Abstract
BackgroundPhase-change ultrasound contrast agents (PCCAs) offer a solution to the inherent limitations associated with using microbubbles for sonoporation; they are characterized by prolonged circulation lifetimes, and their nanometer-scale sizes may allow for passive accumulation in solid tumors. As a first step towards the goal of extravascular cell permeabilization, we aim to characterize the sonoporation potential of a low-boiling point formulation of PCCAs in vitro.MethodsParameters to induce acoustic droplet vaporization and subsequent microbubble cavitation were optimized in vitro using high-speed optical microscopy. Sonoporation of pancreatic cancer cells in suspension was then characterized at a range of pressures (125–600 kPa) and pulse lengths (5–50 cycles) using propidium iodide as an indicator molecule.ResultsWe achieved sonoporation efficiencies ranging from 8 ± 1% to 36 ± 4% (percent of viable cells), as evidenced by flow cytometry. Increasing sonoporation efficiency trended with increasing pulse length and peak negative pressure.ConclusionsWe conclude that PCCAs can be used to induce the sonoporation of cells in vitro, and our results warrant further investigation into the use of PCCAs as extravascular sonoporation agents in vivo.
Highlights
Phase-change ultrasound contrast agents (PCCAs) offer a solution to the inherent limitations associated with using microbubbles for sonoporation; they are characterized by prolonged circulation lifetimes, and their nanometer-scale sizes may allow for passive accumulation in solid tumors
Detection of PCCA vaporization and subsequent cavitation signals Through optical high-speed microscopy and the detection of cavitation signals, we investigated the effect of acoustic pulse length and peak negative pressure on PCCA vaporization (a.k.a. acoustic droplet vaporization (ADV)) and the behavior of resultant microbubbles
At a frequency of 1.0 MHz, we found that our PCCAs undergo ADV at and above peak negative pressures of 300 kPa but never at or below 125 kPa, regardless of pulse length
Summary
Phase-change ultrasound contrast agents (PCCAs) offer a solution to the inherent limitations associated with using microbubbles for sonoporation; they are characterized by prolonged circulation lifetimes, and their nanometer-scale sizes may allow for passive accumulation in solid tumors. Sonoporation refers to the process by which ultrasoundstimulated microbubbles are used to permeabilize cell membranes and enhance the intracellular accumulation of drugs, genes, or indicator dyes [1, 2]. This holds potential as a physical targeting method to drive drug delivery non-invasively and with high spatial specificity. Microbubbles are relatively large (1–10 μm) and cannot escape the vasculature following intravenous administration [8] This can be useful for some applications including drug or gene delivery to vascular endothelial cells [9] and ultrasound-mediated disruption of endothelial tight junctions to open the blood-brain barrier [10, 11]. This necessitates continuous infusion or repeat bolus injections in situations where repeat or long duration treatment is required
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