Abstract
Gas microbubbles stabilized with lipids, surfactants, proteins and/or polymers are widely used clinically as ultrasound contrast agents. Because of their large 1–10 µm size, applications of microbubbles are confined to the blood vessels. Accordingly, there is much interest in generating nanoscale echogenic bubbles (nanobubbles), which can enable new uses of ultrasound contrast agents in molecular imaging and drug delivery, particularly for cancer applications. While the interactions of microbubbles with ultrasound have been widely investigated, little is known about the activity of nanobubbles under ultrasound exposure. In this work, we demonstrate that cryo-electron microscopy (cryo-EM) can be used to image nanoscale lipid and polymer-stabilized perfluorocarbon gas bubbles before and after their destruction with high intensity ultrasound. In addition, cryo-EM can be used to observe electron-beam induced dissipation of nanobubble encapsulated perfluorocarbon gas.
Highlights
Recent reports have demonstrated some of the benefits associated with nanobubbles in applications ranging from molecular imaging to therapeutic delivery[9,10,11,12,13,14]
This study demonstrates that Cryo-electron microscopy (cryo-EM) can be a powerful characterization tool for gas nanobubbles, which are too fragile for imaging by SEM or by negative-stain transmission electron microscopy (TEM)
Both non-crosslinked and crosslinked nanobubbles (CL-NBs) with perfluorocarbon gas cores were prepared for characterization
Summary
Christopher Hernandez 1, Sahil Gulati 2,3, Gabriella Fioravanti[1], Phoebe L. Gas microbubbles stabilized with lipids, surfactants, proteins and/or polymers are widely used clinically as ultrasound contrast agents. Because of their large 1–10 μm size, applications of microbubbles are confined to the blood vessels. There is much interest in generating nanoscale echogenic bubbles (nanobubbles), which can enable new uses of ultrasound contrast agents in molecular imaging and drug delivery, for cancer applications. We demonstrate that cryo-electron microscopy (cryo-EM) can be used to image nanoscale lipid and polymer-stabilized perfluorocarbon gas bubbles before and after their destruction with high intensity ultrasound. To formulate Pluronic (non-crosslinked) nanobubbles, the above mentioned lipid film was hydrated instead in a solution containing 50 μL of glycerol and 1 mL of PBS containing 0.06 wt. The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request
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