How to cite this WIREs title:
WIREs Nanomed Nanobiotechnol

Impact Factor: 7.689

Sugar‐based biopolymers as novel imaging agents for molecular magnetic resonance imaging

Focus Article

Zheng Han, Guanshu Liu

Published Online: Jan 22 2019

DOI: 10.1002/wnan.1551

Full article on Wiley Online Library: HTML PDF

Can't access this content? Tell your librarian.

Sugar‐based biopolymers have been recognized as attractive materials to develop macromolecule‐ and nanoparticle‐based cancer imaging and therapy. However, traditional biopolymer‐based imaging approaches rely on the use of synthetic or isotopic labeling, and because of it, clinical translation often is hindered. Recently, a novel magnetic resonance imaging (MRI) technology, chemical exchange saturation transfer (CEST), has emerged, which allows the exploitation of sugar‐based biopolymers as MRI agents by their hydroxyl protons‐rich nature. In the study, we reviewed recent studies on the topic of CEST MRI detection of sugar‐based biopolymers. The CEST MRI property of each biopolymer was briefly introduced, followed by the pre‐clinical and clinical applications. The findings of these preliminary studies imply the enormous potential of CEST detectable sugar‐based biopolymers in developing highly sensitive and translatable molecular imaging agents and constructing image‐guided biopolymer‐based drug delivery systems. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Emerging Technologies

Illustration of chemical exchange saturation transfer magnetic resonance imaging (MRI) detection of natural dextran, which is achieved by the continuous transfer of saturated protons (red) from hydroxyl groups to surrounding water molecules, generating a reduction in the water signal (MRI contrast) proportional to the dextran concentration and the rate of exchange. The unsaturated hydroxyl protons are shown in blue. S_sat, the water (MRI) signal in the presence of saturation RF pulses. (Reprinted with permission from G. Liu et al. (). Copyright 2017 Nature Publishing Group)

[ Normal View | Magnified View ]

Changes in the dynamic CEST signal in PSMA(+) and PSMA(−) tumors. (a) T2‐weighted image and dynamic CEST maps at 1 ppm after the injection of 375 mg/kg urea‐10 kD‐dextran (injection volume = 100 μL). (b) Mean changes in the CEST signal in PSMA(+) and PSMA(−) tumors in one of the mice for which time dependence was measured. CEST signal enhancement was quantified by ΔMTR_asym = MTR_asym(t) ‑ MTR_asym (t = 0), where the error bars are the standard errors of the CEST signal of all the pixels in each tumor. All CEST images were acquired using a 1.8 μT and 3 s‐long CW pulse. (c) Average CEST signal in the tumor for five mice before (blue) and 1 hr after (red) the injection of urea‐Dex10. The signal difference is shown in black. Error bars are standard deviations of the CEST signal of all five tumors. (d) Bar plots showing the mean changes in CEST signal as quantified by ΔMTR_asym (1 hr) in each type tumor (n = 5 and 3 for urea‐Dex10 and nontargeted Dex10, respectively). *p < 0.05 (Student's t test, two‐tailed and unpaired). (e) in vivo fluorescence image of a representative mouse showing a distinctive tumor uptake of urea‐Dex10 at 60 min after injection. (f) Sections of PSMA(+) PC3‐PIP (top) and PSMA(−) PC3‐flu (bottom) tumors stained with anti‐PSMA. Images were acquired at ×40 magnification. (g) Fluorescence microscopy of nuclei (blue, stained with DAPI) dextran (red, NIR‐600‐labeled). Scale bar = 500 μm for the left three panels and 100 μm for the most right panels, which are the zoomed view of area enclosed in dashed green box in the image on the left. On the right, a scatter plot shows the comparison of the normalized mean fluorescence intensity of three different field of views in the tumors. (Reprinted with permission from G. Liu et al. (). Copyright 2017 Nature Publishing Group)

[ Normal View | Magnified View ]

(a) T2‐weighted image, marked with regions of U87, LS174T, and control white matter (dashed square). (b) CEST contrast map created by averaging 1.2 and 0.9 ppm. Superimposed onto (a) for B₁ = 3.6 μT. (c) MTR_asym curves of the three ROIs marked in (a). (d) MTR_asym values of the two cell lines showing a significant difference (*p < 0.05, Student's t test). Error bars represent standard deviation (n = 3). (Reprinted with permission from Song et al. (). Copyright 2015 Nature Publishing Group)

[ Normal View | Magnified View ]

gagCEST MR images of a human patella in vivo with irradiation at −1.0, +1.0 ppm, and the difference image (a) along with the extracted CEST contrast from the femur and the lateral and medial sides of the patella (b). The total duration of the presaturation pulse sequence was 320 ms at an average RF power of 42 Hz. (Reprinted with permission from Ling et al. (). Copyright 2008 National Academy of Sciences)

[ Normal View | Magnified View ]

Structure illustration of four sugar‐based biopolymers: (a) glycogen, (b) GAG, (c) Mucin1, and (d) dextran

[ Normal View | Magnified View ]

glycoCEST imaging of a perfused fed‐mouse liver at 4.7 T and 37°C. The first image (gray scale) marks the beginning of perfusion (t = 0) with glucose‐free media containing 500 pg/mL glucagon. The liver tissue is darkened because of the CEST effect from presaturation at 1.0 ppm for 1 s at 3.0 μT. Upon further perfusion with glucagon, the liver signal increased, corresponding to a decrease in CEST effect. The colorized glycoCEST images as a function of time during perfusion show the relative CEST intensity [MTR_asym (1 ppm)] of liver tissue as a function of perfusion time. The color scale shows that there are regions of liver where the initial asymmetry difference between ±1 ppm is as high as 55% (orange pixels) and as low as 5% (blue pixels). With time, as glycogen disappears, the CEST images become more uniformly dark blue, corresponding to minimal glycogen. The corresponding glycogen depletion for a homogeneous region of interest is quantified in the graph (n = 4). (Reprinted with permission from P. C. van Zijl et al. (). Copyright 2007 National Academy of Sciences)

[ Normal View | Magnified View ]

References

Adeva‐Andany,, M. M., González‐Lucán,, M., Donapetry‐García,, C., Fernández‐Fernández,, C., & Ameneiros‐Rodríguez,, E. (2016). Glycogen metabolism in humans. BBA Clinical, 5, 85–100.
Anzai,, Y., Mclachlan,, S., Morris,, M., Saxton,, R., & Lufkin,, R. B. (1994). Dextran‐coated superparamagnetic iron oxide, an MR contrast agent for assessing lymph nodes in the head and neck. American Journal of Neuroradiology, 15(1), 87–94.
Armstrong,, J. K., Wenby,, R. B., Meiselman,, H. J., & Fisher,, T. C. (2004). The hydrodynamic radii of macromolecules and their effect on red blood cell aggregation. Biophysical Journal, 87(6), 4259–4270. https://doi.org/10.1529/biophysj.104.047746
Bagga,, P., Haris,, M., D`Aquilla,, K., Wilson,, N. E., Marincola,, F. M., Schnall,, M. D., … Reddy,, R. (2017). Non‐caloric sweetener provides magnetic resonance imaging contrast for cancer detection. Journal of Translational Medicine, 15(1), 119. https://doi.org/10.1186/s12967-017-1221-9
Bar‐Shir,, A., Liu,, G. S., Chan,, K. W. Y., Oskolkov,, N., Song,, X. L., Yadav,, N. N., … Gilad,, A. A. (2014). Human Protamine‐1 as an MRI reporter gene based on chemical exchange. ACS Chemical Biology, 9(1), 134–138. https://doi.org/10.1021/cb400617q
Bar‐Shir,, A., Liu,, G. S., Liang,, Y. J., Yadav,, N. N., McMahon,, M. T., Walczak,, P., … Gilad,, A. A. (2013). Transforming thymidine into a magnetic resonance imaging probe for monitoring gene expression. Journal of the American Chemical Society, 135(4), 1617–1624. https://doi.org/10.1021/ja312353e
Bryson,, J. M., Reineke,, J. W., & Reineke,, T. M. (2012). Macromolecular imaging agents containing lanthanides: Can conceptual promise lead to clinical potential? Macromolecules, 45(22), 8939–8952.
Cai,, K., Haris,, M., Singh,, A., Kogan,, F., Greenberg,, J. H., Hariharan,, H., … Reddy,, R. (2012). Magnetic resonance imaging of glutamate. Nature Medicine, 18(2), 302–306. https://doi.org/10.1038/nm.2615
Chan,, K. W., Liu,, G., Song,, X., Kim,, H., Yu,, T., Arifin,, D. R., … McMahon,, M. T. (2013). MRI‐detectable pH nanosensors incorporated into hydrogels for in vivo sensing of transplanted‐cell viability. Nature Materials, 12(3), 268–275. https://doi.org/10.1038/nmat3525
Chan,, K. W., McMahon,, M. T., Kato,, Y., Liu,, G., Bulte,, J. W., Bhujwalla,, Z. M., … van Zijl,, P. C. (2012). Natural d‐glucose as a biodegradable MRI contrast agent for detecting cancer. Magnetic Resonance in Medicine, 68(6), 1764–1773. https://doi.org/10.1002/mrm.24520
Chan,, K. W. Y., Yu,, T., Qiao,, Y., Liu,, Q., Yang,, M., Patel,, H., … McMahon,, M. T. (2014). A diaCEST MRI approach for monitoring liposomal accumulation in tumors. Journal of Controlled Release, 180, 51–59. https://doi.org/10.1016/j.jconrel.2014.02.005
Chang,, R., Ueki,, I., Troy,, J., Deen,, W., Robertson,, C. R., & Brenner,, B. (1975). Permselectivity of the glomerular capillary wall to macromolecules. II. Experimental studies in rats using neutral dextran. Biophysical Journal, 15(9), 887.
Chen,, L. Q., Howison,, C. M., Jeffery,, J. J., Robey,, I. F., Kuo,, P. H., & Pagel,, M. D. (2014). Evaluations of extracellular pH within in vivo tumors using acidoCEST MRI. Magnetic Resonance in Medicine, 72(5), 1408–1417. https://doi.org/10.1002/mrm.25053
Chen,, S. Z., Yuan,, J., Deng,, M., Wei,, J., Zhou,, J., & Wang,, Y. X. (2016). Chemical exchange saturation transfer (CEST) MR technique for in‐vivo liver imaging at 3.0 tesla. European Radiology, 26(6), 1792–1800. https://doi.org/10.1007/s00330-015-3972-0
Cobb,, J. G., Li,, K., Xie,, J., Gochberg,, D. F., & Gore,, J. C. (2014). Exchange‐mediated contrast in CEST and spin‐lock imaging. Magnetic Resonance Imaging, 32(1), 28–40. https://doi.org/10.1016/j.mri.2013.08.002
Dansereau,, R. N., & Line,, B. R. (1994). Preparation of Dextran‐70 injection labeled with technetium‐99m for use as a cardiac blood‐pool imaging agent. American Journal of Hospital Pharmacy, 51(22), 2797–2800.
Daryaei,, I., & Pagel,, M. D. (2015). Double agents and secret agents: The emerging fields of exogenous chemical exchange saturation transfer and T2‐exchange magnetic resonance imaging contrast agents for molecular imaging. Research and Reports in Nuclear Medicine, 5, 19–32. https://doi.org/10.2147/RRNM.S81742
Deng,, M., Chen,, S. Z., Yuan,, J., Chan,, Q., Zhou,, J., & Wang,, Y. X. (2016). Chemical exchange saturation transfer (CEST) MR technique for liver imaging at 3.0 tesla: An evaluation of different offset number and an after‐meal and over‐night‐fast comparison. Molecular Imaging and Biology, 18(2), 274–282. https://doi.org/10.1007/s11307-015-0887-8
Dreher,, M. R., Liu,, W., Michelich,, C. R., Dewhirst,, M. W., Yuan,, F., & Chilkoti,, A. (2006). Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers. Journal of the National Cancer Institute, 98(5), 335–344. https://doi.org/10.1093/jnci/djj070
Dubick,, M. A., & Wade,, C. E. (1994). A review of the efficacy and safety of 7.5% NaCl/6% dextran 70 in experimental animals and in humans. Journal of Trauma‐Injury, Infection, and Critical Care, 36(3), 323–330.
Goldenberg,, J. M., Pagel,, M. D., & Cárdenas‐Rodríguez,, J. (2018). Characterization of d‐maltose as a T2‐exchange contrast agent for dynamic contrast‐enhanced MRI. Magnetic Resonance in Medicine, 80(3), 1158–1164. https://doi.org/10.1002/mrm.27082
Goodarzi,, N., Varshochian,, R., Kamalinia,, G., Atyabi,, F., & Dinarvand,, R. (2013). A review of polysaccharide cytotoxic drug conjugates for cancer therapy. Carbohydrate Polymers, 92(2), 1280–1293. https://doi.org/10.1016/j.carbpol.2012.10.036
Haris,, M., Cai,, K., Singh,, A., Hariharan,, H., & Reddy,, R. (2011). In vivo mapping of brain myo‐inositol. NeuroImage, 54(3), 2079–2085. https://doi.org/10.1016/j.neuroimage.2010.10.017
Haris,, M., Singh,, A., Cai,, K., Nath,, K., Crescenzi,, R., Kogan,, F., … Reddy,, R. (2013). MICEST: A potential tool for non‐invasive detection of molecular changes in Alzheimer`s disease. Journal of Neuroscience Methods, 212(1), 87–93. https://doi.org/10.1016/j.jneumeth.2012.09.025
Heinze,, T., Liebert,, T., Heublein,, B., & Hornig,, S. (2006). Functional polymers based on dextran. In D. Klemm (Ed.), Polysaccharides II (pp. 199–291). New York, NY: Springer.
Hills,, B. (1991). Multinuclear NMR studies of water in solutions of simple carbohydrates. I. Proton and deuterium relaxation. Molecular Physics, 72(5), 1099–1121.
Jin,, T., & Kim,, S. G. (2014). Advantages of chemical exchange‐sensitive spin‐lock (CESL) over chemical exchange saturation transfer (CEST) for hydroxyl‐ and amine‐water proton exchange studies. NMR in Biomedicine, 27(11), 1313–1324. https://doi.org/10.1002/nbm.3191
Jin,, T., Mehrens,, H., Wang,, P., & Kim,, S. G. (2016). Glucose metabolism‐weighted imaging with chemical exchange‐sensitive MRI of 2‐deoxyglucose (2DG) in brain: Sensitivity and biological sources. NeuroImage, 143, 82–90. https://doi.org/10.1016/j.neuroimage.2016.08.040
Jin,, T., Wang,, P., Zong,, X., & Kim,, S. G. (2012). Magnetic resonance imaging of the Amine‐Proton EXchange (APEX) dependent contrast. NeuroImage, 59(2), 1218–1227. https://doi.org/10.1016/j.neuroimage.2011.08.014
Jones,, C. K., Huang,, A., Xu,, J., Edden,, R. A., Schär,, M., Hua,, J., … McMahon,, M. T. (2013). Nuclear Overhauser enhancement (NOE) imaging in the human brain at 7T. NeuroImage, 77, 114–124.
Jones,, K. M., Pollard,, A. C., & Pagel,, M. D. (2018). Clinical applications of chemical exchange saturation transfer (CEST) MRI. Journal of Magnetic Resonance Imaging, 47(1), 11–27. https://doi.org/10.1002/jmri.25838
Juras,, V., Winhofer,, Y., Szomolanyi,, P., Vosshenrich,, J., Hager,, B., Wolf,, P., … Trattnig,, S. (2015). Multiparametric MR imaging depicts glycosaminoglycan change in the Achilles tendon during ciprofloxacin administration in healthy men: Initial observation. Radiology, 275(3), 763–771. https://doi.org/10.1148/radiol.15140484
Kim,, M., Chan,, Q., Anthony,, M. P., Cheung,, K. M., Samartzis,, D., & Khong,, P. L. (2011). Assessment of glycosaminoglycan distribution in human lumbar intervertebral discs using chemical exchange saturation transfer at 3 T: Feasibility and initial experience. NMR in Biomedicine, 24(9), 1137–1144. https://doi.org/10.1002/nbm.1671
Kogan,, F., Hariharan,, H., & Reddy,, R. (2013). Chemical exchange saturation transfer (CEST) imaging: Description of technique and potential clinical applications. Current Radiology Reports, 1(2), 102–114. https://doi.org/10.1007/s40134-013-0010-3
Langereis,, S., De Lussanet,, Q. G., Van Genderen,, M. H., Backes,, W. H., & Meijer,, E. (2004). Multivalent contrast agents based on gadolinium‐diethylenetriaminepentaacetic acid‐terminated poly (propylene imine) dendrimers for magnetic resonance imaging. Macromolecules, 37(9), 3084–3091.
Larsen,, C. (1989). Dextran prodrugs—Structure and stability in relation to therapeutic activity. Advanced Drug Delivery Reviews, 3(1), 103–154.
Lee,, J. S., Xia,, D., Jerschow,, A., & Regatte,, R. R. (2016). In vitro study of endogenous CEST agents at 3 T and 7 T. Contrast Media and Molecular Imaging, 11(1), 4–14. https://doi.org/10.1002/cmmi.1652
Li,, Y., Chen,, H., Xu,, J., Yadav,, N. N., Chan,, K. W., Luo,, L., … Liu,, G. (2016). CEST theranostics: Label‐free MR imaging of anticancer drugs. Oncotarget, 7(6), 6369–6378. https://doi.org/10.18632/oncotarget.7141
Li,, Y., Qiao,, Y., Chen,, H., Bai,, R., Staedtke,, V., Han,, Z., … Liu,, G. (2018). Characterization of tumor vascular permeability using natural dextrans and CEST MRI. Magnetic Resonance in Medicine, 79(2), 1001–1009. https://doi.org/10.1002/mrm.27014
Ling,, W., Regatte,, R. R., Navon,, G., & Jerschow,, A. (2008). Assessment of glycosaminoglycan concentration in vivo by chemical exchange‐dependent saturation transfer (gagCEST). Proceedings of the National Academy of Sciences of the United States of America, 105(7), 2266–2270. https://doi.org/10.1073/pnas.0707666105
Liu,, G., Moake,, M., Har‐el,, Y. E., Long,, C. M., Chan,, K. W., Cardona,, A., … McMahon,, M. T. (2012). In vivo multicolor molecular MR imaging using diamagnetic chemical exchange saturation transfer liposomes. Magnetic Resonance in Medicine, 67(4), 1106–1113. https://doi.org/10.1002/mrm.23100
Liu,, G., Ray Banerjee,, S., Yang,, X., Yadav,, N., Lisok,, A., Jablonska,, A., … van Zijl,, P. (2017). A dextran‐based probe for the targeted magnetic resonance imaging of tumours expressing prostate‐specific membrane antigen. Nature Biomedical Engineering, 1(12), 977–982. https://doi.org/10.1038/s41551-017-0168-8
Liu,, G., Song,, X., Chan,, K. W., & McMahon,, M. T. (2013). Nuts and bolts of chemical exchange saturation transfer MRI. NMR in Biomedicine, 26(7), 810–828. https://doi.org/10.1002/nbm.2899
Liu,, G. S., Liang,, Y. J., Bar‐Shir,, A., Chan,, K. W. Y., Galpoththawela,, C. S., Bernard,, S. M., … Gilad,, A. A. (2011). Monitoring enzyme activity using a diamagnetic chemical exchange saturation transfer magnetic resonance imaging contrast agent. Journal of the American Chemical Society, 133(41), 16326–16329. https://doi.org/10.1021/ja204701x
Liu,, H., Jablonska,, A., Li,, Y., Cao,, S., Liu,, D., Chen,, H., … Liu,, G. (2016). Label‐free CEST MRI detection of citicoline‐liposome drug delivery in ischemic stroke. Theranostics, 6(10), 1588–1600. https://doi.org/10.7150/thno.15492
Liu,, P., Yue,, C., Shi,, B., Gao,, G., Li,, M., Wang,, B., … Cai,, L. (2013). Dextran based sensitive theranostic nanoparticles for near‐infrared imaging and photothermal therapy in vitro. Chemical Communications, 49(55), 6143–6145.
Liu,, Q., Jin,, N., Fan,, Z., Natsuaki,, Y., Tawackoli,, W., Pelled,, G., … Li,, D. (2013). Reliable chemical exchange saturation transfer imaging of human lumbar intervertebral discs using reduced‐field‐of‐view turbo spin echo at 3.0 T. NMR in Biomedicine, 26(12), 1672–1679. https://doi.org/10.1002/nbm.3001
Liu,, Z. H., Jiao,, Y. P., Wang,, Y. F., Zhou,, C. R., & Zhang,, Z. Y. (2008). Polysaccharides‐based nanoparticles as drug delivery systems. Advanced Drug Delivery Reviews, 60(15), 1650–1662. https://doi.org/10.1016/J.Addr.2008.09.001
Ljungström,, K.‐G. (2006). Invited commentary: Pretreatment with dextran 1 makes dextran 40 therapy safer. Journal of Vascular Surgery, 43(5), 1070–1072.
Ljungstrom,, K.‐G., Renck,, H., Strandberg,, K., Hedin,, H., Richter,, W., & Widerlov,, E. (1983). Adverse reactions to dextran in Sweden 1970–1979. Acta Chirurgica Scandinavica, 149(3), 253–262.
Lock,, L. L., Li,, Y., Mao,, X., Chen,, H., Staedtke,, V., Bai,, R., … Cui,, H. (2017). One‐component supramolecular filament hydrogels as theranostic label‐free magnetic resonance imaging agents. ACS Nano, 11(1), 797–805. https://doi.org/10.1021/acsnano.6b07196
Longo,, D. L., Dastru,, W., Digilio,, G., Keupp,, J., Langereis,, S., Lanzardo,, S., … Aime,, S. (2011). Iopamidol as a responsive MRI‐chemical exchange saturation transfer contrast agent for pH mapping of kidneys: in vivo studies in mice at 7 T. Magnetic Resonance in Medicine, 65(1), 202–211. https://doi.org/10.1002/mrm.22608
Longo,, D. L., Moustaghfir,, F. Z., Zerbo,, A., Consolino,, L., Anemone,, A., Bracesco,, M., & Aime,, S. (2017). EXCI‐CEST: Exploiting pharmaceutical excipients as MRI‐CEST contrast agents for tumor imaging. International Journal of Pharmaceutics, 525(1), 275–281.
Longo,, D. L., Sun,, P. Z., Consolino,, L., Michelotti,, F. C., Uggeri,, F., & Aime,, S. (2014). A general MRI‐CEST ratiometric approach for pH imaging: Demonstration of in vivo pH mapping with iobitridol. Journal of the American Chemical Society, 136(41), 14333–14336. https://doi.org/10.1021/ja5059313
Matsunaga,, K., Hara,, K., Imamura,, T., Fujioka,, T., Takata,, J., & Karube,, Y. (2005). Technetium labeling of dextran incorporating cysteamine as a ligand. Nuclear Medicine and Biology, 32(3), 279–285.
McMahon,, M. T., Gilad,, A. A., Zhou,, J. Y., Sun,, P. Z., Bulte,, J. W. M., & van Zijl,, P. C. M. (2006). Quantifying exchange rates in chemical exchange saturation transfer agents using the saturation time and saturation power dependencies of the magnetization transfer effect on the magnetic resonance imaging signal (QUEST and QUESP): pH calibration for poly‐l‐lysine and a starburst dendrimer. Magnetic Resonance in Medicine, 55(4), 836–847. https://doi.org/10.1002/mrm.20818
Mehvar,, R. (2000). Dextrans for targeted and sustained delivery of therapeutic and imaging agents. Journal of Controlled Release, 69(1), 1–25.
Meyer,, J.‐P., Tully,, K. M., Jackson,, J., Dilling,, T. R., Reiner,, T., & Lewis,, J. S. (2018). Bioorthogonal masking of circulating antibody–TCO groups using tetrazine‐functionalized dextran polymers. Bioconjugate Chemistry, 29(2), 538–545.
Miller,, C. O., Cao,, J., Chekmenev,, E. Y., Damon,, B. M., Cherrington,, A. D., & Gore,, J. C. (2015). Noninvasive measurements of glycogen in perfused mouse livers using chemical exchange saturation transfer NMR and comparison to (13)C NMR spectroscopy. Analytical Chemistry, 87(11), 5824–5830. https://doi.org/10.1021/acs.analchem.5b01296
Mohanty,, A. K., Misra,, M., & Drzal,, L. T. (2005). Natural fibers, biopolymers, and biocomposites. Boca Raton, FL: Taylor & Francis Group.
Moon,, B. F., Jones,, K. M., Chen,, L. Q., Liu,, P., Randtke,, E. A., Howison,, C. M., & Pagel,, M. D. (2015). A comparison of iopromide and iopamidol, two acidoCEST MRI contrast media that measure tumor extracellular pH. Contrast Media and Molecular Imaging, 10(6), 446–455. https://doi.org/10.1002/cmmi.1647
Morais,, M., Campello,, M. P., Xavier,, C., Heemskerk,, J., Correia,, J. D. G., Lahoutte,, T., … Santos,, I. (2014). Radiolabeled mannosylated dextran derivatives bearing an NIR‐fluorophore for sentinel lymph node imaging. Bioconjugate Chemistry, 25(11), 1963–1970.
Nasrallah,, F. A., Pages,, G., Kuchel,, P. W., Golay,, X., & Chuang,, K. H. (2013). Imaging brain deoxyglucose uptake and metabolism by glucoCEST MRI. Journal of Cerebral Blood Flow and Metabolism, 33(8), 1270–1278. https://doi.org/10.1038/jcbfm.2013.79
Ngen,, E. J., Bar‐Shir,, A., Jablonska,, A., Liu,, G., Song,, X., Ansari,, R., … Gilad,, A. A. (2016). Imaging the DNA alkylator melphalan by CEST MRI: An advanced approach to theranostics. Molecular Pharmaceutics, 13(9), 3043–3053. https://doi.org/10.1021/acs.molpharmaceut.6b00130
Paull,, J. (1987). A prospective study of dextran‐induced anaphylactoid reactions in 5745 patients. Anaesthesia and Intensive Care, 15(2), 163–167.
Rebizak,, R., Schaefer,, M., & Dellacherie,, É. (1997). Polymeric conjugates of Gd3+− diethylenetriaminepentaacetic acid and dextran. 1. Synthesis, characterization, and paramagnetic properties. Bioconjugate Chemistry, 8(4), 605–610.
Rivlin,, M., Horev,, J., Tsarfaty,, I., & Navon,, G. (2013). Molecular imaging of tumors and metastases using chemical exchange saturation transfer (CEST) MRI. Scientific Reports, 3, 3045. https://doi.org/10.1038/srep03045
Rivlin,, M., & Navon,, G. (2016). Glucosamine and N‐acetyl glucosamine as new CEST MRI agents for molecular imaging of tumors. Scientific Reports, 6, 32648. https://doi.org/10.1038/srep32648
Rivlin,, M., & Navon,, G. (2017). CEST MRI of 3‐O‐methyl‐d‐glucose on different breast cancer models. Magnetic Resonance in Medicine, 79(2), 1061–1069. https://doi.org/10.1002/mrm.26752
Rivlin,, M., Tsarfaty,, I., & Navon,, G. (2014). Functional molecular imaging of tumors by chemical exchange saturation transfer MRI of 3‐O‐methyl‐d‐glucose. Magnetic Resonance in Medicine, 72(5), 1375–1380. https://doi.org/10.1002/mrm.25467
Ryoo,, D., Xu,, X., Li,, Y., Tang,, J. A., Zhang,, J., van Zijl,, P. C. M., & Liu,, G. (2017). Detection and quantification of hydrogen peroxide in aqueous solutions using chemical exchange saturation transfer. Analytical Chemistry, 89(14), 7758–7764. https://doi.org/10.1021/acs.analchem.7b01763
Schleich,, C., Bittersohl,, B., Miese,, F., Schmitt,, B., Muller‐Lutz,, A., Sondern,, M., … Zilkens,, C. (2016). Glycosaminoglycan chemical exchange saturation transfer at 3T MRI in asymptomatic knee joints. Acta Radiologica, 57(5), 627–632. https://doi.org/10.1177/0284185115598811
Schmiedl,, U., Ogan,, M., Paajanen,, H., Marotti,, M., Crooks,, L. E., Brito,, A. C., & Brasch,, R. C. (1987). Albumin labeled with Gd‐Dtpa as an intravascular, blood pool enhancing agent for MR imaging—Biodistribution and imaging studies. Radiology, 162(1), 205–210. https://doi.org/10.1148/radiology.162.1.3786763
Sehgal,, A. A., Li,, Y., Lal,, B., Yadav,, N. N., Xu,, X., Xu,, J., … van Zijl,, P. C. M. (2018). CEST MRI of 3‐O‐methyl‐d‐glucose uptake and accumulation in brain tumors. Magnetic Resonance in Medicine. https://doi.org/10.1002/mrm.27489
Snoussi,, K., Bulte,, J. W. M., Gueron,, M., & van Zijl,, P. C. M. (2003). Sensitive CEST agents based on nucleic acid imino proton exchange: Detection of poly(rU) and of a dendrimer‐poly(rU) model for nucleic acid delivery and pharmacology. Magnetic Resonance in Medicine, 49(6), 998–1005. https://doi.org/10.1002/mrm.10463
Song,, X., Airan,, R. D., Arifin,, D. R., Bar‐Shir,, A., Kadayakkara,, D. K., Liu,, G., … Bulte,, J. W. (2015). Label‐free in vivo molecular imaging of underglycosylated mucin‐1 expression in tumour cells. Nature Communications, 6, 6719. https://doi.org/10.1038/ncomms7719
Sun,, G., Feng,, J., Jing,, F., Pei,, F., & Liu,, M. (2003). Synthesis and evaluation of novel polysaccharide‐Gd‐DTPA compounds as contrast agent for MRI. Journal of Magnetism and Magnetic Materials, 265(2), 123–129.
Swierczewska,, M., Han,, H. S., Kim,, K., Park,, J. H., & Lee,, S. (2016). Polysaccharide‐based nanoparticles for theranostic nanomedicine. Advanced Drug Delivery Reviews, 99(Pt A), 70–84. https://doi.org/10.1016/j.addr.2015.11.015
Symons,, M. C. R., Benbow,, J. A., & Harvey,, J. M. (1980). Hydroxyl‐proton resonance shifts for a range of aqueous sugar solutions. Carbohydrate Research, 83(1), 9–20. https://doi.org/10.1016/S0008-6215(00)85359-8
Tassa,, C., Shaw,, S. Y., & Weissleder,, R. (2011). Dextran‐coated iron oxide nanoparticles: A versatile platform for targeted molecular imaging, molecular diagnostics, and therapy. Accounts of Chemical Research, 44(10), 842–852.
Thorén,, L. (1980). The dextrans—Clinical data. Developments in Biological Standardization, 48, 157–167.
van Zijl,, P. C., & Sehgal,, A. A. (2016). Proton chemical exchange saturation transfer (CEST) MRS and MRI. eMagRes, 5, 1–26. https://doi.org/10.1002/9780470034590.emrstm1482
van Zijl,, P. C., Jones,, C. K., Ren,, J., Malloy,, C. R., & Sherry,, A. D. (2007). MRI detection of glycogen in vivo by using chemical exchange saturation transfer imaging (glycoCEST). Proceedings of the National Academy of Sciences of the United States of America, 104(11), 4359–4364. https://doi.org/10.1073/pnas.0700281104
van Zijl,, P. C., & Yadav,, N. N. (2011). Chemical exchange saturation transfer (CEST): What is in a name and what isn`t? Magnetic Resonance in Medicine, 65(4), 927–948. https://doi.org/10.1002/mrm.22761
Varshosaz,, J. (2012). Dextran conjugates in drug delivery. Expert Opinion on Drug Delivery, 9(5), 509–523.
Walker‐Samuel,, S., Ramasawmy,, R., Torrealdea,, F., Rega,, M., Rajkumar,, V., Johnson,, S. P., … Golay,, X. (2013). In vivo imaging of glucose uptake and metabolism in tumors. Nature Medicine, 19(8), 1067–1072. https://doi.org/10.1038/nm.3252
Wang,, F., Kopylov,, D., Zu,, Z., Takahashi,, K., Wang,, S., Quarles,, C. C., … Takahashi,, T. (2016). Mapping murine diabetic kidney disease using chemical exchange saturation transfer MRI. Magnetic Resonance in Medicine, 76(5), 1531–1541. https://doi.org/10.1002/mrm.26045
Wang,, S. C., Wikstrom,, M. G., White,, D. L., Klaveness,, J., Holtz,, E., Rongved,, P., … Brasch,, R. C. (1990). Evaluation of Gd‐DTPA‐labeled dextran as an intravascular MR contrast agent: Imaging characteristics in normal rat tissues. Radiology, 175(2), 483–488. https://doi.org/10.1148/radiology.175.2.1691513
Ward,, K. M., Aletras,, A. H., & Balaban,, R. S. (2000). A new class of contrast agents for MRI based on proton chemical exchange dependent saturation transfer (CEST). Journal of Magnetic Resonance, 143(1), 79–87. https://doi.org/10.1006/jmre.1999.1956
Wei,, W., Lambach,, B., Jia,, G., Kaeding,, C., Flanigan,, D., & Knopp,, M. V. (2017). A phase I clinical trial of the knee to assess the correlation of gagCEST MRI, delayed gadolinium‐enhanced MRI of cartilage and T2 mapping. European Journal of Radiology, 90, 220–224. https://doi.org/10.1016/j.ejrad.2017.02.030
Wu,, X., Feng,, Y., Jeong,, E. K., Emerson,, L., & Lu,, Z. R. (2009). Tumor characterization with dynamic contrast enhanced magnetic resonance imaging and biodegradable macromolecular contrast agents in mice. Pharmaceutical Research, 26(9), 2202–2208. https://doi.org/10.1007/s11095-009-9935-x
Xu,, X., Chan,, K. W., Knutsson,, L., Artemov,, D., Xu,, J., Liu,, G., … van Zijl,, P. C. (2015). Dynamic glucose enhanced (DGE) MRI for combined imaging of blood‐brain barrier break down and increased blood volume in brain cancer. Magnetic Resonance in Medicine, 74(6), 1556–1563. https://doi.org/10.1002/mrm.25995
Xu,, X., Xu,, J., Chan,, K. W. Y., Liu,, J., Liu,, H., Li,, Y., … van Zijl,, P. C. M. (2018). GlucoCEST imaging with on‐resonance variable delay multiple pulse (onVDMP) MRI. Magnetic Resonance in Medicine, 81, 47–56. https://doi.org/10.1002/mrm.27364
Yadav,, N. N., Xu,, J., Bar‐Shir,, A., Qin,, Q., Chan,, K. W., Grgac,, K., … van Zijl,, P. C. (2014). Natural d‐glucose as a biodegradable MRI relaxation agent. Magnetic Resonance in Medicine, 72(3), 823–828. https://doi.org/10.1002/mrm.25329
Yang,, X., Song,, X. L., Banerjee,, S. R., Li,, Y. G., Byun,, Y., Liu,, G. S., … McMahon,, M. T. (2016). Developing imidazoles as CEST MRI pH sensors. Contrast Media and Molecular Imaging, 11(4), 304–312. https://doi.org/10.1002/cmmi.1693
Yang,, X., Song,, X. L., Li,, Y. G., Liu,, G. S., Banerjee,, S. R., Pomper,, M. G., & McMahon,, M. T. (2013). Salicylic acid and analogues as diaCEST MRI contrast agents with highly shifted exchangeable proton frequencies. Angewandte Chemie, 52(31), 8116–8119. https://doi.org/10.1002/anie.201302764
Zhang,, J., Han,, Z., Lu,, J., Li,, Y., Liao,, X., van Zijl,, P. C. M., … Liu,, G. (2018). Triazoles as T2‐exchange MRI contrast agents for the detection of nitrilase activity. Chemistry, 24(56), 15013–15018. https://doi.org/10.1002/chem.201802663
Zhang,, J., Li,, Y., Slania,, S., Yadav,, N. N., Liu,, J., Wang,, R., … Liu,, G. (2018). Phenols as diamagnetic T2‐exchange magnetic resonance imaging contrast agents. Chemistry, 24(6), 1259–1263. https://doi.org/10.1002/chem.201705772
Zhang,, X.‐Y., Wang,, F., Afzal,, A., Xu,, J., Gore,, J. C., Gochberg,, D. F., & Zu,, Z. (2016). A new NOE‐mediated MT signal at around −1.6 ppm for detecting ischemic stroke in rat brain. Magnetic Resonance Imaging, 34(8), 1100–1106.
Zhou,, J., Payen,, J. F., Wilson,, D. A., Traystman,, R. J., & van Zijl,, P. C. (2003). Using the amide proton signals of intracellular proteins and peptides to detect pH effects in MRI. Nature Medicine, 9(8), 1085–1090. https://doi.org/10.1038/nm907
Zhou,, Z., Bez,, M., Tawackoli,, W., Giaconi,, J., Sheyn,, D., de Mel,, S., … Li,, D. (2016). Quantitative chemical exchange saturation transfer MRI of intervertebral disc in a porcine model. Magnetic Resonance in Medicine, 76(6), 1677–1683. https://doi.org/10.1002/mrm.26457
Zinderman,, C. E., Landow,, L., & Wise,, R. P. (2006). Anaphylactoid reactions to dextran 40 and 70: Reports to the United States Food and Drug Administration, 1969 to 2004. Journal of Vascular Surgery, 43(5), 1004–1009.

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

The latest WIREs articles in your inbox

Sign Up for Article Alerts