Heading toward Macromolecular and Nanosized Bioresponsive MRI Probes for Successful Functional Imaging

Abstract

The quest for bioresponsive or smart contrast agents (SCAs) in molecular imaging, in particular magnetic resonance imaging (MRI), is progressively increasing since they allow for the monitoring of essential biological processes on molecular and cellular levels in a dynamic fashion. These are offshoot molecules of common contrast agents that are sensitive to biochemical changes in their environment, capable of reporting on such changes by inducing MRI signal alteration. Various mechanistic approaches and different types of SCAs have been developed in order to visualize desired processes, using diverse imaging protocols and methods. To date, the most frequently exploited probes are paramagnetic molecules that change longitudinal or transverse relaxation at proton frequency, or so-called T- and T-weighted probes, respectively. Moreover, SCAs operating by the chemical exchange saturation transfer mechanism, suitable for F MRI or possessing hyperpolarized nuclei have also appeared in the past decade, slowly finding their role in functional imaging studies. Following these mechanistic principles, a large number of SCAs suitable for diverse targets have been reported to date. This Account condenses this exciting progress, particularly focusing on probes designed for abundant targets that are suitable for practical, in vivo utilization. To date, the greatest advancements have been certainly made in the preparation of pH sensitive probes, which usually contain protonable groups that interact with paramagnetic centers, or take advantage of supramolecular (dis)assembling to induce the MRI signal change, thereupon enabling pH mapping in vivo. In a complementary approach, a combination of metal chelating ligands for Ca or Zn with MR reporting units results in a wide variety of SCAs that operate with different contrast mechanisms and can be used for initial functional experiments. Finally, the first examples of molecular sensing by creating host-guest complexes to track neurotransmitter flux have also been recently reported, allowing the study of brain function in an unprecedented manner. Nevertheless, wider SCA utilization in vivo has not yet been achieved. There are a few reasons for this disparity between their nominal potential and practical usage, with one of the major reasons being the low sensitivity of the MRI technique. Subsequently, the production of detectable signal change can be achieved using higher concentrations of the bioresponsive probe; however, the biocompatibility of these probes then starts to play an important role. An elegant solution to these practical challenges has been found with the integration of multiple small-sized SCAs into macromolecular and nanosized probes. In such case, the multivalent SCAs are able to circumvent the sensitivity issue, thus enhancing the MR signal and desired contrast changes. Moreover, they prolong the probe tissue retention time, while often reducing their toxicity. Finally, with altered size and properties, they allow for exploitation of mechanisms that induce the contra...

Coordination Properties of GdDO3A-Based Model Compounds of Bioresponsive MRI Contrast Agents

“…The log K 1 and log K 2 values of L 1 and L 3 are very similar and somewhat lower than those of L 2 and L 4 . This phenomenon can be attributed, at least in part, to the longer propyl linker connecting the nitrogen atom of the macrocycle and the amide group in L 2 and L 4 , which likely results in a lower electron-withdrawing effect of the amide moiety.…”

“…Indeed, the first protonation constant determined for DO3A in 0.15 M NaCl is 1.3 log K units lower than that obtained in 0.1 M KCl, which shows that Chart 1. Structures of Paramagnetic Complexes LnL [1][2][3][4] (Ln = Gd, Eu, Yb) Investigated in This Work and Their Analogy to the Ca-Responsive Bis-Macrocyclic Contrast Agents SCA 1,2 6 Na + complex formation is partially responsible for the low protonation constants determined for L 1−4 . The slightly higher log K 1 H values of L 2,4 in comparison to those of L 1,3 might also be explained by the higher stability of the Na + complexes formed by the latter ligands.…”

“…Specifically, we anticipated that two ligands (L 1,2 ) can mimic the coordination of the responsive unit with the paramagnetic metal center in the absence of the analyte by installing a carboxylate on the N-methylene group of the side chain (i.e., SCA 1,2 in the absence of Ca 2+ ). On the other hand, the absence of the carboxylate at the N,N-dimethyl group in the remaining two ligands L 3,4 could serve as the model of coordination properties in the presence of the metal analyte (i.e., SCA 1,2 in the presence of Ca 2+ ), as we anticipated that the missing carboxylate group coordinates to the added analyte and is not available to the DO3A-derived responsive unit. In addition, the influence of the distance of the 2-(methylamino)acetate group or N,N-dimethylamino group was investigated by preparing ligands with two different chain lengths between the DO3A unit and the amide bearing the aforementioned amine groups, specifically ethyl or propyl linkers for ligands L 1,3 and L 2,4 , respectively.…”

Engineering of inorganic nanoparticles as magnetic resonance imaging contrast agents

“…However, the complexity of this process is much greater than initially expected, calling for broad expertise in a multidisciplinary manner through chemistry, physics, biology, and engineering. The goal of this review is not to comprehensively summarize nanoparticulate CAs for MRI that have been reported so far, 26 as there are many reviews available that list the major types of NPs as CAs (Gd 3+ -based T 1 CAs, 11,27 magnetic T 2 CAs, 14,15,28-30 and dual- T 1 / T 2 CAs 9,31 ) or summarize a special application of CAs ( e.g ., bioresponsive CAs, 32-34 and multimodal CAs 24 ). Instead, this review intends to comprehensively discuss the main rules and mechanisms of nanoparticulate CAs, key factors influencing the relaxation of CAs, and innovative strategies to engineer CAs with high relaxivity.…”

Dendrimer-based magnetic resonance imaging agents for brain cancer

“…These agents, which are referred to stimulus-responsive or smart contrast agents, are sensitive to specific fluctuations in the local environment, such as pH, biological metal ion concentration or enzymatic activity, and are capable of reporting on such changes by inducing alterations in the MRI signal [119][120][121][122][123][124]. The change in relaxivity of these agents before and after stimulation is the most important factor in evaluating the efficiency of a stimulus-responsive contrast agent [125].…”