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

Abstract

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 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 is 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 excess surfactant. Finally, by controlling for the partial fluidization caused by the adsorption of protein, P@hMSNs may be used as thermometric sensors of bulk fluid temperature. These findings not only impact the utilization of nanoscale agents as stimulusresponsive ultrasound contrast agents, but also have broader implications for how cavitation may be initiated at surfaces coated by a surfactant.

Gas-stabilizing nanoparticles for ultrasound imaging and therapy of cancer

“…Cavitation onset peak negative pressures for hydrophobic MSNs coated with different lipids with different tail lengths (right). Adapted from reference [ 79 ], Copyright 2019, American Chemical Society …”

“…In the last decade, we have witnessed rapid growth in the field with the development of several different GSNs. These nanoparticles have already been utilized in different applications to detect and treat cancer [ 40 , 48 , 80 , 104 ] and others such as cardiovascular diseases [ 73 , 79 , 87 ]. These studies have also significantly increased our understanding of the cavitation inception by nanoparticles.…”

Comprehensive review on ultrasound-responsive theranostic nanomaterials: mechanisms, structures and medical applications

“…Phospholipid-stabilized hydrophobic MSNs could promote cavitation at their surfaces and MB formation under US exposure, which led to contrast enhancement. When the lipids were in the gel phase below their melting temperature, p@hMSN generated detectable MBs after exposure to US, indicating that the lipid was effective for MB generation and contrast enhancement [ 590 ]. Paris et al designed MSNs that displayed submicrometer-sized cavitation nuclei and evaluated their extravasation and biodistribution using US-induced inertial cavitation.…”

Hydrophobically Modified Silica-Coated Gold Nanorods for Generating Nonlinear Photoacoustic Signals

“…In this paper, we report a unique contrast agent that is designed to induce cavitation on the surface at low laser fluence and thus impart a nonlinear PA response while also maintaining a strong PA response in the linear regime. Previously, we showed that hydrophobically modified mesoporous silica nanoparticles facilitate acoustic cavitation by stabilizing the formation of gas pockets on the surface. − Here, gold nanorods with plasmon resonance in the near infrared (NIR) were coated first with silica and then covalently modified with hydrophobic alkyl chains. To impart dispersibility in aqueous solvents, the nanoparticles were resuspended with a monolayer of phospholipids (Figure ).…”