Nano-emulsions. Comprehensive Report

This report gives comprehensive review of the nano-emulsion project between UVA and Virginia Tech which has been generously supported by the Focused Ultrasound Foundation. The purpose of this project is to develop an acoustic coupling bath that is effectively invisible to MRI scans and also remains acoustically compatible with clinical transcranial FUS procedures. This remains important to the clinical translation of FUS because the commonly used acoustic coupling bath of degassed water persistently degrades the quality of MR guidance imaging. Our project proposes an acoustic coupling bath doped with specially designed iron oxide nanoparticles that 1) have a high ability to decay MRI signals, (as quantified by the r2 relaxivity), 2) have diameters less than 100 nm, and 3) are coated with a hydrophilic coating. We hypothesize that these three innovations will produce a lightly doped water bath with identical mechanical, acoustic, thermal, biocompatibility, and electromagnetic properties as water, but with virtually no observable appearance or effect on guidance MR imaging. Finally, the low particle concentrations, small particle sizes, and specific coating will prevent the particles from stabilizing gas bubbles and seeding cavitation nuclei in the transducer’s pre-focal field.We are pleased to report nearly total success on this project, with an affirmation of all hypotheses stated above.

Improved therapeutic antibody delivery to xenograft tumors using cavitation nucleated by gas-entrapping nanoparticles

Aims: Testing ultrasound-mediated cavitation for enhanced delivery of the therapeutic antibody cetuximab to tumors in a mouse model. Methods: Tumors with strong EGF receptor expression were grown bilaterally. Cetuximab was coadministered intravenously with cavitation nuclei, consisting of either the ultrasound contrast agent Sonovue or gas-stabilizing nanoscale SonoTran Particles. One of the two tumors was exposed to focused ultrasound. Passive acoustic mapping localized and monitored cavitation activity. Both tumors were then excised and cetuximab concentration was quantified. Results: Cavitation increased tumoral cetuximab concentration. When nucleated by Sonovue, a 2.1-fold increase (95% CI 1.3- to 3.4-fold) was measured, whereas SonoTran Particles gave a 3.6-fold increase (95% CI 2.3- to 5.8-fold). Conclusions: Ultrasound-mediated cavitation, especially when nucleated by nanoscale gas-entrapping particles, can noninvasively increase site-specific delivery of therapeutic antibodies to solid tumors.

Establishment of cavitation inception speed judgment criteria by cavitation noise analysis for underwater vehicles

Cavitation occurs on objects that move underwater at high speeds, and it is accompanied by an increase in hull vibrations, a reduction in propulsion performance, and an increase in noise that is important for warships and submarines. Of the various types of cavitations, tip vortex cavitations (TVC) are the earliest occurring and are considered the most important in terms of cavitation inception speed (CIS). This study predicts the cavitation inception speed by conducting cavitation noise analyses. The trend of the noise according to the cavitation numbers before and after CIS was analysed, and the quantitative criteria to determine the CIS were presented through established procedures. The CIS value obtained through the analysis was verified by comparing it against the value obtained experimentally. The methods used to analyse the cavitation inception speed are developed using bubble dynamics for cavitation noises. First, flow-field information was obtained downstream of the wing to estimate the external force acting on the bubbles, and this was used to calculate the behaviour of the cavitation bubbles. The bubble dynamics analyses were performed for each cavitation nuclei by Lagrange approach to calculate the behaviour of the bubbles. The number of cavitation nuclei was calculated based on the density function with random placement upstream of the wing. The cavitation noise was analysed for various cavitation numbers, and the tendency of the noise generated for each case was investigated. The noise analysis results and the CIS predictions were compared and verified with the measured values in the Large Cavitation Tunnel (LCT) of the Korea Research Institute of Ship & Ocean Engineering (KRISO). Using these results, the effect of the tip vortex cavitation on the total flow noise was analysed, and CIS determination criteria using noise values was validated and established.

Exploiting Lipid and Polymer Nanocarriers to Improve the Anticancer Sonodynamic Activity of Chlorophyll

Sonodynamic therapy is an emerging approach that uses low-intensity ultrasound to activate a sonosensitizer agent triggering its cytotoxicity for selective cancer cell killing. Several molecules have been proposed as sonosensitizer agents, but most of these, as chlorophyll, are strongly hydrophobic with a low selectivity towards cancer tissues. Nanocarriers can help to deliver more efficiently the sonosensitizer agents in the target tumor site, increasing at the same time their sonodynamic effect, since nanosystems act as cavitation nuclei. Herein, we propose the incorporation of unmodified plant-extracted chlorophyll into nanocarriers with different composition and structure (i.e., liposomes, solid lipid nanoparticles and poly(lactic-co-glycolic acid) nanoparticles) to obtain aqueous formulations of this natural pigment. The nanocarriers have been deeply characterized and then incubated with human prostatic cancer cells (PC-3) and spheroids (DU-145) to assess the influence of the different formulations on the chlorophyll sonodynamic effect. The highest sonodynamic cytotoxicity was obtained with chlorophyll loaded into poly(lactic-co-glycolic acid) nanoparticles, showing promising results for future clinical investigations on sonodynamic therapy.

Nanoscale bubble study of cavitation inception on a platinum surface using molecular dynamics simulation

The transient properties of liquid argon cavitation nuclei in platinum surface were studied by means of molecular dynamics simulation. The bubble nucleation, with a certain size and stability on the wall surface, was studied by different tensile distances and different wall wettabilities. Also the parameters of cavitation nuclei development, the system pressure, and the total pressure were analysed. The stability of cavitating nucleus growth is closely related to the metastable degree of the system and the wettability of the wall. The tensile distance of the wall surface has a critical value, and stretching greater than the critical value will induce a greater degree of instability in the system, which is conducive to the growth of the cavitation nucleus. A hydrophobic wall is more conducive to the growth of a cavitation nucleus, which is beneficial to spontaneous growth among cavitated nuclei, whereas a hydrophobic exerts has an inhibitory influence on cavitation nuclei.