with disulfide bonds. (b) Schematic core‐encapsulated GdIII liposomes (CE‐Gd), surface‐conjugated GdIII liposomes (SC‐Gd), and dual‐Gd liposomes (both surface and core are loaded with GdIII chelates, represented by orange stars). (c) Fluorescence image of human umbilical vein endothelial cells (HUVEC) incubated with green emitting RGD‐pQDs, which were internalized and localized in the perinuclear region. (d) Fluorescence image of HUVEC incubated with pQDs. Compared with panel (c), panel (d) displayed much less green fluorescence, which was attributed to nonspecific cellular uptake of pQDs. (e) Schematic illustration of quantum dots coated with GdIII chelates and PEG‐lipids (pQDs). (Reprinted with permission from Ref . Copyright 2006 American Chemical Society; from Ref . Copyright 1999 Wiley‐Liss Inc.; from Ref . Copyright 2009 PLoS One)
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The principles of magnetic resonance imaging. (a) Protons align either parallel (majority) or antiparallel (minority) and precess under external magnetic field B0. (b) Upon the introduction of RF pulses, protons are excited, with relaxation occurring following removal of the RF pulses. Graphical representation of (c) T1 relaxation (Eq. ) and (d) T2 relaxation (Eq. ). (Reprinted with permission from Ref . Copyright 2009 Wiley‐VCH Verlag GmbH & Co. KGaA)
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CEST of Ln (III) chelates anchored on the surface of mesoporous silica nanoparticles. (a) T2w, (b) T1w, and (c–e) STmap at 5.5, 7.5, and 15 ppm, respectively; Labeled capillary positions 1–5 correspond to (1) GdDO3A–MCM‐41, (2) EuDO3A–MCM‐41, (3) TmDO3A–MCM‐41, (4) TbDO3A–MCM‐41, and (5) unlabeled MCM‐41; schematic representation of: (f) the interaction between LnDO3A‐like chelates and the surface of the organo‐modified MCM‐41; (f) Ln (III) chelates anchored on organo‐modified mesoporous silica nanoparticles. (Reprinted with permission from Ref . Copyright 2014 The Royal Society of Chemistry)
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Comparison among different nanoparticle based CEST probes with the same Ln metal in terms of size and sensitivity. As shown, lipoCEST demonstrated the highest sensitivity, while Ln‐dendrimers and Ln‐micelles exhibited the lowest sensitivity. (Reprinted with permission from Ref . Copyright 2014 The Royal Society of Chemistry)
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CEST principle: (a) exchangeable solute protons are selectively saturated at a specific resonance frequency (RF) (8.25 ppm for amide protons), and the saturation is subsequently transferred to water (4.75 ppm). Nonsaturated protons (black) are replaced by saturated solute protons (blue), and the process will be repeated to generate a discernable effect on the water signal intensity. (b) The saturation transfer causes water signal attenuation after tsat. (c) Z spectrum (or CEST spectrum, MT spectrum). When RF irradiates at 4.75 ppm, the water signal disappears because of direct saturation (DS), and the frequency is set to 0 ppm in Z spectrum. After a period of RF saturation (tsat), CEST effect becomes obvious, and the frequency of solute protons (amide protons) is 8.25–4.75 = 3.5 ppm. (d) MTRasym spectrum: asymmetry analysis of Z spectrum to remove DS effect. Various exchange pathways: (e) proton exchange, (f) molecule exchange, (g) proton and molecule exchange, (h) compartment exchange, and (i) molecule‐mediated compartment exchange. (Reprinted with permission from Ref . Copyright 2013 John Wiley & Sons, Ltd; from Ref . Copyright 2011 Wiley‐Liss, Inc.)
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An example of caspase responsive MRI contrast agent. (a) Chemical structures of the C‐SNAM probe and the proposed intramolecular cyclization upon disulfide reduction and caspase‐3/7 triggered DEVD peptide cleavage, and the resulting self‐assembly into nanoparticles. (b) Mechanism of C‐SNAM for in vivo MR imaging of caspase‐3/7 activity in a chemotherapy responsive tumor. (c) T1‐weighted MR imaging of HeLa tumors prior to injection, and 40 and 12 min postinjection. Baseline group was not treated with chemotherapy, while treated group was. (Reprinted with permission from Ref . Copyright 2014 The Royal Society of Chemistry)
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Examples of stimuli‐repsonsive MRI contrast agents. H2O2 responsive contrast agent: (a) schematic representation of activation by hydrogen peroxide: gadolinium oxide nanoparticles (purple spheres) were released upon polymer degradation triggered by hydrogen peroxide. pH‐responsive contrast agent: (b) representation showing the core MnO content unloading from the urchin‐shaped [email protected]3O4 nanoparticle at low pH. (c) Magnetic resonance images of leached out MnII ions from pH 5 PBS buffer (color coded). (D) Temporal color‐coded T1‐ultrashort echo time MR images of a tumor after intravenous injection of hollow [email protected]3O4 nano‐urchin. (Reprinted with permission from Ref . Copyright 2013 American Chemical Society; from Ref . Copyright 2011 Wiley‐VCH Verlag GmbH & Co. KGaA)
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Schematic illustration of the Ferumoxtran‐10 transport pathway. Extravasation from blood vessels to the interstitial space occurred following phagocytosis by macrophages, and was then transported to normal lymph nodes. (Reprinted with permission from Ref . Copyright 2003 Massachusetts Medical Society)
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Tracking neural stem cells in patients with brain trauma. (a) Photomicrograph of neural stem cells labeled with iron oxide nanoparticles (Prussian blue staining, and neutral red counterstaining). (b) TEM image of neural stem cells labelled with iron oxide nanoparticles. Cluster of iron oxide nanoparticles were close to the Golgi apparatus (black arrow), which confirmed iron oxide nanoparticles entering cells. (c)–(h) MRI scanning of patient receiving neural stem cells labeled with Feridex I.V. (c) Scan before implantation. No pronounced hypointense signal was found around the lesion in the left temporal lobe (asterisk). (d–e) Scan on day 1 after implantation. The magnified image of E showed four hypointense signals (black arrows) at injection site. (f–h) Magnified images taken on days 7, 14, and 21. By day 7, dark signals posterior to the lesion were observed (white arrow). By day 14, hypointense signals at the injection site faded, while another dark signal intensified at the border of damaged tissues. (Reprinted with permission from Ref . Copyright 2006 Massachusetts Medical Society)
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In vivo MRI tracking of adipose‐derived mesenchymal stem cells labelled with mesoporous silica‐coated hollow manganese oxide. (a) Schematic illustration of [email protected]2 nanoparticles and labeling of MSCs. (b) TEM image of [email protected]2 nanoparticles. Particle diameter = 65 nm, MnO core size = 15 nm. (c) High‐resolution TEM image of a single nanoparticle, clearly showing the mesoporous silica shell and hollow MnO core structures. In vivo MRI of transplanted MSCs: (d) unlabeled MSCs. No hyperintense signal was detected (red arrow). (e) Hyperintense signals (green arrows) resulting from transplantation of [email protected]2 nanoparticles labeled MSCs were still visible 14 days after injection. (Reprinted with permission from Ref . Copyright 2011 American Chemical Society)
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Smart theranostic agents of Prussian blue‐based core‐shell hollow mesoporous nanoparticles. (a) Transmission electron microscopy (TEM) images of HMPB‐Mn. (b) HMPB‐Mn loaded with DOX enters cell via endocytosis. Upon reaching a low pH site, such as an endosome, the nanocarrier released DOX and MnII simultaneously, which acted as both T1‐weighted MRI contrast agents and chemotherapy agent for cancer treatment. (c) Schematic illustration of pH triggered release of DOX and MnII. (Reprinted with permission from Ref . Copyright 2015 Wiley‐VCH Verlag GmbH & Co. KGaA)
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In vivo biomaterial localization with Gd‐labeled peptide nanofibers. (a) Schematic illustration of the ‘clicking’ of Gd(HPN3DO3A) to the alkyne peptoid. Chemical structure of the self‐assembling MRI contrast agents PA1–PA4. (b) Cartoon of self‐assembled nanofibers of PA1. In vivo evaluation of PA1 and PA3: (c) 4 μL of PA gels were injected into each of six wild‐type mice (injection point indicated by white arrows), and anatomical scan of mouse legs was performed immediately upon injection (top row) and after 4 days (bottom row). PA1 produced positive contrast in T1‐weighted MRI, while PA3 produced negative contrast in T2‐weighted MRI. (d) Average T1 times from the region of interest and the background measured several millimeters from the PA injection site. PA1 possessed the shortest T1 time (highest r1 relaxivity). (Reprinted with permission from Ref . Copyright 2014 American Chemical Society)
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Design and characterization of dual‐modality supramolecular nanoprobes. (a) Rational design of supramolecular dual‐modality nanoprobes, composed of a hydrophobic domain to promote self‐assembly, a fluorophore for optical imaging, a GdIII chelator for MR contrast, and a hydrophilic headgroup. (b) Chemical structures of PACA 1 and PACA 2. Fluorescence images of KB‐3‐1 cells after incubation (2 h) with (c) PACA 1 (200 μM) and (d) PACA 2 (50 μM). Scale bars were 20 µm. (e, f) The plots of 1/T1 versus concentration for [Gd (III)]‐1 and [Gd (III)]‐2. Slopes as r1. (Reprinted with permission from Ref . Copyright 2015 The Royal Society of Chemistry)
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Self‐assembled peptide amphiphile nanostructures containing Gd‐based magnetic moieties. (a) AFM image of nanofibers. (b) Atomic force microscopy (AFM) image of nanospheres. (c) Molecular design of 1, 2, 3. (d) MR images of phantom gels formed from (1) the control PA of 1, (2) a mixture of 1 and 2, (3) a mixture of 1 and 3, and (4) Gd‐DTPA. The mixture of 1 and 3 demonstrated the highest contrast due to the increase in τr of GdIII chelates. (Reprinted with permission from Refs . Copyright 2005 American Chemical Society)
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