Phospholipid-Coated Hydrophobic Mesoporous Silica Nanoparticles Enhance Thrombectomy by High-Intensity Focused Ultrasound with Low Production of Embolism-Inducing Clot Debris.

Here we report the efficacy of a nanoparticle-assisted high-intensity focused ultrasound (HIFU) treatment that selectively destroys blood clots while minimizing generation of microparticles, or microemboli, that can cause further complications postsurgery. Treatment of malignant blood clots (thrombi) and the resulting emboli are critical problems for numerous patients, and treatments addressing these conditions would benefit from advancements in noninvasive procedures such as HIFU. While recanalization of occlusive blood clots is currently addressed with surgical intervention that seeks to minimize formation of large emboli, there is a danger of microemboli (micrometer-size particles) that have been theorized to be responsible for the poor correlation between apparent surgical success and patient outcome. Here, the addition of phospholipid-coated hydrophobically modified silica nanoparticles (P@hMSNs) improved the efficacy of HIFU treatment by serving as cavitation nuclei for mechanical disruption of thrombi. This treatment was evaluated for the ability to clear the HIFU focal area of a thick and dense thrombus within 10 min. Moreover, it was found that the use of P@hMSN+HIFU treatment generated a significantly smaller microembolic load as compared to comparison techniques, including a HIFU + microbubble contrast agent, HIFU alone, and direct mechanical disruption. This reduction in the microembolic load can occur either with primary removal of the clot by P@hMSN+HIFU or by insonation of the clot fragments after mechanical thrombectomy. Lastly, this method was evaluated in a flow model, where nonocclusive model thrombi and model emboli were mechanically ablated within the focal area within 15 s. Together, these results represent a combination therapy capable of resolving thrombi and microembolisms resulting from thrombectomy through localized destruction of clotted material.

Temperature-Responsive Hydrophobic Silica Nanoparticle Ultrasound Contrast Agents Directed by Phospholipid Phase Behavior.

In this paper, we report ultrasonically active nanoscale contrast agents that behave as thermometric sensors through phase change in their stabilizing phospholipid monolayer. Phospholipid-stabilized, hydrophobic mesoporous silica nanoparticles (P@hMSNs) are known to interact with high-intensity focused ultrasound (HIFU) to promote cavitation at their surfaces, which can be used for both imaging and therapy. We show that the lateral lipid phase behavior of the phosphocholine lipid dictates the acoustic contrast of the P@hMSNs. When the lipids are in the gel phase below their melting temperature, the P@hMSNs generate detectable microbubbles when exposed to HIFU. However, if the lipids exhibit a liquid expanded phase, the P@hMSNs cease to generate bubbles in response to HIFU insonation. We verify that the heating and subsequent transition of lipid coating the hMSN are associated with the loss of acoustic response by doping laurdan dye into the lipid monolayer and imaging lipid phase through red shifts in emission spectra. Similarly, cessation of cavitation was also induced by adding a fluidizing surfactant such as Triton X, which could be reversed upon washing away the excess surfactant. Finally, by controlling for the partial fluidization caused by the adsorption of protein, P@hMSNs may be used as thermometric sensors of the bulk fluid temperature. These findings not only impact the utilization of nanoscale agents as stimulus-responsive ultrasound contrast agents but also have broader implications for how cavitation may be initiated at surfaces coated by a surfactant.