Understanding Acoustic Cavitation Initiation by Porous Nanoparticles: Toward Nanoscale Agents for Ultrasound Imaging and Therapy

Abstract

Ultrasound is widely applied in medical diagnosis and therapy due to its safety, high penetration depth, and low cost. In order to improve the contrast of sonographs and efficiency of the ultrasound therapy, echogenic gas bodies or droplets (with diameters from 200 nm to 10 µm) are often used, which are not very stable in the bloodstream and unable to penetrate into target tissues. Recently, it was demonstrated that nanobubbles stabilized by nanoparticles can nucleate ultrasound responsive microbubbles under reduced acoustic pressures, which is very promising for the development of nanoscale (<100 nm) ultrasound agents. However, there is still very little understanding about the effects of nanoparticle properties on the stabilization of nanobubbles and nucleation of acoustic cavitation by these nanobubbles. Here, a series of mesoporous silica nanoparticles with sizes around 100 nm but with different morphologies were synthesized to understand the effects of nanoparticle porosity, surface roughness, hydrophobicity, and hydrophilic surface modification on acoustic cavitation inception by porous nanoparticles. The chemical analyses of the nanoparticles showed that, while the nanoparticles were prepared using the same silica precursor (TEOS) and surfactant (CTAB), they revealed varying amounts of carbon impurities, hydroxyl content, and degrees of silica crosslinking. Carbon impurities or hydrophobic modification with methyl groups is found to be essential for nanobubble stabilization by mesoporous silica nanoparticles. The acoustic cavitation experiments in the presence of ethanol and/or bovine serum albumin (BSA) demonstrated that acoustic cavitation is predominantly nucleated by the nanobubbles stabilized at the nanoparticle surface not inside the mesopores. Finally, acoustic cavitation experiments with rough and smooth nanoparticles were suggested that a rough nanoparticle surface is needed to largely preserve surface nanobubbles after coating the surface with hydrophilic macromolecules, which is required for in vivo applications of nanoparticles.

Phospholipid Capped Mesoporous Nanoparticles for Targeted High Intensity Focused Ultrasound Ablation

“…In addition, the progress and location of therapy may be monitored by imaging the generated bubbles during ablation using common ultrasound imaging equipment. Recently, we [34, 35] and others [36–40] showed that hydrophobic micro/nanoparticles dispersed in aqueous media can generate bubbles when subjected to an ultrasound pulse with peak negative pressures of a few MPa. Under reduced acoustic pressures, air stabilized at the hydrophobic interface act as nucleation sites for bubble growth.…”

“…The bubble grows outside the particle from the contribution of the dissolved gases and water vapor, followed by collapse. [34, 37, 38] Such bubble generating micro/nanoparticles were applied to improve the contrast of ultrasound images by our group, [34, 35] and as well as to enhance the drug delivery efficiency by others. [37] Also, Zhao, et al, [40] recently used hydrophobic MSNs to kill cancer cells by reactive oxygen species generation under continuous low energy ultrasound (LEUS) insonation rather than pulsed HIFU.…”

“…However, inducing receptor-mediated uptake into cancer cells has remained largely unexplored, mainly due to the difficulties in functionalizing hydrophobic particles without diminishing their ability to generate bubbles by acoustic driving. [35, 38] Here, to create bubble-generating nanoparticles under reduced acoustic pressures with functionalizable surfaces, we coated phospholipid monolayers on hydrophobic MSNs to stabilize them in aqueous media. The hydrophobic interface stabilizes the air pockets needed for bubble generation [34, 35] and the phospholipid layer allows further functionalization with PEG and folic acid to improve dispersibility in biological media and facilitate their uptake by cancer cells, respectively.…”

“…[55] Image contrast was evaluated in the presence of FA-PL-dMSN as described in our previous reports (Figure S6a). [26, 34, 35, 56] Samples dispersed in PBS at different concentrations between 0 and 200 μg mL −1 were placed in a plastic tube with low acoustic attenuation, which was submerged in a water tank and placed on a HIFU transducer. A phased array scanning probe (Acuson 4V1) operating at 1.5 MHz in Cadence Contrast Pulse Sequencing (CPS) mode was aligned in the x-direction to detect the generated bubbles when insonated with a HIFU transducer operating at 1.1 MHz.…”

“…On the other hand, FA-PEG-MSN at the same particle concentration did not produce any contrast in the ultrasound images (Figure 2a), proving that a hydrophobic interface is required to stabilize air pockets for nucleation of bubbles under reduced acoustic pressures. [35] To quantify the ultrasound response of the particles, three 15 s videos were recorded for each sample and the brightness of the region of interest was quantified using MATLAB (Mathworks, Inc.). Figure 2b shows the ultrasound contrast intensity produced by the ultrasound agents at different concentrations.…”