On-chip targeted single cell sonoporation with microbubble destruction excited by surface acoustic waves
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Abstract:
We demonstrate that a surface acoustic wave at tens of megahertz frequency is capable of inducing microbubble cluster destruction at a desired location to achieve a single cell's reparable sonoporation. By controlling the position of the microbubble cluster relative to the targeted cell precisely, the effective size of the collapsing microbubbles is measured to be less than 0.68 times the diameter of microbubble cluster. Furthermore, the sonoporation efficiency and the cell viability are 82.4% ± 6.5% and 90% ± 8.7%, respectively, when the targeted cell is within the effective microbubble destruction region.Keywords:
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Until now, targeted microbubbles have only been used for molecular imaging, not drug delivery. Drug uptake using microbubbles can be induced by sonoporation, a method that induces transient cell membrane pores by oscillating or jetting microbubbles so that therapeutics can enter the cell. So far, sonoporation has only been induced using non-targeted microbubbles. This study focuses on inducing sonoporation with CD31-targeted microbubbles in endothelial cells. Targeted microbubble-cell behavior upon insonification at 1 MHz (6× 10 cycle sine-wave bursts, 80 kPa peak negative acoustic pressure) was studied with a high-speed camera. The cell-impermeable propidium iodide (PI) was used as indicator for increased endothelial cell membrane permeability due to sonoporation. During insonification, the adhered microbubbles oscillated and were not destroyed. Cell deformation was not detected. Microbubbles larger than 3.0 ¿m or a relative vibration > 0.5 induced PI uptake in the area surrounding the bubble. This study reveals that targeted microbubbles can induce sonoporation. This feature may now be used in molecular imaging using ultrasound, thereby combining imaging and drug delivery.
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Molecular Imaging
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It has been proven, that the cellular uptake of drugs and genes is increased, when the region of interest is under ultrasound insonification, and even more when a contrast agent is present. This increased uptake has been attributed to the formation of transient porosities in the cell membrane, which are big enough for the transport of drugs into the cell (sonoporation). Owing to this technique, new ultrasound contrast agents that incorporate a therapeutic compound have become of interest. Combining ultrasound contrast agents with therapeutic substances, such a chemotherapeutics and virus vectors, may lead to a simple and economic method to instantly cure upon diagnosis, using conventional ultrasound scanners. There are two hypotheses for explaining the sonoporation phenomenon, the first being microbubble oscillations near a cell membrane, the second being microbubble jetting through the cell membrane. Based on modeling, high-speed photography, and recent cellular uptake measurements, it is concluded that microbubble jetting behavior is less likely to be the dominant sonoporation mechanism. Ultrasound-directed drug delivery using microbubbles is a promising method that has great potential in the treatment of malignant disorders.
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The past several decades have witnessed great progress in "smart drug delivery", an advance technology that can deliver genes or drugs into specific locations of patients' body with enhanced delivery efficiency. Ultrasound-activated mechanical force induced by the interactions between microbubbles and cells, which can stimulate so-called "sonoporation" process, has been regarded as one of the most promising candidates to realize spatiotemporal-controllable drug delivery to selected regions. Both experimental and numerical studies were performed to get in-depth understanding on how the microbubbles interact with cells during sonoporation processes, under different impact parameters. The current work gives an overview of the general mechanism underlying microbubble-mediated sonoporation, and the possible impact factors (e.g., the properties of cavitation agents and cells, acoustical driving parameters and bubble/cell micro-environment) that could affect sonoporation outcomes. Finally, current progress and considerations of sonoporation in clinical applications are reviewed also.
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Microbubble-facilitated sonoporation, or the ultrasound-induced disruption of plasma membrane, provides new opportunities for intracellular delivery of therapeutic agents. However, ultrasound mediated microbubble-cell interaction is difficult to control due to the very nature of unconfined microbubbles in solution, resulting in relatively low delivery efficiency and often variable delivery outcome. It is desirable to develop techniques in order to achieve reproducible, robust delivery outcome. By utilizing targeted microbubbles to control and confine microbubbles near the cells and examine the detailed biophysical and cellular processes of the interaction of ultrasound-driven microbubbles with cells, we seek to obtain improved understanding of the disruption of cell plasma membrane, cellular uptake, and subsequent downstream effects in sonoporation. In this presentation, we describe our studies that examined these aspects and the important factors involved in sonoporation outcome using multidisciplinary approaches and at the single cell level.
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Sonication
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Molecular ultrasound imaging uses targeted contrast agents consisting of microbubbles. Drug uptake using microbubbles can be induced by sonoporation, a method that induces transient cell membrane pores by oscillating or jetting microbubbles so that therapeutics can enter the cell. This study focuses on inducing sonoporation with CD31-targeted microbubbles in endothelial cells at low acoustic pressures. Biotinylated lipid coated microbubbles with a C4F10 gas core were made by sonication including CD31 antibody conjugation. Microbubble-cell behavior upon insonification at 1 MHz (6 × 10 cycle sine-wave bursts) at 80, 120, and 200 kPa peak negative acoustic pressure was studied with the Brandaris 128 high-speed camera at a frame rate of 12 Mfs. The cell-impermeable propidium iodide was used as indicator for increased cell membrane permeability due to sonoporation and was detected using fluorescence imaging. A total of 31 cells were studied, wherein all had one microbubble attached per cell. After insonifying the targeted microbubbles at 80, 120, and 200 kPa, only 6 burst of each 10 cycles, 12 cells PI uptake. This study reveals that targeted microbubbles can induce sonoporation. This feature may now be used in molecular imaging using ultrasound, thereby combining imaging and drug delivery.
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Propidium iodide
Molecular Imaging
Sonication
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Sonoporation
Extravasation
Membrane permeability
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Therapeutic ultrasound has been in use for over 70 years but has primarily been a thermal modality. Sonoporation, the use of ultrasound and stable gas microbubbles in the size range of 2–10 µm to form transient pores in cell membranes, has been of great interest in the past 15 years. This technique could be used to improve the delivery of current drugs in very localised regions. There are several phenomena behind sonoporation that all occur non-exclusively: push, pull, jetting, inertial cavitation, shear and, translation. Pre-clinical work has shown that sonoporation can be used to reduce primary tumour burden and inhibit metastatic development. Our clinical trial showed that ultrasound in combination with microbubbles and chemotherapy can effectively double the number of chemotherapy cycles patients can undergo, meaning that the patients were healthier for a longer period of time. Nevertheless, sonoporation is still in its infancy and there is vast room for improvement in both the areas of microbubbles and ultrasound
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