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

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.