Effects of the microbubble shell physicochemical properties on ultrasound-mediated drug delivery to the brain

Wu, Shih-Ying; Chen, Cherry C.; Tung, Yu-Chi; Olumolade, Oluyemi; Konofagou, Elisa E.

doi:10.1016/j.jconrel.2015.06.007

Cited by 65 publications

(44 citation statements)

References 41 publications

(60 reference statements)

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“…We therefore suggest that for these cationic lipid-shelled microbubbles and acoustic parameters, BBB opening depends primarily on the microbubble persistence in the circulation. This may in part explain why microbubbles with longer acyl-chain lipids, which were shown to circulate longer 23, also demonstrated greater trans-BBB delivery 24.…”

Section: Discussionmentioning

confidence: 99%

Microbubble gas volume: A unifying dose parameter in blood-brain barrier opening by focused ultrasound

et al. 2017

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Focused ultrasound with microbubbles is being developed to transiently, locally and noninvasively open the blood-brain barrier (BBB) for improved pharmaceutical delivery. Prior work has demonstrated that, for a given concentration dose, microbubble size affects both the intravascular circulation persistence and extent of BBB opening. When matched to gas volume dose, however, the circulation half-life was found to be independent of microbubble size. In order to determine whether this holds true for BBB opening as well, we independently measured the effects of microbubble size (2 vs. 6 µm diameter) and concentration, covering a range of overlapping gas volume doses (1-40 µL/kg). We first demonstrated precise targeting and a linear dose-response of Evans Blue dye extravasation to the rat striatum for a set of constant microbubble and ultrasound parameters. We found that dye extravasation increased linearly with gas volume dose, with data points from both microbubble sizes collapsing to a single line. A linear trend was observed for both the initial sonication (R 2 =0.90) and a second sonication on the contralateral side (R 2 =0.68). Based on these results, we conclude that microbubble gas volume dose, not size, determines the extent of BBB opening by focused ultrasound (1 MHz, ~0.5 MPa at the focus). This result may simplify planning for focused ultrasound treatments by constraining the protocol to a single microbubble parameter -gas volume dose -which gives equivalent results for varying size distributions. Finally, using optimal parameters determined for Evan Blue, we demonstrated gene delivery and expression using a viral vector, dsAAV1-CMV-EGFP, one week after BBB disruption, which allowed us to qualitatively evaluate neuronal health.

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Section: Discussionmentioning

confidence: 99%

Microbubble gas volume: A unifying dose parameter in blood-brain barrier opening by focused ultrasound

et al. 2017

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“…This can be useful for some applications including drug or gene delivery to vascular endothelial cells [9] and ultrasound-mediated disruption of endothelial tight junctions to open the blood-brain barrier [10, 11]. However, extravascular sonoporation for the purpose of improved drug or gene delivery within a target tissue is not feasible.…”

Section: Introductionmentioning

confidence: 99%

An evaluation of the sonoporation potential of low-boiling point phase-change ultrasound contrast agents in vitro

et al. 2017

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BackgroundPhase-change ultrasound contrast agents (PCCAs) offer a solution to the inherent limitations associated with using microbubbles for sonoporation; they are characterized by prolonged circulation lifetimes, and their nanometer-scale sizes may allow for passive accumulation in solid tumors. As a first step towards the goal of extravascular cell permeabilization, we aim to characterize the sonoporation potential of a low-boiling point formulation of PCCAs in vitro.MethodsParameters to induce acoustic droplet vaporization and subsequent microbubble cavitation were optimized in vitro using high-speed optical microscopy. Sonoporation of pancreatic cancer cells in suspension was then characterized at a range of pressures (125–600 kPa) and pulse lengths (5–50 cycles) using propidium iodide as an indicator molecule.ResultsWe achieved sonoporation efficiencies ranging from 8 ± 1% to 36 ± 4% (percent of viable cells), as evidenced by flow cytometry. Increasing sonoporation efficiency trended with increasing pulse length and peak negative pressure.ConclusionsWe conclude that PCCAs can be used to induce the sonoporation of cells in vitro, and our results warrant further investigation into the use of PCCAs as extravascular sonoporation agents in vivo.Electronic supplementary materialThe online version of this article (doi:10.1186/s40349-017-0085-z) contains supplementary material, which is available to authorized users.

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“…Since its initial use during BBB opening in small animals19, PCD has been expanded to various types of contrast agents such as microbubbles of various sizes25, various shells26, and nanodroplets27 reporting a positive correlation between BBB opening and cavitation dose. A feedback control mechanism for BBB opening based on ultraharmonics and subharmonics was established in small animals2829.…”

mentioning

confidence: 99%

Characterizing Focused-Ultrasound Mediated Drug Delivery to the Heterogeneous Primate Brain In Vivo with Acoustic Monitoring

Sánchez

Samiotaki

et al. 2016

Sci Rep

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Focused ultrasound with microbubbles has been used to noninvasively and selectively deliver pharmacological agents across the blood-brain barrier (BBB) for treating brain diseases. Acoustic cavitation monitoring could serve as an on-line tool to assess and control the treatment. While it demonstrated a strong correlation in small animals, its translation to primates remains in question due to the anatomically different and highly heterogeneous brain structures with gray and white matteras well as dense vasculature. In addition, the drug delivery efficiency and the BBB opening volume have never been shown to be predictable through cavitation monitoring in primates. This study aimed at determining how cavitation activity is correlated with the amount and concentration of gadolinium delivered through the BBB and its associated delivery efficiency as well as the BBB opening volume in non-human primates. Another important finding entails the effect of heterogeneous brain anatomy and vasculature of a primate brain, i.e., presence of large cerebral vessels, gray and white matter that will also affect the cavitation activity associated with variation of BBB opening in different tissue types, which is not typically observed in small animals. Both these new findings are critical in the primate brain and provide essential information for clinical applications.

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Effects of the microbubble shell physicochemical properties on ultrasound-mediated drug delivery to the brain

Cited by 65 publications

References 41 publications

Microbubble gas volume: A unifying dose parameter in blood-brain barrier opening by focused ultrasound

Microbubble gas volume: A unifying dose parameter in blood-brain barrier opening by focused ultrasound

An evaluation of the sonoporation potential of low-boiling point phase-change ultrasound contrast agents in vitro

Characterizing Focused-Ultrasound Mediated Drug Delivery to the Heterogeneous Primate Brain In Vivo with Acoustic Monitoring

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