Compartmentalized agents: A powerful strategy for enhancing the detection sensitivity of chemical exchange saturation transfer contrast

Abstract

Since the very beginnings of the chemical exchange saturation transfer (CEST) technique, poor overall sensitivity has appeared to be one of its strongest limitations for future applications. Research has therefore focused on designing systems, such as supramolecular and nanosized agents, that contain a high number of magnetically equivalent mobile spins. However, the number of mobile spins offered by these systems is still limited by their composition and surface/volume ratio. The design of compartmentalized agents, that is, systems where an aqueous inner core is separated from the MRI‐detected bulk pool via a semipermeable barrier/membrane, is very much a step forward for the technique. These vesicular systems can (i) act as biocompatible and versatile carriers for dia‐, para‐, and hetero‐nuclear CEST probes, thus offering new application options; and (ii) act as CEST probes themselves via the encapsulation of a suitable agent (e.g., a paramagnetic shift reagent) that can change the resonance frequency of the spin pool in the inner compartment only. LipoCEST agents were the pioneers in the latter category, as they are able to grant picomolar sensitivity (in terms of nanoparticle concentration), and paved the way for new applications for CEST agents, especially in the theranostic research area. The use of larger, natural vesicular systems, such as yeasts and cells, in which the huge number of intravesicular spins lowers the detection threshold to a femtomolar limit, is a further step forward in the development of compartmentalized CEST agents. Finally, interesting combinations of nanovesicular and cellular compartmentalized systems have been proposed, thus highlighting how the approach has the potential to drive CEST agents towards completing their journey to mature clinical translation.

A Magnetic Resonance Imaging‐Chemical Exchange Saturation Transfer (MRI‐CEST) Method for the Detection of Water Cycling across Cellular Membranes

“…In our work, the so called "CEST @2ppm " [27] was chosen as intracellular CEST signal instead of APT to avoid the possible bias in the calculation of the CEST effect associated to the presence of the Nuclear Overhauser Effect (NOE) signal at À 3.4 ppm. [13,16,26,39] CEST @2ppm is due to the exchangeable protons of creatine, creatinine and other amines, resonating at about 2 ppm from the bulk water signal (chemical structures are shown in Figure 1A). Since no confounding signal at À 2 ppm is present, the analysis of CEST @2ppm should result simpler and more robust than APT.…”

“…In recent years a new contrast enhancing procedure is under intense scrutiny for widening the field of applications in respect to what can be obtained with the currently used relaxation-based systems. [12,13] It relies on the transfer of saturated magnetization to the bulk water signal operated by the transfer of exchanging protons properly irradiated with a second irradiation radiofrequency field (CEST = Chemical Exchange Saturation Transfer). [13][14][15][16][17] Several endogenous and exogenous molecules have been so far investigated as CEST CAs, with very interesting applications in the field of cancer phenotyping and neurological diseases.…”

Special issue on chemical exchange saturation transfer MRI

“…These agents and their mechanism of contrast are covered comprehensively by Ferrauto and Terreno. 12 Protein-based CEST agents are reviewed by Gilad et al 13 Here, the rationale of enzyme-substrate pairs as CEST contrast enhancers is discussed along with theoretical considerations to improve peptide selectivity and specificity for CEST optimized protein synthesis in situ in cells. 13 Reviews of specific metabolites or agents are covered next.…”

“…Overviews of diaCEST, paraCEST, and compartmentalized agents are given by Longo et al, 10 Sherry et al, 11 and Ferrauto and Terreno 12 respectively. Importantly, Longo et al review and identify diamagnetic compounds that have suitable biosafety profiles for use in medical applications 10 .…”

“…Compartmentalized agents are the most sensitive for CEST contrast due to their dependence on the total concentration of water in the compartment. These agents and their mechanism of contrast are covered comprehensively by Ferrauto and Terreno 12 . Protein‐based CEST agents are reviewed by Gilad et al 13 Here, the rationale of enzyme–substrate pairs as CEST contrast enhancers is discussed along with theoretical considerations to improve peptide selectivity and specificity for CEST optimized protein synthesis in situ in cells 13 …”