The preparation of ultrasmall and rigid platforms (USRPs) that are covalently coupled to macrocycle-based, calcium-responsive/smart contrast agents (SCAs), and the initial in vitro and in vivo validation of the resulting nanosized probes (SCA-USRPs) by means of magnetic resonance imaging (MRI) is reported. The synthetic procedure is robust, allowing preparation of the SCA-USRPs on a multigram scale. The resulting platforms display the desired MRI activity—i.e., longitudinal relaxivity increases almost twice at 7 T magnetic field strength upon saturation with Ca(2+). Cell viability is probed with the MTT assay using HEK-293 cells, which show good tolerance for lower contrast agent concentrations over longer periods of time. On intravenous administration of SCA-USRPs in living mice, MRI studies indicate their rapid accumulation in the renal pelvis and parenchyma. Importantly, the MRI signal increases in both kidney compartments when CaCl2 is also administrated. Laser-induced breakdown spectroscopy experiments confirm accumulation of SCA-USRPs in the renal cortex. To the best of our knowledge, these are the first studies which demonstrate calcium-sensitive MRI signal changes in vivo. Continuing contrast agent and MRI protocol optimizations should lead to wider application of these responsive probes and development of superior functional methods for monitoring calcium-dependent physiological and pathological processes in a dynamic manner.
We report the heteroditopic ligand H5L, which contains a DO3A unit for Gd(3+) complexation connected to an NO2A moiety through a N-propylacetamide linker. The synthesis of the ligand followed a convergent route that involved the preparation of 1,4-bis(tert-butoxycarbonylmethyl)-1,4,7-triazacyclononane following the orthoamide strategy. The luminescence lifetimes of the Tb((5)D4) excited state measured for the TbL complex point to the absence of coordinated water molecules. Density functional theory calculations and (1)H NMR studies indicate that the EuL complex presents a square antiprismatic coordination in aqueous solution, where eight coordination is provided by the seven donor atoms of the DO3A unit and the amide oxygen atom of the N-propylacetamide linker. Addition of Zn(2+) to aqueous solutions of the TbL complex provokes a decrease of the emission intensity as the emission lifetime becomes shorter, which is a consequence of the coordination of a water molecule to the Tb(3+) ion upon Zn(2+) binding to the NO2A moiety. The relaxivity of the GdL complex recorded at 7 T (25 °C) increases by almost 150% in the presence of 1 equiv of Zn(2+), while Ca(2+) and Mg(2+) induced very small relaxivity changes. In vitro magnetic resonance imaging experiments confirmed the ability of GdL to provide response to the presence of Zn(2+).
Bioresponsive MRI contrast agents sensitive to Ca(II) fluctuations may play a critical role in the development of functional molecular imaging methods to study brain physiology or abnormalities in muscle contraction. A great challenge in their chemistry is the preparation of probes capable of inducing a strong signal variation that could be detected in a robust way. To this end, the incorporation of small molecular weight bioresponsive agents into nanocarriers can improve the overall properties in a few ways: (i) the agent can be delivered into the tissue of interest, increasing the local concentration; (ii) its biokinetic properties and retention time will improve; (iii) the high molecular weight and size of the nanocarrier may cause additional changes in the MRI signal and raise the chances for their detection in functional experiments. In this work, we report the preparation of the new class of liposome-based, Ca-sensitive MRI agents. We synthesized a novel amphiphilic ligand which was incorporated into the liposome bilayer. A remarkable increase of ∼420% in longitudinal relaxivity r 1 , from 7.3 mM −1 s −1 to 38.1 mM −1 s −1 at 25°C and 21.5 MHz in the absence and presence of Ca(II), respectively, was achieved by the most active liposomal formulation. To the best of our knowledge, this is the highest change in r 1 observed for Ca-sensitive agents at physiological pH and can be explained by simultaneous Ca-triggered increase in hydration and reduction of local motion of Gd(III) complex, which can be followed at low magnetic fields.
Cyclen-based macrocyclic ligands have an essential role in the development of contrast agents for magnetic resonance imaging (MRI). A prevailing need for preparation of multifunctional probes triggered a number of attempts to synthesize and derivatise ligands which efficiently chelate lanthanide ions and have advantageous MRI properties. This digest article summarizes the most common synthetic approaches for the preparation of macrocyclic ligands based on cyclen depending on the desired application
We report a methodology which enables the preparation of dendrimeric contrast agents sensitive to Ca(2+) when starting from the monomeric analogue. The Ca-triggered longitudinal relaxivity response of these agents is not compromised by undertaking synthetic transformations, despite structural changes. The in vivo MRI studies in the rat cerebral cortex indicate that diffusion properties of dendrimeric contrast agents have great advantages as compared to their monomeric equivalents.
We report a detailed characterization of the thermodynamic stability and dissociation kinetics of Gd complexes with DO3A derivatives containing a (methylethylcarbamoylmethylamino)acetic acid (L), (methylpropylcarbamoylmethylamino)acetic acid (L), 2-dimethylamino- N-ethylacetamide (L), or 2-dimethylamino- N-propylacetamide (L) group attached to the fourth nitrogen atom of the macrocyclic unit. These ligands are model systems of Ca- and Zn-responsive contrast agents (CA) for application in magnetic resonance imaging (MRI). The results of the potentiometric studies ( I = 0.15 M NaCl) provide stability constants with log K values in the range 13.9-14.8. The complex speciation in solution was found to be quite complicated due to the formation of protonated species at low pH, hydroxido complexes at high pH, and stable dinuclear complexes in the case of L. At neutral pH significant fractions of the complexes are protonated at the amine group of the amide side chain (log K = 7.2-8.1). These ligands form rather weak complexes with Mg and Ca but very stable complexes with Cu (log K = 20.4-22.3) and Zn (log K = 15.5-17.6). Structural studies using a combination of H NMR and luminescence spectroscopy show that the amide group of the ligand is coordinated to the metal ion at pH ∼8.5, while protonation of the amine group provokes the decoordination of the amide O atom and a concomitant increase in the hydration number and proton relaxivity. The dissociation of the complexes occurs mainly through a rather efficient proton-assisted pathway, which results in kinetic inertness comparable to that of nonmacrocyclic ligands such as DTPA rather than DOTA-like complexes.
Bioresponsive magnetic resonance imaging (MRI) contrast agents hold great potential for noninvasive tracking of essential biological processes. Consequently, a number of MR sensors for several imaging protocols have been developed, attempting to produce the maximal signal difference for a given event. Here we introduce an approach which could substantially improve the detection of physiological events with fast kinetics. We developed a nanosized, calcium-sensitive dendrimeric probe that changes longitudinal and transverse relaxation times with different magnitudes. The change in their ratio is rapidly recorded by means of a balanced steady-state free precession (bSSFP) imaging protocol. The employed methodology results in an almost four times greater signal gain per unit of time as compared to conventional T-weighted imaging with small sized contrast agents. Furthermore, it is suitable for high resolution functional MRI at high magnetic fields. This methodology could evolve into a valuable tool for rapid monitoring of various biological events.
In the present work the first investigation ever of calcium sensitive dendrimer relaxation mechanisms at low fields is reported.
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