Synergy of Key Properties Promotes Dendrimer Conjugates as Prospective Ratiometric Bioresponsive Magnetic Resonance Imaging Probes

Abstract

Bioresponsive or smart contrast agents (SCAs) sensitive to Ca2+ are of extreme interest in the development of functional magnetic resonance imaging (MRI) techniques as they can aid in tracking neural activity in vivo. To this end, the design of macromolecular systems based on nanoscaffolds such as dendrimers functionalized with multiple MRI contrast agents has been used to conveniently increase the local concentration of paramagnetic MR reporters and slow the diffusion time of the probe, which are favorable in vivo characteristics. Moreover, previous studies with Ca-sensitive dendrimeric MRI probes revealed favorable properties crucial in the development of a ratiometric T 2/T 1-imaging method that provided a higher contrast-to-noise ratio compared to conventional T 1- or T 2-weighted imaging protocols. We therefore developed a series of novel dendrimeric MRI probes (DCAs) with differing structural properties and charge distributions. We thoroughly studied their features such as the relaxometric behavior and size change and examined their electrostatic behaviors prior to and after the addition of Ca2+. The most active DCA displayed a common increase in r 1 (3.11 to 5.72 mM–1 s–1) and a remarkable increase in r 2 (7.44 to 34.57 mM–1 s–1), resulting in a r 2/r 1 ratio increase of the factor 2.52, which is greater than what was previously achieved. These changes in r 1 and r 2 were followed with a hydrodynamic diameter increase from 7.1 ± 1.2 to 8.5 ± 0.7 nm upon the addition of Ca2+, along with a decrease in the negative surface charge of the nanoparticle. Overall, our findings indicate that highly responsive DCAs can be developed only through a combination of properties such as changes in hydration and size of the molecule, which are a consequence of intramolecular structural and electrostatic changes in the particle. In turn, they provide a model for future preparations of responsive DCAs that can be utilized for both T 1-weighted and ratiometric T 2/T 1-weighted imaging to visualize essential biological processes in a dynamic fashion.

RGD-Peptide Functionalization Affects the In Vivo Diffusion of a Responsive Trimeric MRI Contrast Agent through Interactions with Integrins

“…The magnitude of the observed relaxivity increase is consistent with what is reported for multimeric lanthanide-based MRI CAs responsive to Ca 2+ coordination. 39 …”

“… 17 , 44 Additionally, the r 2 response is almost 2-fold higher than the r 1 , as expected for a system of this category. 39 Namely, the multimeric nature of the probe increases the structural rigidity of the monomeric units relative to each other, decreasing the local rotational freedom, hence, increasing the r 2 . 45 However, the reported Gd 3 L 3 -RGD is to be considered a medium-molecular weight probe, if compared to the ones based on nanoparticles and smaller molecular probes on the other hand.…”

Investigations into the effects of linker length elongation on the behaviour of calcium-responsive MRI probes

“…Protected nitro compounds 1 and 2 were synthesized following previously reported procedures. 18 Subsequent deprotection with formic acid at 60°C overnight yielded ligands L 1 and L 2 (Scheme 1). Complexation reactions of each ligand with either Yb 3+ , Eu 3+ , Gd 3+ or Y 3+ were all carried out under identical conditions.…”

“…Compounds 1 and 2 were synthesised following published procedures. 18 High resolution mass spectra were recorded on a Bruker Daltonics APEX II (FT-ICR-MS) with an electrospray ionization source. Low resolution mass spectra were recorded on an Agilent ion trap SL 1100 system with an electrospray ionization source.…”

“…Amongst the studied nano-sized conjugates with different monomers, those with butyl and pentyl linkers connecting the common DO3A-and EGTA-derived chelators showed the greatest changes and outlook for potential future application. 18 Intrigued by these results, we embarked on a detailed structural study of these two newly developed monomeric systems. Firstly, we prepared different pairs of diamagnetic and paramagnetic complexes, which allowed the initiation of different types of coordination chemistry studies.…”