Enhanced microbubble contrast agent oscillation following 250 kHz insonation

Ilovitsh, Tali; Ilovitsh, Asaf; Foiret, Josquin; Caskey, Charles F.; Kusunose, Jiro; Fite, Brett Z.; Hua, Zhang; Mahakian, Lisa M.; Tam, Sarah; Butts-Pauly, Kim; Qin, Shengping; Ferrara, Katherine W.

doi:10.1038/s41598-018-34494-5

Cited by 56 publications

(62 citation statements)

References 62 publications

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“…Images of ~20 single nanoemulsion particles, and ~20 oscillating microbubbles were captured and processed. Microbubble are known to expand with sonication at a center frequency of 250 kHz [34]. Indeed, with microbubbles, we observed an expansion ratio of 35 at a peak negative pressure (PNP) of 500 kPa (Fig.…”

Section: These Nanoemulsions Do Not Undergo Large Oscillations or Cavmentioning

confidence: 79%

Polymeric perfluorocarbon nanoemulsions are ultrasound-activated wireless drug infusion catheters

et al. 2019

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Author Contributions QZ and RDA designed the experiments. QZ performed the chemistry of nanoparticle production and physicochemical characterization, carried out the pharmacokinetics study and in vivo biodistribution of the nanoparticles, and performed the in vitro/in vivo ultrasonic drug uncaging experiments, with guidance from MA and assistance from JBW and AK. Cryo-TEM imaging was performed by MAB, RHC, and NHN. QZ and BCY performed the ultrasound imaging and ultrasonic nicardipine uncaging experiments and their analysis. TI and KFW designed and performed the ultra-high-speed optical imaging and passive cavitation detection of the nanoemulsions. QZ, BCY, and RDA prepared the figures and wrote the manuscript, with input and edits from all the authors.

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Section: These Nanoemulsions Do Not Undergo Large Oscillations or Cavmentioning

confidence: 79%

Polymeric perfluorocarbon nanoemulsions are ultrasound-activated wireless drug infusion catheters

et al. 2019

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“…The experimental setup (illustrated in Fig. 2A) was described previously (55) and further described in SI Appendix. Postprocessing of the captured images was performed in Matlab to yield the resting MB radius and expansion ratio.…”

Section: Methodsmentioning

confidence: 99%

“…In the past, it was assumed that MB oscillations are maximized around their resonance frequency (2 to 10 MHz) (51)(52)(53)(54). Recently, we showed that when MBs are excited by a frequency of 250 kHz (an order of magnitude below the resonance frequency of these agents), their oscillations reach an expansion ratio of 35 at a relatively low PNP of 500 kPa (55). For tumor transfection, we hypothesize that the high-amplitude MB oscillations occurring at a center frequency of 250 kHz will enhance the uptake of the genetic material, allowing for more copies to be delivered and resulting in a higher transfection efficacy.…”

mentioning

confidence: 99%

Low-frequency ultrasound-mediated cytokine transfection enhances T cell recruitment at local and distant tumor sites

Ilovitsh

Feng

Foiret

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Robust cytotoxic T cell infiltration has proven to be difficult to achieve in solid tumors. We set out to develop a flexible protocol to efficiently transfect tumor and stromal cells to produce immune-activating cytokines, and thus enhance T cell infiltration while debulking tumor mass. By combining ultrasound with tumor-targeted microbubbles, membrane pores are created and facilitate a controllable and local transfection. Here, we applied a substantially lower transmission frequency (250 kHz) than applied previously. The resulting microbubble oscillation was significantly enhanced, reaching an effective expansion ratio of 35 for a peak negative pressure of 500 kPa in vitro. Combining low-frequency ultrasound with tumor-targeted microbubbles and a DNA plasmid construct, 20% of tumor cells remained viable, and ∼20% of these remaining cells were transfected with a reporter gene both in vitro and in vivo. The majority of cells transfected in vivo were mucin 1+/CD45−tumor cells. Tumor and stromal cells were then transfected with plasmid DNA encoding IFN-β, producing 150 pg/106cells in vitro, a 150-fold increase compared to no-ultrasound or no-plasmid controls and a 50-fold increase compared to treatment with targeted microbubbles and ultrasound (without IFN-β). This enhancement in secretion exceeds previously reported fourfold to fivefold increases with other in vitro treatments. Combined with intraperitoneal administration of checkpoint inhibition, a single application of IFN-β plasmid transfection reduced tumor growth in vivo and recruited efficacious immune cells at both the local and distant tumor sites.

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“…8), respectively. Lower frequencies favor cavitation-mediated bioeffects at low acoustic pressures (Apfel and Holland 1991;Ilovitsh et al 2018). We have shown here that the BBB can be opened in an NHP model at an MI of 0.4 ( Fig.…”

Section: Discussionmentioning

confidence: 56%

A Clinical System for Non-invasive Blood–Brain Barrier Opening Using a Neuronavigation-Guided Single-Element Focused Ultrasound Transducer

Pouliopoulos

Burgess

et al. 2020

Ultrasound in Medicine & Biology

102

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Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is currently being investigated in clinical trials. Here, we describe a portable clinical system with a therapeutic transducer suitable for humans, which eliminates the need for in-line magnetic resonance imaging (MRI) guidance. A neuronavigation-guided 0.25-MHz single-element FUS transducer was developed for non-invasive clinical BBB opening. Numerical simulations and experiments were performed to determine the characteristics of the FUS beam within a human skull. We also validated the feasibility of BBB opening obtained with this system in two non-human primates using U.S. Food and Drug Administration (FDA)-approved treatment parameters. Ultrasound propagation through a human skull fragment caused 44.4 § 1% pressure attenuation at a normal incidence angle, while the focal size decreased by 3.3 § 1.4% and 3.9 § 1.8% along the lateral and axial dimension, respectively. Measured lateral and axial shifts were 0.5 § 0.4 mm and 2.1 § 1.1 mm, while simulated shifts were 0.1 § 0.2 mm and 6.1 § 2.4 mm, respectively. A 1.5-MHz passive cavitation detector transcranially detected cavitation signals of Definity microbubbles flowing through a vessel-mimicking phantom. T 1 -weighted MRI confirmed a 153 § 5.5 mm 3 BBB opening in two non-human primates at a mechanical index of 0.4, using Definity microbubbles at the FDA-approved dose for imaging applications, without edema or hemorrhage. In conclusion, we developed a portable system for non-invasive BBB opening in humans, which can be achieved at clinically relevant ultrasound exposures without the need for in-line MRI guidance. The proposed FUS system may accelerate the adoption of non-invasive FUS-mediated therapies due to its fast application, low cost and portability. (

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Enhanced microbubble contrast agent oscillation following 250 kHz insonation

Cited by 56 publications

References 62 publications

Polymeric perfluorocarbon nanoemulsions are ultrasound-activated wireless drug infusion catheters

Polymeric perfluorocarbon nanoemulsions are ultrasound-activated wireless drug infusion catheters

Low-frequency ultrasound-mediated cytokine transfection enhances T cell recruitment at local and distant tumor sites

A Clinical System for Non-invasive Blood–Brain Barrier Opening Using a Neuronavigation-Guided Single-Element Focused Ultrasound Transducer

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