Insonation Frequency Selection May Assist Detection and Therapeutic Delivery of Targeted Ultrasound Contrast Agents

Abstract

Background: Ultrasound-targeted drug delivery relies on the unique nature of ultrasound contrast agents – they are microbubbles that respond strongly to ultrasound. Intravenously injected microbubbles are smaller than a blood cell. By increasing the ultrasound power, the bubbles can be ruptured at the targeted endothelial wall, locally releasing any molecules in the bubble shell. Furthermore, ultrasound-activated microbubbles are known to cause sonoporation – the process by which ultrasound drives molecules through cellular membranes. However, techniques are required to selectively detect and rupture only those microbubbles on target walls. Method: Experiments are presented on the behaviour of microbubbles on walls. For accuracy, imaging measurements are made on model microbubbles larger than contrast agents. Bubble size was varied and the resonant frequency peak determined. Results: Microbubbles on walls have a shifted frequency in good agreement with theory: a 20–25% downshift from the frequency when far from walls. Effects other than the presence of the wall account for less than 5% of the shift. Discussion: Theory predicts the frequency downshift should be sustained for actual contrast-agent sized bubbles. The effect of real, compliant cell walls requires investigation. An appropriate downshift in the applied ultrasound frequency could selectively tune gene or drug delivery. To make this feasible, it may be necessary to manufacture monodispersed microbubbles.

Nonlinear dynamic behavior of microscopic bubbles near a rigid wall

“…Previous studies of such a configuration showed that the linear natural frequency of the bubble near the wall is shifted downward by a factor of √ 2/3 ≈ 0.82 [16,18]. It was found to be numerically consistent with the predicted values, although for bubbles that were somewhat larger than typical contrast-agent bubbles [15]. Recent experiments with high-speed imaging also demonstrated a downshift in the linear response frequency of actual contrast agents on biological target surfaces [19].…”

“…[18] and the potential value of a frequency shift in identifying targeted microbubbles via a filtering approach has been recognized in Ref. [15]. Therefore, it is expected that the acoustic signature of initially "silent" small bubbles will become more pronounced as they approach the wall.…”

“…Alternatively, it was suggested to "push" microbubbles with the acoustic radiation force so that only the free microbubbles would move, thus enabling the difference from bound microbubbles to be discerned [14]. A further suggestion was to exploit alterations in the linear response frequency [15] that characterize adherent bubbles.…”

Phase-shift, stimuli-responsive Drug Carriers for Targeted Delivery

“…Signals from molecularly targeted adherent agents can be obscured by echoes from tissue and freely circulating microbubbles. Methods have been suggested to distinguish between molecularly targeted and freely floating microbubbles or tissue [125–127]. …”

Quantitative Guidelines for the Prediction of Ultrasound Contrast Agent Destruction During Injection

“…This may be significant because the resonant frequency of the microbubbles depends on their size. If strategies for detection of targeted agents are based on shifts in the microbubble frequency when on target (Payne et al, 2011), unexpected results may occur when these strategies are tested in vivo.…”