Acoustic behavior of microbubbles and implications for drug delivery

Kooiman, Klazina; Vos, Hendrik J.; Versluis, Michel; Jong, Nico de

doi:10.1016/j.addr.2014.03.003

Cited by 333 publications

(353 citation statements)

References 228 publications

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“…The use of small, regular contrast microbubbles such as Sonovue® or Optison® in combination with US has been shown to induce a series of biomechanical effects that may influence the extravasation, distribution, uptake and efficacy of co-administered drugs [13][14][15]. A bubble in the vascular compartment, oscillating in the sound field, will exert direct forces on the endothelial cells creating deformations.…”

Section: Discussionmentioning

confidence: 99%

“…Many of the these approaches explore the use of regular US contrast microbubbles such as Sonovue™ (Bracco Imaging S.p.A, Italy) or Optison™ (GE Healthcare AS, Norway) co-injected with various drug formulations. Insonation of the target pathology, containing microbubbles and drug in vascular compartments, leads to a variety of biomechanical effects that increase the permeability of the endothelial barrier leading to enhanced extravasation, distribution and uptake of drug molecules to target tissue [13][14][15]. Co-injection of Gemcitabine and Sonovue, with localized US insonation for enhanced drug uptake and therapeutic effect during treatment of pancreatic ductal adenocarcinoma is currently being explored in clinical trials [16].…”

Section: Introductionmentioning

confidence: 99%

“…Being small, the magnitude of the biomechanical work they can induce is relatively limited. In addition, being free flowing they display limited contact with the endothelial wall, reducing the level and range of the biomechanical effects [14]. Furthermore, microbubbles are typically cleared from vascular compartments within 2-3 minutes and, finally, to produce sufficient biomechanical work and effect levels, microbubbles often need a high US intensity that induces inertial cavitation, with ensuing safety issues.…”

Section: Introductionmentioning

confidence: 99%

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Acoustic Cluster Therapy (ACT) enhances the therapeutic efficacy of paclitaxel and Abraxane® for treatment of human prostate adenocarcinoma in mice

Wamel

Sontum

Healey

et al. 2016

Journal of Controlled Release

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Acoustic cluster therapy (ACT) is a novel approach for ultrasound mediated, targeted drug delivery. In the current study, we have investigated ACT in combination with paclitaxel and Abraxane® for treatment of a subcutaneous human prostate adenocarcinoma (PC3) in mice. In combination with paclitaxel (12 mg/kg given i.p)., ACT induced a strong increase in therapeutic efficacy; 120 days after study start, 42% of the animals were in stable, complete remission vs. 0% for the paclitaxel only group and the median survival was increased by 86%. In combination with Abraxane® (12 mg paclitaxel/kg given i.v.), ACT induced a strong increase in the therapeutic efficacy; 60 days after study start 100% of the animals were in stable, remission vs. 0% for the Abraxane® only group, 120 days after study start 67% of the animals were in stable, complete remission vs. 0% for the Abraxane® only group. For the ACT + Abraxane group 100% of the animals were alive after 120 days vs. 0% for the Abraxane® only group. Proof of concept for Acoustic Cluster Therapy has been demonstrated; ACT markedly increases the therapeutic efficacy of both paclitaxel and Abraxane® for treatment of human prostate adenocarcinoma in mice.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Acoustic Cluster Therapy (ACT) enhances the therapeutic efficacy of paclitaxel and Abraxane® for treatment of human prostate adenocarcinoma in mice

Wamel

Sontum

Healey

et al. 2016

Journal of Controlled Release

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“…In brief, local US insonation of a pathologic condition (e.g. tumor) containing microbubbles in vascular compartments induces bubble oscillations (stable or inertial cavitation) which lead to a variety of biomechanical effects that enhance extravasation and distribution of drug molecules to target tissue [9][10][11][12][13][14]. This approach may hence be explored to improve on the local specificity of a drug, either co-injected with, or attached to microbubbles.…”

Section: Introductionmentioning

confidence: 99%

Acoustic Cluster Therapy (ACT) — pre-clinical proof of principle for local drug delivery and enhanced uptake

Wamel

Healey

Sontum

et al. 2016

Journal of Controlled Release

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Proof of principle for local drug delivery with Acoustic Cluster Therapy (ACT) was demonstrated in a human prostate adenocarcinoma growing in athymic mice, using near infrared (NIR) dyes as model molecules. A dispersion of negatively charged microbubble/positively charged microdroplet clusters are injected i.v., activated within the target pathology by diagnostic ultrasound (US), undergo an ensuing liquid-to-gas phase shift and transiently deposit 20-30 µm large bubbles in the microvasculature, occluding blood flow for ~ 5-10 min. Further application of low frequency US induces biomechanical effects that increase the vascular permeability, leading to a locally enhanced extravasation of components from the vascular compartment (e.g. released or co-administered drugs). Results demonstrated deposition of activated bubbles in tumor vasculature. Following ACT treatment, a significant and tumor specific increase in the uptake of a co-administered macromolecular NIR dye was shown. In addition, ACT compound loaded with a lipophilic NIR dye to the microdroplet component was shown to facilitate local release and tumor specific uptake. Whereas the mechanisms behind the observed increased and tumor specific uptake are not fully elucidated, it is demonstrated that the ACT concept can be applied as a versatile technique for targeted drug delivery.

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“…These targeted microbubbles, often composed of a perfluorocarbon gas core encapsulated within an antibody-conjugated shell material [12], are in effect artificial gas bodies that would cavitate in response to ultrasound excitation, which could be as short as a single pulse firing [13]. As their binding is known to persist under shear-flow conditions [14,15], they can effectively reside adjacent to the plasma membrane to locally induce membrane disruption over their course of acoustic cavitation [16,17] and concurrently release drugs which may be preloaded onto the microbubble shell [18].…”

Section: Introductionmentioning

confidence: 99%

Membrane blebbing as a recovery manoeuvre in site-specific sonoporation mediated by targeted microbubbles

Leow

Wan

2015

J. R. Soc. Interface.

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Site-specific perforation of the plasma membrane can be achieved through ultrasound-triggered cavitation of a single microbubble positioned adjacent to the cell. However, for this perforation approach (sonoporation), the recovery manoeuvres invoked by the cell are unknown. Here, we report new findings on how membrane blebbing can be a recovery manoeuvre that may take place in sonoporation episodes whose pores are of micrometres in diameter. Each sonoporation site was created using a protocol involving single-shot ultrasound exposure (frequency: 1 MHz; pulse length: 30 cycles; peak negative pressure: 0.45 MPa) which triggered inertial cavitation of a single targeted microbubble (diameter: 1-5 mm). Over this process, live confocal microscopy was conducted in situ to monitor membrane dynamics, model drug uptake kinetics and cytoplasmic calcium ion (Ca 2þ ) distribution. Results show that blebbing would occur at a recovering sonoporation site after its resealing, and it may emerge elsewhere along the membrane periphery. The bleb size was correlated with the pre-exposure microbubble diameter, and 99% of blebbing cases at sonoporation sites were inflicted by microbubbles larger than 1.5 mm diameter (analysed over 124 sonoporation episodes). Blebs were not observed at irreversible sonoporation sites or when sonoporation site repair was inhibited via extracellular Ca 2þ chelation. Functionally, the bleb volume was found to serve as a buffer compartment to accommodate the cytoplasmic Ca 2þ excess brought about by Ca 2þ influx during sonoporation. These findings suggest that membrane blebbing would help sonoporated cells restore homeostasis.

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Acoustic behavior of microbubbles and implications for drug delivery

Cited by 333 publications

References 228 publications

Acoustic Cluster Therapy (ACT) enhances the therapeutic efficacy of paclitaxel and Abraxane® for treatment of human prostate adenocarcinoma in mice

Acoustic Cluster Therapy (ACT) enhances the therapeutic efficacy of paclitaxel and Abraxane® for treatment of human prostate adenocarcinoma in mice

Acoustic Cluster Therapy (ACT) — pre-clinical proof of principle for local drug delivery and enhanced uptake

Membrane blebbing as a recovery manoeuvre in site-specific sonoporation mediated by targeted microbubbles

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