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      The impact of vaporized nanoemulsions on ultrasound-mediated ablation

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          Abstract

          Background

          The clinical feasibility of using high-intensity focused ultrasound (HIFU) for ablation of solid tumors is limited by the high acoustic pressures and long treatment times required. The presence of microbubbles during sonication can increase the absorption of acoustic energy and accelerate heating. However, formation of microbubbles within the tumor tissue remains a challenge. Phase-shift nanoemulsions (PSNE) have been developed as a means for producing microbubbles within tumors. PSNE are emulsions of submicron-sized, lipid-coated, and liquid perfluorocarbon droplets that can be vaporized into microbubbles using short (<1 ms), high-amplitude (>5 MPa) acoustic pulses. In this study, the impact of vaporized phase-shift nanoemulsions on the time and acoustic power required for HIFU-mediated thermal lesion formation was investigated in vitro.

          Methods

          PSNE containing dodecafluoropentane were produced with narrow size distributions and mean diameters below 200 nm using a combination of sonication and extrusion. PSNE was dispersed in albumin-containing polyacrylamide gel phantoms for experimental tests. Albumin denatures and becomes opaque at temperatures above 58°C, enabling visual detection of lesions formed from denatured albumin. PSNE were vaporized using a 30-cycle, 3.2-MHz, at an acoustic power of 6.4 W (free-field intensity of 4,586 W/cm 2) pulse from a single-element, focused high-power transducer. The vaporization pulse was immediately followed by a 15-s continuous wave, 3.2-MHz signal to induce ultrasound-mediated heating. Control experiments were conducted using an identical procedure without the vaporization pulse. Lesion formation was detected by acquiring video frames during sonication and post-processing the images for analysis. Broadband emissions from inertial cavitation (IC) were passively detected with a focused, 2-MHz transducer. Temperature measurements were acquired using a needle thermocouple.

          Results

          Bubbles formed at the HIFU focus via PSNE vaporization enhanced HIFU-mediated heating. Broadband emissions detected during HIFU exposure coincided in time with measured accelerated heating, which suggested that IC played an important role in bubble-enhanced heating. In the presence of bubbles, the acoustic power required for the formation of a 9-mm 3 lesion was reduced by 72% and the exposure time required for the onset of albumin denaturation was significantly reduced (by 4 s), provided that the PSNE volume fraction in the polyacrylamide gel was at least 0.008%.

          Conclusions

          The time or acoustic power required for lesion formation in gel phantoms was dramatically reduced by vaporizing PSNE into bubbles. These results suggest that PSNE may improve the efficiency of HIFU-mediated thermal ablation of solid tumors; thus, further investigation is warranted to determine whether bubble-enhanced HIFU may potentially become a viable option for cancer therapy.

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          Most cited references52

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          Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes.

          Incorporation of dioleoyl N-(monomethoxy polyethyleneglycol succinyl)phosphatidylethanolamine (PEG-PE) into large unilamellar liposomes composed of egg phosphatidylcholine:cholesterol (1:1) does not significantly increase the content leakage when the liposomes are exposed to 90% human serum at 37 degrees C, yet the liposomes show a significant increase in the blood circulation half-life (t1/2 = 5 h) as compared to those without PEG-PE(t1/2 less than 30 min). The PEG-PE's activity to prolong the circulation time of liposomes is greater than that of the ganglioside GM1, a well-described glycolipid with this activity. Another amphipathic PEG derivative, PEG stearate, also prolongs the liposome circulation time, although its activity is less than that of GM1. Amphipathic PEGs may be useful for the sustained release and the targeted drug delivery by liposomes.
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            High-intensity focused ultrasound in the treatment of solid tumours.

            Traditionally, surgery has been the only cure for many solid tumours. Technological advances have catalysed a shift from open surgery towards less invasive techniques. Laparoscopic surgery and minimally invasive techniques continue to evolve, but for decades high-intensity focused ultrasound has promised to deliver the ultimate objective - truly non-invasive tumour ablation. Only now, however, with recent improvements in imaging, has this objective finally emerged as a real clinical possibility.
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              Multifunctional nanocarriers.

              Currently used pharmaceutical nanocarriers, such as liposomes, micelles, nanoemulsions, polymeric nanoparticles and many others demonstrate a broad variety of useful properties, such as longevity in the blood allowing for their accumulation in pathological areas with compromised vasculature; specific targeting to certain disease sites due to various targeting ligands attached to the surface of the nanocarriers; enhanced intracellular penetration with the help of surface-attahced cell-penetrating molecules; contrast properties due to the carrier loading with various contrast materials allowing for direct carrier visualization in vivo; stimuli-sensitivity allowing for drug release from the carriers under certain physiological conditions, and others. Some of those pharmaceutical carriers have already made their way into clinic, while others are still under preclinical development. What could be seen much more rare, however, are the pharmaceutical nanocarriers combining several from the listed abilities. Long-circulating immunoliposomes capable of prolonged residence in the blood and specific target recognition represent one of few examples of this kind. At the same time, the enginnering of multifunctional pharmaceutical nanocarriers combinig several useful preoperties in one particle can significantly enhance the efficacy of many therapeutic and diagnostic protocols. This paper considers current status and possible future directions in the emerging area of multifunctional nanocarriers with primary attention on the combination of such properties as longevity, targetability, intracellular penetration and contrast loading.
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                Author and article information

                Contributors
                Journal
                J Ther Ultrasound
                J Ther Ultrasound
                Journal of Therapeutic Ultrasound
                BioMed Central
                2050-5736
                2013
                25 April 2013
                : 1
                : 2
                Affiliations
                [1 ]Department of Mechanical Engineering, Boston University, 110 Cummington Street, Boston, MA, 02215, USA
                Article
                2050-5736-1-2
                10.1186/2050-5736-1-2
                3988615
                24761223
                fa18dcea-bb5e-4a59-8316-45080c935713
                Copyright © 2013 Zhang et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 9 August 2012
                : 13 January 2013
                Categories
                Research

                phase-shift nanoemulsions,vaporized perfluorocarbon droplets,high-intensity focused ultrasound,thermal ablation,polyacrylamide hydrogels

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