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WIREs Nanomed Nanobiotechnol
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Nanoparticle‐based imaging of inflammatory bowel disease

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Although inflammatory bowel disease (IBD) has been extensively studied, the pathogenesis is still not completely understood. As a result, the treatment options remain unsatisfactory and nonspecific. With the rapid advancement of diagnostic imaging techniques, imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) are playing a more important role in IBD diagnosis and evaluation. Recent developments in nanotechnology utilize an interdisciplinary approach to specifically target molecular or cellular IBD pathological process thereby generating nanoparticles (NPs) with high specificity and diagnostic and/or therapeutic efficacy. Nano‐based imaging, which incorporates nanotechnology and imaging modalities, may allow for the early detection of IBD, the monitoring of disease activity, and may be used to monitor the therapeutic response at cellular and/or molecular level. In this review, we highlight issues related to nano‐based imaging and its application in IBD field. WIREs Nanomed Nanobiotechnol 2016, 8:300–315. doi: 10.1002/wnan.1357 This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging
Comparison of Crohn's disease (CD) and ulcerative colitis (UD). Figure 1(a) shows the typical location of CD (green) and UD (blue) in the GI tract. (b) Immunologic cascade associated with CD and UD. Microbial interactions stimulate innate immune receptors on the luminal surface, such as Toll‐like receptor (TRL) and NOD‐like receptors NLR. The stimulation causes the recruitment of a host of immune cells such as dendritic cells, macrophages, and T cells within the intestinal wall. Dendritic cells release a variety of interleukins (IL) and tissue necrosis factor (TNF). Interactions between the ILs and IL receptors on T cells (defined as TH0 cell in the diagram) cause the release of other IL and the proinflammatory cytokines promote the differentiation of the T cell into other T cell subtypes (TH1–TH17). The T cell subtype is different for UD and CD. These cytokines also promote the formation of natural killer T cells (NKT) that are critical in UD pathogenesis. The interaction between circulating leukocytes and receptors on vascular endothelial cells causes the additional recruitment of lymphocytes and macrophages into the intestinal wall. (Reprinted with permission from Ref . Copyright 2010 Nature Reviews Gastroenterology and Hepatology by Nature Publishing Group)
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In vivo single proton emission computed tomography/positron emission tomography (SPECT/CT) image (snapshot) of the gastrointestinal (GI) track of the mouse 24 h after cell injection. The color overlay is the SPECT image where the brighter the color (red/yellow), the greater the In111 concentration in the tissue. It is evident that there is strong in vivo uptake in both the stomach and intestines.
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Magnetic resonance (MR) images obtained prior to and 24 h after the intravenous administration of superparamagnetic iron oxide (SPIO)‐labeled macrophages in inflammatory bowel disease (IBD) mice. Inserts show zoomed in areas of interest within the bowel as depicted by the red arrows. S indicates the stomach, and L indicates the liver that was observable in the slice imaged.
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Representative images showed oral administration of Mn for the delineation of the intestinal lumen. S indicates stomach and red arrows highlight the intestines.
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Design of targeted nanoparticles (NPs). (a) Lipid‐based NPs. Phospholipids are amphiphilic molecules that contain a hydrophilic head and a hydrophobic tail. Because of the dual character of the lipids as well as the energetically unfavorable contact between the lipid tails and water, amphiphiles will self‐associate into aggregates of different sizes, The length of the hydrophobic chains and the size of the head group determine whether a liposome (bilayer, top) or micelle (single layer, middle) is formed. Modified lipids [i.e., polyethylene glycol (PEG)‐DSPE, DTPA‐bis(stearyl‐amid), and PEG‐malamide‐DSPE] may be easily incorporated directly into the micelle/liposome to allow for modulation of the pharmacokinetics, addition of the active metal ions (via chelation), and addition of the targeting moiety. Targeting moieties such as antibodies may be coupled to the NP by using avidin–biotin linkage or via direct covalent binding via SATA modification. Additionally, the active metal may be present in the core of the lipid NP (bottom). The core, may contain one or several crystals. There are three main categories of iron oxide‐based NPs for MRI: superparamagnetic (SPIO), ultra‐small superparamagnetic (USPIO), and monocrystalline. SPIOs have hydrated size >80 nm and are composed of a core that is a composite and/or agglomerate of several iron oxide crystals. USPIOs exhibit a hydrated size of 20–40 nm and monocrystalline NPs are composed of monodispersed single‐coated iron oxide cores with a hydrated size <20 nm. The lipid‐based coating material prevents aggregation of the iron cores and allows for conjugation of the targeting moieties. (b) Dendrimer‐based NPs: Dendrimers are defined by their generation or G level (top). The structure of a G4 is shown (bottom) and the arrow indicates the outer shell that can be modified. For molecular imaging, G8 dendrimers have been extensively used. This generation has a hydrated diameter of the 9.8 nm prior to conjugation with the targeting moiety. G8 dendrimers have 1024 available binding sites on the outer shell to allow for conjugation with diagnostic metal ions (via chelation), targeting moieties, and other materials such as carboxylate, hydroxyl, and PEG to increase biocompatibility and manipulate the pharmacokinetics and biodistribution. (c) Active metals conjugated directly to the targeting moiety. This approach is typically used for nuclear medicine, as the sensitivity of the single proton emission computed tomography (SPECT) and positron emission tomography (PET) methods are able to detect micro amounts of radio nuclide. Here DOTA chelates (top) or other chelating agents such as CB‐TE2A (bottom) are conjugated directly to the peptide, antibody, or antibody fragment. The chelating agent chosen depends upon the radionuclide used, as certain chelates have higher affinity for certain metal ions.
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Representative images of inflammatory bowel disease (IBD) imaging as a function of imaging modality. (a) Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT): Significant uptake of 18F‐FDG in the distal ileum of a patient with IBD (Reprinted with permission from Ref . Copyright 2010 xxx) (b) CT enterography (CTE): Irregular thickening, loss of mural stratification, and heterogeneous enhancement of the distal ileum by CT in a patient with IgG4‐related disease of the small bowel. Adhesion and aggregation of small bowel loops was also observed (arrows) (Reprinted with permission from Ref . Copyright 2013 Eur J Radiol by Elesvier) (c) MR enterography (MRE): Signal enhancement of the distal ileum. 45 min prior to scanning the patient drank 450 cc of water. Images were then obtained prior to (left) and immediately after (right) the IV injection of a Gd‐based contrast agent. Imaging was performed at 1.5T using coronal SSFP and axial SSFSE imaging sequences. The arrow indicates the thickening of the ileum in a patient with Crohn disease (CD) (Reprinted with permission from Ref . Copyright 2012 Eur J Radiol by Elesvier)
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