LipoCEST and cellCEST imaging agents: opportunities and challenges

Abstract

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 For further resources related to this article, please visit the WIREs website.

CEST‐MRI studies of cells loaded with lanthanide shift reagents

“…Among the 3 tested shift reagents, Dy‐HPDO3A showed the higher shifting ability (approximately 8 ppm). The observed δ In values are related to the second power of the effective magnetic moment of the Lanthanide ion (μ eff Dy = 10.6; μ eff Tm = 7.6; μ eff Eu = 3.5; Figure B) …”

“…An important step ahead to enhance the sensitivity threshold has been achieved by showing that the ensembles of water molecules confined in liposomes or in the cytosol compartment may be exploited as source of exchanging proton pool . In both systems, the compartmentalized water resonance (δ In ) can be shifted from the absorption of the bulk solvent by the presence of a paramagnetic shift reagent (SR) in the inner compartment.…”

Protein Nanostructures Produce Self-Adjusting Hyperpolarized Magnetic Resonance Imaging Contrast through Physical Gas Partitioning

“…This is in contrast with the fixed 1:1 stoichiometry of discrete xenon binders such as CrA and other synthetic and protein-based compounds. Though a 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 partitioning concept also applies to 1 H liposomal CEST agents or labeled red blood cells (called LipoCEST/cellCEST, [37][38][39] performed in water with fixed ~110 M proton concentration), the key concept in this work is that the concentrations of NMR-active spins in both exchange-connected pools scale simultaneously because Henry's law applies at both liquid interfaces with the gas head space and with the volume of the GVs. This conceptually different approach combines significant advantages over CEST agents based on chemical affinity.…”

Chemical Insights into the Issues of Gd Retention in the Brain and Other Tissues Upon the Administration of Gd‐Containing MRI Contrast Agents

“…Looking outside the field of metal complexes, probe developers have envisaged several ways to affect the MRI signal in the regions where the contrast agent is distributed. Among them, it is worth to quote the family of CEST agents . They rely on the transfer of saturated magnetization to the water proton signal, thus signaling their presence by “darkening” the corresponding regions in the MR images.…”