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WIREs Nanomed Nanobiotechnol
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Diamagnetic chemical exchange saturation transfer (diaCEST) liposomes: physicochemical properties and imaging applications

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Chemical exchange saturation transfer (CEST) is a new type of magnetic resonance imaging (MRI) contrast based on labile spins which rapidly exchange with solvent, resulting in an amplification of signal which allows detection of solute protons at millimolar to micromolar concentrations. An additional feature of these agents is that natural organic and biodegradable compounds can provide strong CEST contrast, allowing the development of diamagnetic CEST (diaCEST) MRI contrast agents. The sensitivity of the CEST approach per unit of agent increases further when diaCEST contrast agents are loaded into liposomes to become diaCEST liposomes. In this review, we will discuss the unique and favorable features of diaCEST liposomes which are well suited for in vivo imaging. diaCEST liposomes are nanocarriers which feature high concentrations of encapsulated contrast material, controlled release of payload, and an adjustable coating for passive or active tumor targeting. These liposomes have water permeable bilayers and both the interior and exterior can be fine‐tuned for many biomedical applications. Furthermore, a number of liposome formulations are used in the clinic including Doxil™, which is an approved product for treating patients with cancer for decades, rapid translation of these materials can be envisaged. diaCEST liposomes have shown promise in imaging of cancer, and monitoring of chemotherapy and cell transplants. The unique features of diaCEST liposomes are discussed to provide an overview of the applications currently envisioned for this new technology and to provide an overall insight of their potential. WIREs Nanomed Nanobiotechnol 2014, 6:111–124. doi: 10.1002/wnan.1246 This article is categorized under: Diagnostic Tools > Diagnostic Nanodevices Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

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(a–d) Principle and measurement of chemical exchange saturation transfer (CEST). (e) Each CEST contrast agent has an unique frequency offset from water, allowing the use of the frequency to identify the type of exchangeable protons, such as amine at 2 ppm and amide at 3.5 ppm (f) The color‐encoded CEST contrast of polypeptides, including PLT, PLK and PLR. (Reprinted with permission from Refs and ). Copyright 2011 and 2008 Wiley Inc.
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CEST imaging in cell therapy. (a) The design of diaCEST liposomes containing microcapsules (left), which immunoprotect transplanted cells. (b) CEST images showing a decrease in contrast upon cell death as validated by bioluminescence imaging (c). Indicated are the CEST contrast of empty capsules (−Cells) and capsules with hepatocytes (+Cells); transplanted mice received immunosuppression (+IS) or no immunosuppression (−IS). (Reprinted with permission from Ref ). Copyright 2013 Nature Publishing Group.
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Cancer imaging using diaCEST liposomes. (a) The endogenous contrast of amide protons of proteins for therapeutic evaluation (Reprinted with permission from Ref ). Copyright 2011 Nature Publishing Group. (b) Tumor imaging using the exogenous diaCEST agent d‐glucose (Reprinted with permission from Ref ). Copyright 2012 Wiley Inc. (c) The angiogenesis targeting liposomes in brain tumors. (Reprinted with permission from Ref ). Copyright 2013 Wiley Inc.
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In vivo ‘multicolor’ imaging of diaCEST liposomes. (a) The CEST contrast of liposomes at distinctive frequency offsets. (b) CEST MR image of these liposomes at the lymph nodes with color encoding. (c) Obtained CEST contrast within the lymph nodes. (Reprinted with permission from Ref ). Copyright 2012 Wiley Inc.
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Structure of liposomes shows (a) its components as nanocarriers for contrast agents and/or drugs. (b) Contrast mechanisms for diaCEST liposomes where the RF pulses saturate exchangeable protons on the encapsulated contrast agent (top); in case of paraCEST liposomes, the RF pulses saturate the interior water whose frequency has been shifted by the encapsulated contrast agent (bottom). The amount of contrast generated depends on the size and permeability of liposomes, in addition to the concentration of protons and their relaxation rates.
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Diagnostic Tools > In Vivo Nanodiagnostics and Imaging
Diagnostic Tools > Diagnostic Nanodevices
Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

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