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Keyhani, Keyvan; Guzmán, Héctor R; Parsons, Aimee; Lewis, Thomas N.; Prausnitz, Mark R.

doi:10.1023/a:1013066027759

Cited by 58 publications

(20 citation statements)

References 14 publications

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“…Our observations that cell membrane damage and calcein uptake correlates with the intensity, time, and total energy of ultrasonic exposure is not novel, but is confirmatory of the observations of Prausnitz et al (Guzman et al 2001; Guzman et al 2001; Keyhani et al 2001; Schlicher et al 2006). However, our observation that model drug uptake is a strong function of ambient pressure is novel and aids in explaining the nature of the mechanism that causes membrane damage.…”

Section: Discussionsupporting

confidence: 92%

Over-Pressure Suppresses Ultrasonic-Induced Drug Uptake

Stringham

Viskovska

Richardson

et al. 2009

Ultrasound in Medicine & Biology

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Ultrasound (US) is used to enhance and target delivery of drugs and genes to cancer tissues. The present study further examines the role of acoustic cavitation in US-induced permeabilization of cell membranes and subsequent drug or gene uptake by the cell. Rat colon cancer cells were exposed to ultrasound at various static pressures to examine the hypothesis that oscillating bubbles, also known as cavitating bubbles, permeabilize cells. Increasing pressure suppresses bubble cavitation activity; thus if applied pressure were to reduce drug uptake, cell permeabilization would be strongly linked to bubble cavitation activity. Cells were exposed to 476 kHz pulsed ultrasound at average intensities of 2.75 W/cm2 and 5.5 W/cm2 at various pressures and times in an isothermal chamber. Cell fractions with reversible membrane damage (calcein uptake) and irreversible damage (propidium iodide uptake) were analyzed by flow cytometry. Pressurization to 3 atm nearly eliminated the biological effect of US in promoting calcein uptake. Data also showed a linear increase in membrane permeability based upon increased time and intensity. This research shows that US-mediated cell membrane permeability is likely linked to cavitation bubble activity.

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Section: Discussionsupporting

confidence: 92%

Over-Pressure Suppresses Ultrasonic-Induced Drug Uptake

Stringham

Viskovska

Richardson

et al. 2009

Ultrasound in Medicine & Biology

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“…The enhancement increased proportionally with the energy density and inversely with the frequency. Such dependencies are consistent with previous observations on ultrasonic drug delivery to cells and tissues other than the brain (16,33). In particular, the inverse dependence of drug permeability on frequency suggests the role of US-induced acoustic cavitation in transport enhancement.…”

Section: Discussionsupporting

confidence: 93%

Ultrasound-Enhanced Drug Transport and Distribution in the Brain

et al. 2010

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Drug delivery in the brain is limited by slow drug diffusion in the brain tissue. This study tested the hypothesis that ultrasound can safely enhance the permeation of drugs in the brain. In vitro exposure to ultrasound at various frequencies (85 kHz, 174 kHz, and 1 MHz) enhanced the permeation of tritium-labeled molecules with molecular weight up to 70 kDa across porcine brain tissue. A maximum enhancement of 24-fold was observed at 85 kHz and 1,200 J/cm2. In vivo exposure to 1-MHz ultrasound further demonstrated the ability of ultrasound to facilitate molecule distribution in the brain of a non-human primate. Finally, ultrasound under conditions similar to those used in vivo was shown to cause no damage to plasmid DNA, siRNA, adeno-associated virus, and fetal rat cortical neurons over a range of conditions. Altogether, these studies demonstrate that ultrasound can increase drug permeation in the brain in vitro and in vivo under conditions that did not cause detectable damage.

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“…Likewise, the decrease in cell viability trended towards clustering around specific energy curves. Other studies have found similar results to ours that suggest cell transfection and viability may correlate to ultrasound energy exposure [24,25]. They report optimal energy exposures in the range of 10 to 40 J/cm 2 , using a low frequency of 24 kHz.…”

Section: Discussionsupporting

confidence: 86%

Prolonging pulse duration in ultrasound-mediated gene delivery lowers acoustic pressure threshold for efficient gene transfer to cells and small animals

Tran¹,

Harrang²,

Song³

et al. 2018

Journal of Controlled Release

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While ultrasound-mediated gene delivery (UMGD) has been accomplished using high peak negative pressures (PNPs) of 2 MPa or above, emerging research showed that this may not be a requirement for microbubble (MB) cavitation. Thus, we investigated lower-pressure conditions close to the MB inertial cavitation threshold and focused towards further increasing gene transfer efficiency and reducing associated cell damage. We created a matrix of 21 conditions (n = 3/cond.) to test in HEK293T cells using pulse durations spanning 18 μs–36 ms and PNPs spanning 0.5–2.5 MPa. Longer pulse duration conditions yielded significant increase in transgene expression relative to sham with local maxima between 20 J and 100 J energy curves. A similar set of 17 conditions (n = 4/cond.) was tested in mice using pulse durations spanning 18 μs–22 ms and PNPs spanning 0.5–2.5 MPa. We observed local maxima located between 1 J and 10 J energy curves in treated mice. Of these, several low pressure conditions showed a decrease in ALT and AST levels while maintaining better or comparable expression to our positive control, indicating a clear benefit to allow for effective transfection with minimized tissue damage versus the high-intensity control. Our data indicates that it is possible to eliminate the requirement of high PNPs by prolonging pulse durations for effective UMGD in vitro and in vivo, circumventing the peak power density limitations imposed by piezo-materials used in US transducers. Overall, these results demonstrate the advancement of UMGD technology for achieving efficient gene transfer and potential scalability to larger animal models and human application.

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Abstract: Large numbers of molecules can be delivered intracellularly using low-frequency ultrasound. Both uptake and viability correlate with acoustic energy, which is useful for design and control of ultrasound protocols.

Cited by 58 publications

References 14 publications

Over-Pressure Suppresses Ultrasonic-Induced Drug Uptake

Over-Pressure Suppresses Ultrasonic-Induced Drug Uptake

Ultrasound-Enhanced Drug Transport and Distribution in the Brain

Prolonging pulse duration in ultrasound-mediated gene delivery lowers acoustic pressure threshold for efficient gene transfer to cells and small animals

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