ParaCEST Agents Encapsulated in Reverse Nano-Assembled Capsules (RACs): How Slow Molecular Tumbling Can Quench CEST Contrast

Abstract

Although paraCEST is a method with immense scope for generating image contrast in MRI, it suffers from the serious drawback of high detection limits. For a typical discrete paraCEST agent the detection limit is roughly an order of magnitude higher than that of a clinically used relaxation agent. One solution to this problem may be the incorporation of a large payload of paraCEST agents into a single macromolecular agent. Here we report a new synthetic method for accomplishing this goal: incorporating a large payload of the paraCEST agent DyDOTAM3+ into a Reverse Assembled nano-Capsule. An aggregate can be generated between this chelate and polyacrylic acid (PAA) after the addition of ethylene diamine. Subsequent addition of polyallylamine hydrochloride (PAH) followed by silica nanoparticles generated a robust encapsulating shell and afforded capsule with a mean hydrodynamic diameter of 650 ± 250 nm. Unfortunately this encapsulation did not have the effect of amplifying the CEST effect per agent, but quenched the CEST altogether. The quenching effect of encapsulation could be attributed to the effect of slowing molecular tumbling, which is inevitable when the chelate is incorporated into a nano-scale material. This increases the transverse relaxation rate of chelate protons and a theoretical examination using Solomon Bloembergen Morgan theory and the Bloch equations shows that the increase in the transverse relaxation rate constant for the amide protons, in even modestly sized nano-materials, is sufficient to significantly quench CEST.

Nuclear Magnetic Resonance with Fast Field-Cycling Setup: A Valid Tool for Soil Quality Investigation

“…The model discussed in this sub-section has been confirmed in Payne et al [41], Yadav et al [124], Farashishiko et al [125], and Sharma and Chandra [126].…”

“…More in detail, they behaved as chaotropes up to the concentration of 4 M. Conversely, they showed a kosmotropic behavior above the aforementioned concentration. From a qualitative standpoint, the different effects could be explained considering the prevalence of the chaotropic nature of the cations (either Na + or NH 4 + ) when concentrations were < 4 M and by the prevalence of the kosmotropic nature of nitrate when salt concentration was > 4 M. The model discussed in this sub-section has been confirmed in Payne et al [41], Yadav et al [124], Farashishiko et al [125], and Sharma and Chandra [126].…”

Investigating plasma volume expanders as novel macromolecular MRI‐CEST contrast agents for tumor contrast‐enhanced imaging

“…38,39 In addition, CEST agents based on polymers or liposomes have been designed as vascular agents, exhibiting good CEST contrast, despite some not having been tested in vivo yet. [40][41][42][43][44][45][46] Also, molecules that possess exchangeable hydroxyl groups (-OH) as dextrans can be detected by MRI-CEST without extra labeling procedures. [47][48][49][50][51][52][53] Recently, it was found that dextran molecules with different molecular weights are able to provide a size-dependent CEST contrast.…”

“…Low‐molecular‐weight iodinated agents, clinically approved for X‐ray investigations, have been exploited as perfusion agents for MRI‐CEST application 38,39 . In addition, CEST agents based on polymers or liposomes have been designed as vascular agents, exhibiting good CEST contrast, despite some not having been tested in vivo yet 40‐46 . Also, molecules that possess exchangeable hydroxyl groups (‐OH) as dextrans can be detected by MRI‐CEST without extra labeling procedures 47‐53 .…”

Novel nanomedicine with a chemical-exchange saturation transfer effect for breast cancer treatment in vivo

“…The saturated exchangeable protons then exchange with bulk water protons, resulting in partial loss of the bulk water signal, which then becomes detectable during MRI [32]. CEST MRI can be switched “on” and “off” at will by simply adjusting the RF saturation pulse sequence parameters [33]. Notably, CEST MRI has potential to provide molecular information for diagnosing pathological tissues and detecting molecular responses to treatment [34, 35].…”