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Abstract
We have synthesized a biomaterial consisting of Gd(III) ions chelated to lipid-coated,
size-selected microbubbles for utility in both magnetic resonance and ultrasound imaging.
The macrocyclic ligand DOTA-NHS was bound to PE headgroups on the lipid shell of pre-synthesized
microbubbles. Gd(III) was then chelated to DOTA on the microbubble shell. The reaction
temperature was optimized to increase the rate of Gd(III) chelation while maintaining
microbubble stability. ICP-OES analysis of the microbubbles determined a surface density
of 7.5 × 10(5) ± 3.0 × 10(5) Gd(III)/μm(2) after chelation at 50 °C. The Gd(III)-bound
microbubbles were found to be echogenic in vivo during high-frequency ultrasound imaging
of the mouse kidney. The Gd(III)-bound microbubbles also were characterized by magnetic
resonance imaging (MRI) at 9.4 T by a spin-echo technique and, surprisingly, both
the longitudinal and transverse proton relaxation rates were found to be roughly equal
to that of no-Gd(III) control microbubbles and saline. However, the relaxation rates
increased significantly, and in a dose-dependent manner, after sonication was used
to fragment the Gd(III)-bound microbubbles into non-gas-containing lipid bilayer remnants.
The longitudinal (r(1)) and transverse (r(2)) molar relaxivities were 4.0 ± 0.4 and
120 ± 18 mM(-1)s(-1), respectively, based on Gd(III) content. The Gd(III)-bound microbubbles
may find application in the measurement of cavitation events during MRI-guided focused
ultrasound therapy and to track the biodistribution of shell remnants.