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      Optically and acoustically triggerable sub-micron phase-change contrast agents for enhanced photoacoustic and ultrasound imaging

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          Abstract

          We demonstrate a versatile phase-change sub-micron contrast agent providing three modes of contrast enhancement: 1) photoacoustic imaging contrast, 2) ultrasound contrast with optical activation, and 3) ultrasound contrast with acoustic activation. This agent, which we name ‘Cy-droplet’, has the following novel features. It comprises a highly volatile perfluorocarbon for easy versatile activation, and a near-infrared optically absorbing dye chosen to absorb light at a wavelength with good tissue penetration. It is manufactured via a ‘microbubble condensation’ method. The phase-transition of Cy-droplets can be optically triggered by pulsed-laser illumination, inducing photoacoustic signal and forming stable gas bubbles that are visible with echo-ultrasound in situ. Alternatively, Cy-droplets can be converted to microbubble contrast agents upon acoustic activation with clinical ultrasound. Potentially all modes offer extravascular contrast enhancement because of the sub-micron initial size. Such versatility of acoustic and optical ‘triggerability’ can potentially improve multi-modality imaging, molecularly targeted imaging and controlled drug release.

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          Most cited references 45

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          Tumor delivery of macromolecular drugs based on the EPR effect.

          Enhanced permeability and retention (EPR) effect is the physiology-based principal mechanism of tumor accumulation of large molecules and small particles. This specific issue of Advanced Drug Delivery Reviews is summing up multiple data on the EPR effect-based drug design and clinical outcome. In this commentary, the role of the EPR effect in the intratumoral delivery of protein and peptide drugs, macromolecular drugs and drug-loaded long-circulating pharmaceutical nanocarriers is briefly discussed together with some additional opportunities for drug delivery arising from the initial EPR effect-mediated accumulation of drug-containing macromolecular systems in tumors. Copyright © 2010 Elsevier B.V. All rights reserved.
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            Review of Long-Wavelength Optical and NIR Imaging Materials: Contrast Agents, Fluorophores and Multifunctional Nano Carriers.

            The importance of long wavelength and near infra-red (NIR) imaging has dramatically increased due to the desire to perform whole animal and deep tissue imaging. The adoption of NIR imaging is also growing rapidly due to the availability of targeted biological agents for diagnosis and basic medical research that can be imaged in vivo. The wavelength range of 650-1450 nm falls in the region of the spectrum with the lowest absorption in tissue and therefore enables the deepest tissue penetration. This is the wavelength range we focus on with this review. To operate effectively the imaging agents must both be excited and must emit in this long-wavelength window. We review the agents used both for imaging by absorption, scattering, and excitation (such as fluorescence). Imaging agents comprise both aqueous soluble and insoluble species, both organic and inorganic, and unimolecular and supramolecular constructs. The interest in multi-modal imaging, which involves delivery of actives, targeting, and imaging, requires nanocarriers or supramolecular assemblies. Nanoparticles for diagnostics also have advantages in increasing circulation time and increased imaging brightness relative to single molecule imaging agents. This has led to rapid advances in nanocarriers for long-wavelength, NIR imaging.
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              Formulation and acoustic studies of a new phase-shift agent for diagnostic and therapeutic ultrasound.

              Recent efforts in the area of acoustic droplet vaporization with the objective of designing extravascular ultrasound contrast agents has led to the development of stabilized, lipid-encapsulated nanodroplets of the highly volatile compound decafluorobutane (DFB). We developed two methods of generating DFB droplets, the first of which involves condensing DFB gas (boiling point from -1.1 to -2 °C) followed by extrusion with a lipid formulation in HEPES buffer. Acoustic droplet vaporization of micrometer-sized lipid-coated droplets at diagnostic ultrasound frequencies and mechanical indices were confirmed optically. In our second formulation methodology, we demonstrate the formulation of submicrometer-sized lipid-coated nanodroplets based upon condensation of preformed microbubbles containing DFB. The droplets are routinely in the 200-300 nm range and yield microbubbles on the order of 1-5 μm once vaporized, consistent with ideal gas law expansion predictions. The simple and effective nature of this methodology allows for the development of a variety of different formulations that can be used for imaging, drug and gene delivery, and therapy. This study is the first to our knowledge to demonstrate both a method of generating ADV agents by microbubble condensation and formulation of primarily submicrometer droplets of decafluorobutane that remain stable at physiological temperatures. Finally, activation of DFB nanodroplets is demonstrated using pressures within the FDA guidelines for diagnostic imaging, which may minimize the potential for bioeffects in humans. This methodology offers a new means of developing extravascular contrast agents for diagnostic and therapeutic applications. © 2011 American Chemical Society
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                Author and article information

                Contributors
                Journal
                Photoacoustics
                Photoacoustics
                Photoacoustics
                Elsevier
                2213-5979
                11 April 2017
                June 2017
                11 April 2017
                : 6
                : 26-36
                Affiliations
                [a ]Department of Bioengineering, Imperial College London, London, UK
                [b ]Joint Department of Physics and CRUK Cancer Imaging Centre, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, England, UK
                [c ]Department of Chemistry, Imperial College London, London, UK
                [d ]Department of Medical Imaging, University of Arizona, Tucson, AZ, USA
                Author notes
                [* ]Corresponding author. Current address: Department of Bioengineering, Imperial College London, London, SW7 2AZ, UK. mengxing.tang@ 123456imperial.ac.uk
                Article
                S2213-5979(16)30059-3
                10.1016/j.pacs.2017.04.001
                5423321
                © 2017 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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                Research Article

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