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  1. Article ; Online: Nanoparticle delivery enhancement with acoustically activated microbubbles.

    Mullin, Lee B / Phillips, Linsey C / Dayton, Paul A

    IEEE transactions on ultrasonics, ferroelectrics, and frequency control

    2013  Volume 60, Issue 1, Page(s) 65–77

    Abstract: The application of microbubbles and ultrasound to deliver nanoparticle carriers for drug and gene delivery is an area that has expanded greatly in recent years. Under ultrasound exposure, microbubbles can enhance nanoparticle delivery by increasing ... ...

    Abstract The application of microbubbles and ultrasound to deliver nanoparticle carriers for drug and gene delivery is an area that has expanded greatly in recent years. Under ultrasound exposure, microbubbles can enhance nanoparticle delivery by increasing cellular and vascular permeability. In this review, the underlying mechanisms of enhanced nanoparticle delivery with ultrasound and microbubbles and various proposed delivery techniques are discussed. Additionally, types of nanoparticles currently being investigated in preclinical studies, as well as the general limitations and benefits of a microbubble- based approach to nanoparticle delivery, are reviewed.
    MeSH term(s) Animals ; Gene Transfer Techniques ; Mice ; Microbubbles ; Nanoparticles/administration & dosage ; Nanoparticles/chemistry ; Ultrasonics/methods
    Language English
    Publishing date 2013-01-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ISSN 1525-8955
    ISSN (online) 1525-8955
    DOI 10.1109/TUFFC.2013.2538
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: In vitro parameter optimization for spatial control of focused ultrasound ablation when using low boiling point phase-change nanoemulsions.

    Puett, Connor / Phillips, Linsey C / Sheeran, Paul S / Dayton, Paul A

    Journal of therapeutic ultrasound

    2013  Volume 1, Page(s) 16

    Abstract: Background: Phase-shift nanoemulsions (PSNEs) provide cavitation sites when the perfluorocarbon (PFC) nanodroplets (ND) are vaporized to microbubbles by acoustic energy. Their presence lowers the power required to ablate tissue by high-intensity focused ...

    Abstract Background: Phase-shift nanoemulsions (PSNEs) provide cavitation sites when the perfluorocarbon (PFC) nanodroplets (ND) are vaporized to microbubbles by acoustic energy. Their presence lowers the power required to ablate tissue by high-intensity focused ultrasound (HIFU), potentially making it a safer option for a broader range of treatment sites. However, spatial control over the ablation region can be problematic when cavitation is used to enhance heating. This study explored relationships between vaporization, ablation, and the PSNE concentration in vitro to optimize the acoustic intensity and insonation time required for spatially controlled ablation enhancement using a PSNE that included a volatile PFC component.
    Methods: HIFU (continuous wave at 1 MHz; insonation times of 5, 10, 15, and 20 s; cool-down times of 2, 4, and 6 s; peak negative pressures of 2, 3, and 4 MPa) was applied to albumin-acrylamide gels containing PFC agents (1:1 mix of volatile decafluorobutane and more stable dodecafluoropentane at 10(5) to 10(8) PFC ND per milliliter) or agent-free controls. Vaporization fields (microbubble clouds) were imaged by conventional ultrasound, and ablation lesions were measured directly by calipers. Controlled ablation was defined as the production of 'cigar'-shaped lesions corresponding with the acoustic focal zone. This control was considered to be lost when ablation occurred in prefocal vaporization fields having a predominantly 'tadpole' or oblong shape.
    Results: Changes in the vaporization field shape and location occurred on a continuum with increasing PSNE concentration and acoustic intensity. Working with the maximum concentration-intensity combinations resulting in controlled ablation demonstrated a dose-responsive relationship between insonation time and volumes of both the vaporization fields (approximately 20 to 240 mm(3)) and the ablation lesions (1 to 135 mm(3)) within them.
    Conclusions: HIFU ablation was enhanced by this PSNE and could be achieved using intensities ≤650 W/cm(2). Although the ablation lesions were located within much larger microbubble clouds, optimum insonation times and intensities could be selected to achieve an ablation lesion of desired size and location for a given PSNE concentration. This demonstration of controllable enhancement using a PSNE that contained a volatile PFC component is another step toward developing phase-shift nanotechnology as a potential clinical tool to improve HIFU.
    Language English
    Publishing date 2013-09-13
    Publishing country England
    Document type Journal Article
    ZDB-ID 2714301-6
    ISSN 2050-5736
    ISSN 2050-5736
    DOI 10.1186/2050-5736-1-16
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Intravascular ultrasound detection and delivery of molecularly targeted microbubbles for gene delivery.

    Phillips, Linsey C / Klibanov, Alexander L / Wamhoff, Brian R / Hossack, John A

    IEEE transactions on ultrasonics, ferroelectrics, and frequency control

    2012  Volume 59, Issue 7, Page(s) 1596–1601

    Abstract: We are investigating the combination of microbubble-based targeted drug delivery and intravascular ultrasound (IVUS) imaging as a potential therapy to reduce incidence of restenosis following stent placement in atherosclerotic coronary arteries. The goal ...

    Abstract We are investigating the combination of microbubble-based targeted drug delivery and intravascular ultrasound (IVUS) imaging as a potential therapy to reduce incidence of restenosis following stent placement in atherosclerotic coronary arteries. The goal of these studies was to determine whether IVUS could be used to detect targeted microbubbles and enhance drug/gene delivery through targeting. Quiescent vascular smooth muscle cells (SMCs) were stimulated with cytokine IL-1β to induce the inflammatory cell surface marker vascular cell adhesion molecule 1 (VCAM-1). Molecular-targeted (VCAM-1 Ab or IgG control Ab), fluorescent-labeled microbubbles were conjugated with plasmid DNA expressing green fluorescent protein (GFP, pMax-GFP) and exposed to the inflamed SMCs under flow to measure adhesion compared with control microbubbles. Gene delivery was performed using a modified IVUS catheter to generate 1.5-MHz ultrasound at 200 kPa. Detection of adherent microbubbles to inflamed SMCs in culture and flow chambers was measured using an IVUS catheter and scanner. VCAM-1-targeted microbubbles enhanced adhesion to inflamed SMCs 100-fold over nontargeted microbubbles. Compared with noninflamed SMCs, VCAM-1-targeted microbubbles exhibited a 7.9-fold increase in adhesion to IL-1β-treated cells. Targeted microbubbles resulted in a 5.5-fold increase in plasmid DNA transfection over nontargeted microbubbles in conjunction with a focused 2.54-cm (1-in) diameter 1-MHz transducer and also enhanced transfection by the modified IVUS transducer at 1.5 MHz. Targeted microbubbles (at a density of 3 × 10⁴ microbubbles/mm²) increased IVUS image intensity 13.2 dB over non-microbubble-coated surfaces. Rupture of microbubbles from the modified IVUS transducer resulted in a 53% reduction in image intensity. Taken together, these results indicate that IVUS may be used to detect targeted microbubbles to inflamed vasculature and subsequently deliver a gene/drug locally.
    MeSH term(s) Animals ; Cells, Cultured ; DNA/administration & dosage ; DNA/genetics ; Mice ; Microbubbles/therapeutic use ; Muscle, Smooth, Vascular/diagnostic imaging ; Muscle, Smooth, Vascular/physiology ; Transfection/methods ; Ultrasonography, Interventional/methods
    Chemical Substances DNA (9007-49-2)
    Language English
    Publishing date 2012-07
    Publishing country United States
    Document type Letter ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 1525-8955
    ISSN (online) 1525-8955
    DOI 10.1109/TUFFC.2012.2359
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Erratum: Phase-shift perfluorocarbon agents enhance high intensity focused ultrasound thermal delivery with reduced near-field heating [J. Acoust. Soc. Am. 134, 1473-1482 (2013)].

    Phillips, Linsey C / Puett, Connor / Sheeran, Paul S / Dayton, Paul A / Wilson Miller, G / Matsunaga, Terry O

    The Journal of the Acoustical Society of America

    2013  Volume 134, Issue 6, Page(s) 4575

    Language English
    Publishing date 2013-12
    Publishing country United States
    Document type Journal Article
    ZDB-ID 219231-7
    ISSN 1520-8524 ; 0001-4966
    ISSN (online) 1520-8524
    ISSN 0001-4966
    DOI 10.1121/1.4828830
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Localized ultrasound enhances delivery of rapamycin from microbubbles to prevent smooth muscle proliferation.

    Phillips, Linsey C / Klibanov, Alexander L / Wamhoff, Brian R / Hossack, John A

    Journal of controlled release : official journal of the Controlled Release Society

    2011  Volume 154, Issue 1, Page(s) 42–49

    Abstract: Microbubble contrast agents have been shown to enhance reagent delivery when activated by ultrasound. We hypothesized that ultrasound would enhance delivery of rapamycin, an antiproliferative agent, from the shell of microbubbles, thus reducing ... ...

    Abstract Microbubble contrast agents have been shown to enhance reagent delivery when activated by ultrasound. We hypothesized that ultrasound would enhance delivery of rapamycin, an antiproliferative agent, from the shell of microbubbles, thus reducing proliferation of vascular smooth muscle cells. Our objective was to determine optimal ultrasound parameters that maximized therapeutic efficacy, maintained cell adherence, and minimized the drug exposure time. In vitro assays determined that ultrasound (1 MHz, 0.5% duty cycle) is required to successfully deliver rapamycin from microbubbles and reduce proliferation. Co-injection of rapamycin with control microbubbles did not result in a reduction in proliferation. Successful reduction in proliferation (>50%) required pulses at least 10 cycles in length and at least 300 kPa peak negative pressure at which point 90% of cells remained adherent. The anti-proliferative effect was also localized within a 6mm wide zone by focusing the ultrasound beam.
    MeSH term(s) Animals ; Antibiotics, Antineoplastic/administration & dosage ; Antibiotics, Antineoplastic/adverse effects ; Cell Proliferation/drug effects ; Cells, Cultured ; Drug Carriers/chemistry ; Drug Compounding ; Endothelial Cells/drug effects ; Endothelial Cells/pathology ; Microbubbles ; Microscopy, Phase-Contrast ; Muscle, Smooth, Vascular/cytology ; Muscle, Smooth, Vascular/drug effects ; Muscle, Smooth, Vascular/pathology ; Phonophoresis ; Rats ; Sirolimus/administration & dosage ; Sirolimus/adverse effects ; Time Factors
    Chemical Substances Antibiotics, Antineoplastic ; Drug Carriers ; Sirolimus (W36ZG6FT64)
    Language English
    Publishing date 2011-04-23
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 632533-6
    ISSN 1873-4995 ; 0168-3659
    ISSN (online) 1873-4995
    ISSN 0168-3659
    DOI 10.1016/j.jconrel.2011.04.020
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: The implementation of acoustic angiography for microvascular and angiogenesis imaging.

    Dayton, Paul A / Gessner, Ryan C / Phillips, Linsey / Shelton, Sarah E / Heath Martin, K / Lee, Mike / Foster, F Stuart

    Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference

    2015  Volume 2014, Page(s) 4283–4285

    Abstract: Recently, it has been demonstrated that through the use of contrast agents and multi-frequency transducer technology, high resolution and high signal to noise ultrasound images can be obtained which illustrate microvascular structure in unprecedented ... ...

    Abstract Recently, it has been demonstrated that through the use of contrast agents and multi-frequency transducer technology, high resolution and high signal to noise ultrasound images can be obtained which illustrate microvascular structure in unprecedented detail for an ultrasound modality. The enabling technology is ultrasound transducers which are fabricated with elements which can excite microbubble contrast agents near resonance and detect their broadband harmonics at a much higher bandwidth (several times the fundamental frequency). The resulting images contain very little background from tissue scattering and thus provide high contrast, and can have a resolution on the order of 130 microns with an appropriate high frequency receiving element. Because microbubbles are strictly an intravascular agent, this approach enables visualization of microvascular morphology with unique clarity, providing insight into angiogenesis associated with tumor development.
    MeSH term(s) Angiography/methods ; Animals ; Contrast Media ; Fibrosarcoma/blood supply ; Fibrosarcoma/diagnostic imaging ; Humans ; Mice ; Microbubbles ; Microvessels/diagnostic imaging ; Neovascularization, Pathologic/diagnostic imaging ; Rats ; Signal-To-Noise Ratio ; Transducers ; Ultrasonography
    Chemical Substances Contrast Media
    Language English
    Publishing date 2015-01-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2694-0604
    ISSN (online) 2694-0604
    DOI 10.1109/EMBC.2014.6944571
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Targeted gene transfection from microbubbles into vascular smooth muscle cells using focused, ultrasound-mediated delivery.

    Phillips, Linsey C / Klibanov, Alexander L / Wamhoff, Brian R / Hossack, John A

    Ultrasound in medicine & biology

    2010  Volume 36, Issue 9, Page(s) 1470–1480

    Abstract: We investigated a method for gene delivery to vascular smooth muscle cells using ultrasound triggered delivery of plasmid DNA from electrostatically coupled cationic microbubbles. Microbubbles carrying reporter plasmid DNA were acoustically ruptured in ... ...

    Abstract We investigated a method for gene delivery to vascular smooth muscle cells using ultrasound triggered delivery of plasmid DNA from electrostatically coupled cationic microbubbles. Microbubbles carrying reporter plasmid DNA were acoustically ruptured in the vicinity of smooth muscle cells in vitro under a range of acoustic pressures (0 to 950 kPa) and pulse durations (0 to 100 cycles). No effect on gene transfection or viability was observed from application of microbubbles, DNA or ultrasound alone. Microbubbles in combination with ultrasound (500-kPa, 1-MHz, 50-cycle bursts at a pulse repetition frequency [PRF] of 100 Hz) significantly reduced viability both with DNA (53 +/- 27%) and without (19 +/- 8%). Maximal gene transfection ( approximately 1% of cells) occurred using 50-cycle, 1-MHz pulses at 300 kPa, which resulted in 40% viability of cells. We demonstrated that we can locally deliver DNA to vascular smooth muscle cells in vitro using microbubble carriers and focused ultrasound.
    MeSH term(s) Animals ; Cells, Cultured ; Drug Delivery Systems ; Gene Transfer Techniques ; Genetic Vectors ; Microbubbles ; Muscle, Smooth, Vascular/diagnostic imaging ; Plasmids ; Rats ; Ultrasonography
    Language English
    Publishing date 2010-08-25
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 186150-5
    ISSN 1879-291X ; 0301-5629
    ISSN (online) 1879-291X
    ISSN 0301-5629
    DOI 10.1016/j.ultrasmedbio.2010.06.010
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Localized ultrasound enhances delivery of rapamycin from microbubbles to prevent smooth muscle proliferation

    Phillips, Linsey C / Klibanov, Alexander L / Wamhoff, Brian R / Hossack, John A

    Journal of controlled release. 2011 Aug. 25, v. 154, no. 1

    2011  

    Abstract: Microbubble contrast agents have been shown to enhance reagent delivery when activated by ultrasound. We hypothesized that ultrasound would enhance delivery of rapamycin, an antiproliferative agent, from the shell of microbubbles, thus reducing ... ...

    Abstract Microbubble contrast agents have been shown to enhance reagent delivery when activated by ultrasound. We hypothesized that ultrasound would enhance delivery of rapamycin, an antiproliferative agent, from the shell of microbubbles, thus reducing proliferation of vascular smooth muscle cells. Our objective was to determine optimal ultrasound parameters that maximized therapeutic efficacy, maintained cell adherence, and minimized the drug exposure time. In vitro assays determined that ultrasound (1MHz, 0.5% duty cycle) is required to successfully deliver rapamycin from microbubbles and reduce proliferation. Co-injection of rapamycin with control microbubbles did not result in a reduction in proliferation. Successful reduction in proliferation (>50%) required pulses at least 10cycles in length and at least 300kPa peak negative pressure at which point 90% of cells remained adherent. The anti-proliferative effect was also localized within a 6mm wide zone by focusing the ultrasound beam.
    Keywords drugs ; exposure duration ; in vitro studies ; microbubbles ; myocytes ; smooth muscle ; ultrasonics
    Language English
    Dates of publication 2011-0825
    Size p. 42-49.
    Publishing place Elsevier B.V.
    Document type Article
    ZDB-ID 632533-6
    ISSN 1873-4995 ; 0168-3659
    ISSN (online) 1873-4995
    ISSN 0168-3659
    DOI 10.1016/j.jconrel.2011.04.020
    Database NAL-Catalogue (AGRICOLA)

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  9. Article ; Online: Focused ultrasound-mediated drug delivery from microbubbles reduces drug dose necessary for therapeutic effect on neointima formation--brief report.

    Phillips, Linsey C / Dhanaliwala, Ali H / Klibanov, Alexander L / Hossack, John A / Wamhoff, Brian R

    Arteriosclerosis, thrombosis, and vascular biology

    2011  Volume 31, Issue 12, Page(s) 2853–2855

    Abstract: Objective: We hypothesized that (1) neointima formation in a rat carotid balloon injury model could be reduced in vivo following targeted ultrasound delivery of rapamycin microbubbles (RMBs), and (2) the addition of dual-mode ultrasound decreases the ... ...

    Abstract Objective: We hypothesized that (1) neointima formation in a rat carotid balloon injury model could be reduced in vivo following targeted ultrasound delivery of rapamycin microbubbles (RMBs), and (2) the addition of dual-mode ultrasound decreases the total amount of drug needed to reduce neointima formation.
    Methods and results: Balloon injury was performed in rat carotids to induce neointima formation. High or low doses of RMBs were injected intravenously and ruptured at the site of injury with ultrasound. Compared with nontreated injured arteries, neointima formation was reduced by 0% and 35.9% with 10(8) RMBs and by 28.7% and 34.9% in arteries treated with 10(9) RMBs with and without ultrasound, respectively.
    Conclusions: Without ultrasound, 10-fold higher concentrations of RMBs were needed to reduce neointima formation by at least 28%, whereas 10(8) RMBs combined with ultrasound were sufficient to achieve the same therapeutic effect, demonstrating that this technology may have promise for localized potent drug therapy.
    MeSH term(s) Animals ; Carotid Arteries/pathology ; Carotid Artery Injuries/drug therapy ; Carotid Artery Injuries/etiology ; Carotid Artery Injuries/pathology ; Catheterization/adverse effects ; Cell Division/drug effects ; Dose-Response Relationship, Drug ; Drug Delivery Systems/methods ; Microbubbles/therapeutic use ; Models, Animal ; Neointima/drug therapy ; Neointima/etiology ; Neointima/prevention & control ; Rats ; Rats, Sprague-Dawley ; Sirolimus/administration & dosage ; Sirolimus/pharmacology ; Sirolimus/therapeutic use ; Ultrasonics/methods
    Chemical Substances Sirolimus (W36ZG6FT64)
    Language English
    Publishing date 2011-09-29
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Validation Study
    ZDB-ID 1221433-4
    ISSN 1524-4636 ; 1079-5642
    ISSN (online) 1524-4636
    ISSN 1079-5642
    DOI 10.1161/ATVBAHA.111.238170
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Microbubble-mediated intravascular ultrasound imaging and drug delivery.

    Dixon, Adam J / Kilroy, Joseph P / Dhanaliwala, Ali H / Chen, Johnny L / Phillips, Linsey C / Ragosta, Michael / Klibanov, Alexander L / Wamhoff, Brian R / Hossack, John A

    IEEE transactions on ultrasonics, ferroelectrics, and frequency control

    2015  Volume 62, Issue 9, Page(s) 1674–1685

    Abstract: Intravascular ultrasound (IVUS) provides radiation-free, real-time imaging and assessment of atherosclerotic disease in terms of anatomical, functional, and molecular composition. The primary clinical applications of IVUS imaging include assessment of ... ...

    Abstract Intravascular ultrasound (IVUS) provides radiation-free, real-time imaging and assessment of atherosclerotic disease in terms of anatomical, functional, and molecular composition. The primary clinical applications of IVUS imaging include assessment of luminal plaque volume and real-time image guidance for stent placement. When paired with microbubble contrast agents, IVUS technology may be extended to provide nonlinear imaging, molecular imaging, and therapeutic delivery modes. In this review, we discuss the development of emerging imaging and therapeutic applications that are enabled by the combination of IVUS imaging technology and microbubble contrast agents.
    MeSH term(s) Animals ; Carotid Arteries/diagnostic imaging ; Drug Delivery Systems/methods ; Humans ; Microbubbles ; Rabbits ; Swine ; Ultrasonography, Interventional/methods
    Language English
    Publishing date 2015-11-13
    Publishing country United States
    Document type Journal Article
    ISSN 1525-8955
    ISSN (online) 1525-8955
    DOI 10.1109/TUFFC.2015.007143
    Database MEDical Literature Analysis and Retrieval System OnLINE

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