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WIREs Nanomed Nanobiotechnol
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LipoCEST and cellCEST imaging agents: opportunities and challenges

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From the early days of CEST agents’ disclosure, it was evident that their potential for in vivo applications was strongly hampered by the intrinsic low sensitivity. Therefore, much work has been devoted to seek out suitable routes to achieve strong CEST contrast enhancement. The use of nanosized systems turned out to be a strategic choice, because a very large amount of CEST agents can be delivered at the site of interest. However, the breakthrough innovation in term of increase of sensitivity was found by designing the lipoCEST agents. The naturally inspired, liposomes vesicles, when loaded with paramagnetic lanthanide‐based shift reagents, can be transformed into CEST probes. The large number of water molecules entrapped inside the inner cavity of the nanovesicles represents an enormous pool of exchanging protons for the generation of CEST contrast, whereas the presence of the shift reagent increases the separation in chemical shift of their nuclear magnetic resonance signal from that of the bulk water, thus allowing for a proper exchange regime for the activation of CEST contrast. From lipoCEST, it has been rather straightforward to evolve to cellCEST in order to exploit the cytoplasmatic water molecules as source of the CEST effect, once cells have been loaded with the proper shift reagent. The red blood cells were found to be particularly suitable for the development of the cellCEST concept. Finally, an understanding of the main determinants of the CEST effects in nanosized and cellular‐sized agents has allowed the design of innovative lipoCEST/RBC aggregates for potential theranostic applications. WIREs Nanomed Nanobiotechnol 2016, 8:602–618. doi: 10.1002/wnan.1385 This article is categorized under: Diagnostic Tools > Diagnostic Nanodevices Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Biology-Inspired Nanomaterials > Lipid-Based Structures
(a) Scheme of lipoCEST/RBCs aggregates and comparison of Z‐spectra of control RBCs (black line) with lipoCEST/RBCs aggregates (red line); (b) variation of intracellular water chemical shift upon anchoring different number of lipoCEST vesicles on the surface (by using big‐ or small‐sized Dy‐lipoCEST). (Reprinted with permission from Ref . Copyright 2014 American Chemical Society)
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(a) ST‐spectra of tumor region before (red line) and after (blue line) the i.v. administration of Dy‐labeled‐RBCs in mouse bearing subcutaneous TS/A breast cancer; (b) CEST map upon irradiation at Dy‐labeled‐RBCs frequency. (Reprinted with permission from Ref . Copyright 2014 American Chemical Society)
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(a) Schema of hypotonic swelling for labeling of RBCs with lanthanide (III) complexes; (b) Z‐ and (c) ST‐spectra of Dy‐labeled‐RBCs (black) and untreated RBCs (red); (d) variation of intracellular water chemical shift as a function of the Ln(III)‐ion effective magnetic moment (μeff). (Reprinted with permission from Ref . Copyright 2014 American Chemical Society)
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(a) Z‐ and (b) ST‐spectra of biotin‐containing lipoCEST agents with variable concentrations of streptavidin; (c) variation of ST and (b) intracellular water chemical shift as a function of the concentration of streptavidin.
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Main routes to enhance lipoCEST sensitivity by increasing Kex and/or the number of mobile protons.
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(a) Three generations of lipoCEST agents; (b) representative ST‐spectra of multicolor lipoCEST agents; and (c) In vivo simultaneous detection of two lipoCEST agents. (Reprinted with permission from Ref . Copyright 2013 John Wiley and Sons)
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(a) Scheme of preparation of osmotically shrunken lipoCEST agents; (b) nuclear magnetic resonance (NMR) spectra of lipoCEST agents in medium at increasing osmolarity (from 40 mOsm/L to 600 mOsm/L); (c) representative cryo‐transmission electron microscopy image of lipoCEST; and (d) orientation of lipoCESTs in the magnetic field and the chemical shift of the intravesicular water protons for aspherical lipoCEST agents as reported by Burdinski et al. (Reprinted with permission from Ref . Copyright 2013 John Wiley and Sons; Ref . Copyright 2009 John Wiley and Sons; Ref . Copyright 2019 John Wiley and Sons)
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(a) Scheme of liposomes preparation; (b) representative nuclear magnetic resonance (NMR) spectrum of lipoCEST agent; (c) representative Z‐spectrum of lipoCEST; and (d) CEST‐MR image of phatom containing capillaries filled with different concentrations of lipoCEST. (Reprinted with permission from Ref . Copyright 2013 John Wiley and Sons; Ref . Copyright 2008 Elsevier)
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(a) Z‐spectrum of in vivo liposome/RBCs aggregates, at t = 0 (left) and t = 1 h (right), reporting positive (3.2 ppm) and negative (−4.2 ppm) signals belonging to RBCs and lipoCESTs, respectively. CEST% map of tumor region with irradiation RF offset at 3.2 ppm at t = 0 and (b) and t = 1 h (c). CEST% map with irradiation RF offset at −4.2 ppm signal at t = 0 (d) and t = 1 h (e). The ROI has been circled with a white line. (Reprinted with permission from Ref . Copyright 2014 American Chemical Society)
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Some examples of developed nanosized CEST agents. (Reprinted with permission from Ref . Copyright 2007 Nature Publishing Group; Ref . Copyright 2003 John Wiley and Sons; Ref . Copyright 2003 John Wiley and Sons; Ref . Copyright 2007 Springer; Ref . Copyright 2007 John Wiley and Sons; Ref . Copyright 2009 American Chemical Society; Ref . Copyright 2014 Royal Society of Chemistry)
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Diagnostic Tools > Diagnostic Nanodevices
Biology-Inspired Nanomaterials > Lipid-Based Structures
Diagnostic Tools > In Vivo Nanodiagnostics and Imaging

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