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

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          Abstract

          Background

          Phase-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.

          Methods

          Parameters 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.

          Results

          We 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.

          Conclusions

          We 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 material

          The 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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          Most cited references27

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          Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment.

          Novel anti-neoplastic agents such as gene targeting vectors and encapsulated carriers are quite large (approximately 100-300 nm in diameter). An understanding of the functional size and physiological regulation of transvascular pathways is necessary to optimize delivery of these agents. Here we analyze the functional limits of transvascular transport and its modulation by the microenvironment. One human and five murine tumors including mammary and colorectal carcinomas, hepatoma, glioma, and sarcoma were implanted in the dorsal skin-fold chamber or cranial window, and the pore cutoff size, a functional measure of transvascular gap size, was determined. The microenvironment was modulated: (i) spatially, by growing tumors in subcutaneous or cranial locations and (ii) temporally, by inducing vascular regression in hormone-dependent tumors. Tumors grown subcutaneously exhibited a characteristic pore cutoff size ranging from 200 nm to 1.2 microm. This pore cutoff size was reduced in tumors grown in the cranium or in regressing tumors after hormone withdrawal. Vessels induced in basic fibroblast growth factor-containing gels had a pore cutoff size of 200 nm. Albumin permeability was independent of pore cutoff size. These results have three major implications for the delivery of therapeutic agents: (i) delivery may be less efficient in cranial tumors than in subcutaneous tumors, (ii) delivery may be reduced during tumor regression induced by hormonal ablation, and (iii) permeability to a molecule is independent of pore cutoff size as long as the diameter of the molecule is much less than the pore diameter.
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            Understanding ultrasound induced sonoporation: definitions and underlying mechanisms.

            In the past two decades, research has underlined the potential of ultrasound and microbubbles to enhance drug delivery. However, there is less consensus on the biophysical and biological mechanisms leading to this enhanced delivery. Sonoporation, i.e. the formation of temporary pores in the cell membrane, as well as enhanced endocytosis is reported. Because of the variety of ultrasound settings used and corresponding microbubble behavior, a clear overview is missing. Therefore, in this review, the mechanisms contributing to sonoporation are categorized according to three ultrasound settings: i) low intensity ultrasound leading to stable cavitation of microbubbles, ii) high intensity ultrasound leading to inertial cavitation with microbubble collapse, and iii) ultrasound application in the absence of microbubbles. Using low intensity ultrasound, the endocytotic uptake of several drugs could be stimulated, while short but intense ultrasound pulses can be applied to induce pore formation and the direct cytoplasmic uptake of drugs. Ultrasound intensities may be adapted to create pore sizes correlating with drug size. Small molecules are able to diffuse passively through small pores created by low intensity ultrasound treatment. However, delivery of larger drugs such as nanoparticles and gene complexes, will require higher ultrasound intensities in order to allow direct cytoplasmic entry. Copyright © 2013 Elsevier B.V. All rights reserved.
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              Sonoporation from jetting cavitation bubbles.

              The fluid dynamic interaction of cavitation bubbles with adherent cells on a substrate is experimentally investigated. We find that the nonspherical collapse of bubbles near to the boundary is responsible for cell detachment. High-speed photography reveals that a wall bounded flow leads to the detachment of cells. Cells at the edge of the circular area of detachment are found to be permanently porated, whereas cells at some distance from the detachment area undergo viable cell membrane poration (sonoporation). The wall flow field leading to cell detachment is modeled with a self-similar solution for a wall jet, together with a kinetic ansatz of adhesive bond rupture. The self-similar solution for the delta-type wall jet compares very well with the full solution of the Navier-Stokes equation for a jet of finite thickness. Apart from annular sites of sonoporation we also find more homogenous patterns of molecule delivery with no cell detachment.
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                Author and article information

                Contributors
                sfix@email.unc.edu
                anthony.novell@univ-tours.fr
                yyun@ncat.edu
                padayton@email.unc.edu
                carena3@elon.edu
                Journal
                J Ther Ultrasound
                J Ther Ultrasound
                Journal of Therapeutic Ultrasound
                BioMed Central (London )
                2050-5736
                24 January 2017
                24 January 2017
                2017
                : 5
                : 7
                Affiliations
                [1 ]ISNI 0000000122483208, GRID grid.10698.36, Eshelman School of Pharmacy, , University of North Carolina Chapel Hill, ; Chapel Hill, NC USA
                [2 ]ISNI 0000000122483208, GRID grid.10698.36, Joint Department of Biomedical Engineering, , University of North Carolina Chapel Hill and North Carolina State University, ; Chapel Hill, NC USA
                [3 ]ISNI 0000 0001 0287 4439, GRID grid.261037.1, FIT BEST Laboratory, Chemical, Biological and Bioengineering Department, , North Carolina A&T State University, ; Greensboro, NC USA
                [4 ]ISNI 0000 0001 0686 4414, GRID grid.255496.9, Laboratory for Therapeutic Directed Energy, Department of Physics, , Elon University, ; Elon, NC USA
                Article
                85
                10.1186/s40349-017-0085-z
                5260003
                02dd8774-ac36-407d-857d-8d563ffb4c21
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 9 July 2016
                : 6 January 2017
                Funding
                Funded by: North Carolina Translational and Clinical Sciences Institute
                Award ID: #4DR21402
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000057, National Institute of General Medical Sciences;
                Award ID: #K12-GM000678
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2017

                sonoporation,ultrasound,drug delivery,acoustic droplet vaporization,nanodroplet

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