Spontaneous Nucleation of Stable Perfluorocarbon Emulsions for Ultrasound Contrast Agents

Abstract

Phase-change contrast agents are rapidly developing as an alternative to microbubbles for ultrasound imaging and therapy. These agents are synthesized and delivered as liquid droplets and vaporized locally to produce image contrast. They can be used like conventional microbubbles but with the added benefit of reduced size and improved stability. Droplet-based agents can be synthesized with diameters on the order of 100 nm, making them an ideal candidate for extravascular imaging or therapy. However, their synthesis requires low boiling point perfluorocarbons (PFCs) to achieve activation (i.e., vaporization) thresholds within FDA approved limits. Minimizing spontaneous vaporization while producing liquid droplets using conventional methods with low boiling point PFCs can be challenging. In this study, a new method to produce PFC nanodroplets using spontaneous nucleation is demonstrated using PFCs with boiling points ranging from −37 to 56 °C. Sometimes referred to as the ouzo method, the process relies on saturating a cosolvent with the PFC before adding a poor solvent to reduce solvent quality, forcing droplets to spontaneously nucleate. This approach can produce droplets ranging from under 100 nm to over 1 μm in diameter. Ternary plots showing solvent and PFC concentrations leading to droplet nucleation are presented. Additionally, acoustic activation thresholds and size distributions with varying PFC and solvent conditions are measured and discussed. Finally, ultrasound contrast imaging is demonstrated using ouzo droplets in an animal model.

Nanosized Phase‐Changeable “Sonocyte” for Promoting Ultrasound Assessment

“…[9] Therefore, alternative ultrasound contrast agents have been contentedly developed, such as inorganic nanocomposites, echogenic liposomes, and particularly phase-change perfluorocarbon (PFC) nanodroplets. [10][11][12] PFC nanodroplets have good biocompatibility and phase changeable nature, allowing for converting to microbubbles under ultrasound stimulation to enhance contrast signals. [13] Accumulating evidences demonstrate that PFC nanodroplets exhibit the good permeation between blood vessels and targeted tissues, making them possible to achieve major organ imaging.…”

Transcranial activation and imaging of low boiling point phase‐change contrast agents through the temporal bone using an ultrafast interframe activation ultrasound sequence

“…To further decrease the activation pressure and potential side effect of acoustic exposure, PCCAs with octafluropropane (C 3 F 8 ) core gas could be used in the future, although these PCCAs are less stable at 37°C than the DFB-core PCCAs used in the present study. 46,[70][71][72] One limitation of the present study is that there were a few echogenic signals in the background in both UIAU [indicated by arrows in Fig. 3(b)] and AMPI [ Fig.…”

Spatially Localized Sono-Photoacoustic Activation of Phase-Change Contrast Agents

“…They are liquid droplets with a PFC core stabilized with a lipid, protein, polymer, or particle-based shell [ [6] , [7] , [8] , [9] , [10] ]. Although they can be synthesized using core and shell materials chemically identical to currently FDA approved gaseous microbubble contrast agents, they differ from microbubbles in that they are stored and delivered as liquid droplets [ [10] , [11] , [12] ]. In liquid state, they are acoustically transparent, preventing US shadowing.…”

“…In liquid state, they are acoustically transparent, preventing US shadowing. Additionally, they are stable and can be stored for as long as weeks to months [ 10 , 12 , 13 ].…”