Dendrimeric calcium-responsive MRI contrast agents with slow in vivo diffusion

Abstract

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.

Ultrasmall Nanoplatforms as Calcium‐Responsive Contrast Agents for Magnetic Resonance Imaging

“…The rapid elimination of SCA‐USRPs also indicates absence of interaction with various tissues components which could cause slower clearance. This is in line with our previous findings where SCAs with nonphosphonate‐containing Ca‐chelators exhibited fast diffusion in vivo, while only the phosphonate‐containing SCAs exhibited aggregation or interaction with the tissue and hence slower diffusion in vivo . Combined with the findings from DLS measurements which showed no indication of Ca‐induced aggregate formation (see above), SCA‐USRPs thus exhibit very favorable biokinetic properties suitable for desired purpose, which is sensing of Ca 2+ in vivo.…”

“…The longitudinal relaxivities were calculated and the values of three independent experiments were fitted, resulting in a mean conditional dissociation constant K d = 1.9 × 10 −3 ± 0.5 × 10 −3 m (mean±standard deviation (SD), n = 3), which matches the levels of extracellular Ca 2+ in the brain very well. [4a] In addition, the r 1 value of the free SCA‐USRPs (in the absence of Ca 2+ ) was 3.60 × 10 −3 ± 0.15 × 10 −3 m −1 s −1 (mean ± SD, n = 3), whereas the r 1 value of the SCA‐USRPs fully bound to Ca 2+ was 7.03 × 10 −3 ± 0.17 × 10 −3 m −1 s −1 (mean ± SD, n = 3), which results in a total 95% increase in r 1 and is in full agreement with results obtained with dendrimeric SCA …”

“…Due to the necessity of performing the coupling of monomeric SCA to nanoparticles in an aqueous medium, we had to modify our recently reported intermediate 1 , which is only soluble in polar organic solvents, and prepare a water‐soluble reactive macrocyclic precursor ( Scheme ). We have therefore hydrolyzed t ‐butyl esters with trifluoroacetic acid to obtain the acid 2 .…”

“…In normal brain tissue, these SCA‐USRPs could be used to follow the extracellular Ca 2+ fluctuations that take place during neuronal activity. Slower diffusion rates relative to their dendrimeric analogues, and the ability to trigger the MRI signal change as a function of Ca 2+ concentration, may lead to development of a new molecular functional MRI method that allows investigation of brain function in an unprecedented manner.…”

A novel nitroreductase-enhanced MRI contrast agent and its potential application in bacterial imaging

“…To further improve the enhancing effects and detect physiological changes at the molecular level, the smart MRI contrast agents have been developed and used 12 , 13 , 14 , 15 . These probes are capable of monitoring physiological processes by changing signal properties with changes in the physiological environment, such as enzyme 16 , 17 , 18 , 19 , 20 , metal ion concentration 20 , 21 , 22 , 23 , pH value 24 , 25 , temperature 26 , etc. Recently, applications of enzyme-activatable MRI contrast agents have been reported.…”