Fluid flow influences ultrasound-assisted endothelial membrane permeabilization and calcium flux

Memari, Elahe; Hui, Fiona; Yusefi, Hossein; Helfield, Brandon

doi:10.1016/j.jconrel.2023.05.004

Cited by 6 publications

(8 citation statements)

References 69 publications

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“…While an explanation for these observations is outside the scope of the current study, potential contributing factors include (1) time needed for MB replenishment, and (2) transient changes in cerebrovascular physiology that affects MB concentration, flow rate, or dynamics during sonication. In support of the former, recent work has shown that fluid dynamics, specifically flow rate, affects the ultrasound and MB-mediated permeabilization of in vitro human umbilical and brain endothelial cells (Memari et al 2023). In that study, flow rate of 30 ml min −1 led to a 2-3-fold increase in endothelial cell permeabilization compared to a flow rate of 5 ml min −1 , which was linked to a substantial increase in intracellular Ca 2+ levels.…”

Section: Discussionmentioning

confidence: 78%

The impact of pulse repetition frequency on microbubble activity and drug delivery during focused ultrasound-mediated blood-brain barrier opening

Fletcher,

Zhang,

Chisholm

et al. 2024

Phys. Med. Biol.

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Objective. Pulsed focused ultrasound (FUS) can deliver therapeutics to the brain by using intravenous microbubbles (MBs) to open the blood-brain barrier (BBB). MB emissions indicate treatment outcomes, like BBB opening (harmonics) and damage (broadband). Typically, a pulse repetition frequency (PRF) of 1 Hz is used, but the effect of PRF on MBs is not fully understood. We investigated the effect of PRF on MB activity and tracer delivery. Approach. The effect of PRF (0.125, 0.25, 0.5, 1, and 2 Hz) on MB activity was monitored through harmonic and wideband emissions during FUS sonications of the rat brain at 274.3 kHz. BBB opening was quantified through fluorescence imaging to estimate the concentration of Trypan Blue (TB) dye following a 75-pulse FUS exposure for PRFs of 1 and 0.25 Hz. Main results. At a fixed acoustic pressure, the percentage change in maximum harmonic amplitude compared to the control (PRF = 1 Hz) decreased with increasing PRF, with a median change of 73.8% at 0.125 Hz and −38.3% at 2 Hz. There was no difference in the pressure threshold for broadband emissions between PRFs of 0.25 and 1 Hz. PRF = 0.25 Hz, led to a 68.2% increase in the mean concentration of TB measured after FUS, with a 53.9% increase in the mean harmonic sum, compared with PRF = 1 Hz. Harmonic emissions-based control at PRF = 0.25 Hz yielded similar TB delivery, with less damage at histology, compared with 1 Hz. Significance. For a fixed number of FUS pulses, reducing the PRF was shown to increase the magnitude of harmonic emissions and TB delivery, but not the threshold for broadband emissions. While further research is necessary to understand the mechanisms involved, these results may be useful to improve clinical safety margins and sensitivity to detecting small harmonic signals from cavitating MBs.

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Section: Discussionmentioning

confidence: 78%

The impact of pulse repetition frequency on microbubble activity and drug delivery during focused ultrasound-mediated blood-brain barrier opening

Fletcher,

Zhang,

Chisholm

et al. 2024

Phys. Med. Biol.

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“…Propidium iodide (PI, P4864; Sigma–Aldrich) was used as a drug model (669.39 Da; hydrodynamic radius of 0.6 nm) to investigate the influence of peak negative pressure (PNP; 100, 200, 300, and 400 kPa) and MB concentration (2 × 10 7 , 4 × 10 7 , and 8 × 10 7 MB/mL) on spheroid permeabilization. This molecule is a nonpermeant and fluorescent DNA intercalating agent, which is commonly used as a membrane integrity marker to investigate the membrane permeabilization. − This fluorescent dye has a very low fluorescent intensity in an aqueous solution, while its quantum yield is 1000-fold enhanced after its intracellular uptake and binding to DNA. A suspension of 5 spheroids in 1.5 mL of McCoy’s 5A medium supplemented with 1% FCS was placed in a dedicated plastic cuvette.…”

Section: Methodsmentioning

confidence: 99%

Delivery of Anticancer Drugs Using Microbubble-Assisted Ultrasound in a 3D Spheroid Model

Roy,

Alix,

Burlaud-Gaillard

et al. 2024

Mol. Pharmaceutics

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Tumor spheroids are promising three-dimensional (3D) in vitro tumor models for the evaluation of drug delivery methods. The design of noninvasive and targeted drug methods is required to improve the intratumoral bioavailability of chemotherapeutic drugs and reduce their adverse off-target effects. Among such methods, microbubble-assisted ultrasound (MB-assisted US) is an innovative modality for noninvasive targeted drug delivery. The aim of the present study is to evaluate the efficacy of this US modality for the delivery of bleomycin, doxorubicin, and irinotecan in colorectal cancer (CRC) spheroids. MB-assisted US permeabilized the CRC spheroids to propidium iodide, which was used as a drug model without affecting their growth and viability. Histological analysis and electron microscopy revealed that MB-assisted US affected only the peripheral layer of the CRC spheroids. The acoustically mediated bleomycin delivery induced a significant decrease in CRC spheroid growth in comparison to spheroids treated with bleomycin alone. However, this US modality did not improve the therapeutic efficacy of doxorubicin and irinotecan on CRC spheroids. In conclusion, this study demonstrates that tumor spheroids are a relevant approach to evaluate the efficacy of MB-assisted US for the delivery of chemotherapeutics.

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“…The ultrasound delivery platform has been reported previously [ 26 ]. Briefly, a customized acoustically coupled inverted microscope (Ti2-A, Nikon, Melville, New York, USA) was developed by fixing a compatible support and coupling cone for the ultrasound transducer (single-element 1 MHz, unfocused, diameter 2a = 12.7 mm; A303S- SU, , Waltham, MA, USA) on the microscopy platform.…”

Section: Methodsmentioning

confidence: 99%

Shear stress preconditioning and microbubble flow pattern modulate ultrasound-assisted plasma membrane permeabilization

Memari,

Helfield

2024

Materials Today Bio

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Fluid flow influences ultrasound-assisted endothelial membrane permeabilization and calcium flux

Cited by 6 publications

References 69 publications

The impact of pulse repetition frequency on microbubble activity and drug delivery during focused ultrasound-mediated blood-brain barrier opening

The impact of pulse repetition frequency on microbubble activity and drug delivery during focused ultrasound-mediated blood-brain barrier opening

Delivery of Anticancer Drugs Using Microbubble-Assisted Ultrasound in a 3D Spheroid Model

Shear stress preconditioning and microbubble flow pattern modulate ultrasound-assisted plasma membrane permeabilization

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