Calcium-sensitive MRI contrast agents based on superparamagnetic iron oxide nanoparticles and calmodulin.
We describe a family of calcium indicators for magnetic resonance imaging (MRI), formed by combining a powerful iron oxide nanoparticle-based contrast mechanism with the versatile calcium-sensing protein calmodulin and its targets. Calcium-dependent protein-protein interactions drive particle clustering and produce up to 5-fold changes in T2 relaxivity, an indication of the sensors' potency. A variant based on conjugates of wild-type calmodulin and the peptide M13 reports concentration changes near 1 microM Ca(2+), suitable for detection of elevated intracellular calcium levels. The midpoint and cooperativity of the response can be tuned by mutating the protein domains that actuate the sensor. Robust MRI signal changes are achieved even at nanomolar particle concentrations (<1 microM in calmodulin) that are unlikely to buffer calcium levels. When combined with technologies for cellular delivery of nanoparticulate agents, these sensors and their derivatives may be useful for functional molecular imaging of biological signaling networks in live, opaque specimens.
Atanasijevic
Tatjana
T
Department of Nuclear Science and Engineering, and Francis Bitter Magnet Laboratory, Massachusetts Institute of Technology, 150 Albany Street, NW14-2213, Cambridge, MA 02139, USA.
Shusteff
Maxim
M
Fam
Peter
P
Jasanoff
Alan
A
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002147:Calmodulin / Q000737:chemistry / Q000378:metabolism*; D002417:Cattle; D003287:Contrast Media / Q000737:chemistry*; D003911:Dextrans; D052203:Ferrosoferric Oxide; D007501:Iron / Q000737:chemistry* / Q000378:metabolism; D008027:Light; D008279:Magnetic Resonance Imaging / Q000379:methods*; D058185:Magnetite Nanoparticles; D018625:Microscopy, Atomic Force; D049329:Nanostructures / Q000737:chemistry*; D010087:Oxides / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D012542:Scattering, Radiation; D013997:Time Factors
D002147:Calmodulin; D003287:Contrast Media; D003911:Dextrans; D058185:Magnetite Nanoparticles; D010087:Oxides; D007501:Iron; C065507:ferumoxides; D002118:Calcium; D052203:Ferrosoferric Oxide