Innovative Design of Ca-Sensitive Paramagnetic Liposomes Results in an Unprecedented Increase in Longitudinal Relaxivity

Abstract

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.

Recent advances on liposomal nanoparticles: synthesis, characterization and biomedical applications

“…Most of the preparation methods of liposomes include the exploitation of potentially toxic solvents such as diethyl ether, methanol, and chloroform (Garello et al 2016). The final product may contain remnants of these toxic solvents chip in potential toxicity and affect the stability of the lipid vesicles.…”

“…Other kind of bioactive molecules also could be encapsulated within nanoliposomes via this method regarding their temperature sensitivities. Mozafari et al showed that preparing nanoliposomes via heating method result in none-toxic nanoliposomes to cultured cells, whereas nanoliposomes provided by former prevalent preparation techniques showed substantial levels of cytotoxicity due to using volatile solvents (Garello et al 2016). Producing of nanoliposomes in industrial scales is another important feature of this method.…”

Smart MRI Agents for Detecting Extracellular Events In Vivo: Progress and Challenges

“…Typically, these agents are injected intracisternally at concentrations in the low micromolar range. Additionally, several calcium-responsive paraCEST agents have been developed [62], as well as several functional MRI (fMRI) methods using oligomerization/aggregation of calcium-responsive agents [63,64]. These agents remain under use as a research tool only; to our knowledge, there are no active clinical translational approaches underway.…”

Lanthanide Complexes in Molecular Magnetic Resonance Imaging and Theranostics

“…The visualization of membrane potentials by MRI remains a dream today. Calcium detection has been at the center of many studies and important chemistry efforts have been made to develop Ca‐sensitive MRI probes, without successful in vivo translation so far. NTs play a key role in signal transduction and the first NT responsive MRI probes appeared in recent years .…”

“…Major biomarkers to give direct information on neural transmission involve membrane potential, calcium ions and NTs. [11] The visualization of membrane potentials by MRI remains ad ream today.C alcium detection has been at the centero f many studies and important chemistry efforts have been made to develop Ca-sensitive MRI probes, [12][13][14] without successful in vivo translation so far.N Ts play ak ey role in signal transduction and the first NT responsive MRI probes appearedi nr ecent years. [15] NTsa re af amily of over one hundred molecules involved in synaptic transmission of very different chemical natures.…”