Sonoporation

Source: Wikipedia, the free encyclopedia.
Schematic of Sonoporation Mechanism. This figure depicts the general understanding of sonoporation where a dedicated sonoporator applies ultrasound to induce microbubble cavitation and eventually pore formation. The therapeutic gene or drug of interest thus may translocate within the cell.

Sonoporation, or cellular sonication, is the

microbubbles to enhance delivery of these large molecules.[1]
The exact mechanism of sonoporation-mediated membrane translocation remains unclear, with a few different hypotheses currently being explored.

Sonoporation is under active study for the introduction of foreign

MHz) ultrasound has been demonstrated to result in complete cellular death (rupturing), thus cellular viability
must also be accounted for when employing this technique.

Equipment

Sonoporation is performed with a dedicated sonoporator. Sonoporation may also be performed with custom-built piezoelectric transducers connected to bench-top function generators and acoustic amplifiers. Standard ultrasound medical devices may also be used in some applications.

Measurement of the acoustics used in sonoporation is listed in terms of mechanical index, which quantifies the likelihood that exposure to diagnostic ultrasound will produce an adverse biological effect by a non-thermal action based on pressure.[3]

Microbubble contrast agents

Microbubble contrast agents are generally used in contrast-enhanced ultrasound applications to enhance the acoustic impact of ultrasound. For sonoporation specifically, microbubbles are used to significantly enhance membrane translocation of molecular therapeutics.[4]

General features

The microbubbles used today are composed of a gas core and a surrounding shell. The makeup of these elements may vary depending on the preferred physical and chemical properties.

perfluorocarbon.[6]

Mechanism of action

Microbubble gas cores have high compressibility relative to their liquid environment, making them highly responsive to acoustic application. As a result of ultrasound stimulation, microbubbles undergo expansion and contraction, a phenomenon called stable cavitation. If a microbubble is attached to the cell membrane, the microbubble oscillations produced by ultrasound stimulation may push and pull on the membrane to produce a membrane opening. These rapid oscillations are also responsible for adjacent fluid flow called microstreaming which increases pressure on surrounding cells producing further sonoporation to whole cell populations.[7] The physical mechanisms supposedly involved with microbubble-enhanced sonoporation have been referred to as push, pull, microstreaming, translation, and jetting.[8]

Membrane translocation mechanism

The mechanism by which molecules cross cellular membrane barriers during sonoporation remains unclear. Different theories exist that may potentially explain barrier permeabilization and molecular delivery. The dominant hypotheses include pore formation, endocytosis, and membrane wounds.

Pore formation

Schematic representation of molecular translocation via endocytosis. The second representation from the left illustrates the endocytotic mechanism involving clathrin-coated pits.

Pore formation following ultrasound application was first reported in 1999 in a study that observed cell membrane craters following ultrasound application at 255 kHz.[9] Later, sonoporation mediated microinjection of dextran molecules showed that membrane permeability mechanisms differ depending on the size of dextran molecules. Microinjection of dextran molecules from 3 to 70 kDa was reported to have crossed the cellular membrane via transient pores. In contrast, dextran molecules of 155 and 500 kDa were predominantly found in vesicle-like structures, likely indicating the mechanism of endocytosis.[10] This variability in membrane behavior has led to other studies investigating membrane rupture and resealing characteristics depending on ultrasound amplitude and duration.

Endocytosis

Various cellular reactions to ultrasound indicate the mechanism of molecular uptake via endocytosis. These observed reactionary phenomena include ion exchange, hydrogen peroxide, and cell intracellular calcium concentration. Studies have used patch clamping techniques to monitor membrane potential ion exchange for the role of endocytosis in sonoporation. Ultrasound application to cells and adjacent microbubbles was shown to produce marked cell membrane hyperpolarization along with progressive intracellular calcium increase, which is believed to be a consequence of calcium channels opening in response to microbubble oscillations. These findings act as support for ultrasound application inducing calcium-mediated uncoating of clathrin-coated pits seen in traditional endocytosis pathways.[11][12] Other work reported sonoporation induced the formation of hydrogen peroxide, a cellular reaction that is also known to be involved with endocytosis.[9]

Membrane wounds

Mechanically created wounds in the plasma membrane have been observed as a result of sonoporation-produced shear forces. The nature of these wounds may vary based on the degree of acoustic cavitation leading to a spectrum of cell behavior, from membrane blebbing to instant cell lysis. Multiple studies examining membrane wounds note observing resealing behavior, a process dependent on recruitment of ATP and intracellular vesicles.[9]

Membrane resealing

Following sonoporation-mediated membrane permeabilization, cells can automatically repair the membrane openings through a phenomenon called "reparable sonoporation."[13] The membrane resealing process has been shown to be calcium-dependent. This property may suggest that the membrane repair process involves a cell's active repair mechanism in response to the cellular influx of calcium.[14]

Preclinical studies

A study showing verified preclinical efficacy of acoustic targeted drug delivery.

In vitro

The first study reporting molecular delivery using ultrasound was a 1987 in vitro study attempting to transfer

antibiotic resistance ultimately led to further in vitro studies that hinted at the potential for sonoporation transfection of plasmid DNA and siRNA
in vivo.

In vivo

In vivo ultrasound mediated drug delivery was first reported in 1991[15] and many other preclinical studies involving sonoporation have followed. This method is being used to deliver therapeutic drugs or genes to treat a variety of diseases including: Stroke, Cancer, Parkinson's, Alzheimer's...[13] The preclinical utility of sonoporation is well illustrated through past tumor radiation treatments which have reported a more than 10-fold cellular destruction when ionizing radiation is coupled with ultrasound-mediated microbubble vascular disruption. This increase in delivery efficiency could allow for the appropriate reduction in therapeutic dosing.[16]

References

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  2. ISBN 978-981-256-685-0
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  3. doi:10.1121/1.1901757
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  4. ^ Fowlkes JB, Kripfgans OD, Carson PL (2004). Microbubbles for ultrasound diagnosis and therapy. 2nd IEEE International Symposium on Biomedical Imaging: Macro to Nano (IEEE Cat No. 04EX821). Vol. 2. New York: IEEE. pp. 29–32.
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  7. PMID 24856171
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  8. S2CID 260344222
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  9. ^
    PMID 26486338
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  10. S2CID 23063345
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  11. PMID 19828232
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  12. PMID 17189059
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    ISSN 2311-5521
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  14. PMID 18158198
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  15. ^
    PMID 25237622
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  16. PMID 19285783
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