State-of-the-art materials for ultrasound-triggered drug delivery.

Ultrasound is a unique and exciting theranostic modality that can be used to track drug carriers, trigger drug release and improve drug deposition with high spatial precision. In this review, we briefly describe the mechanisms of interaction between drug carriers and ultrasound waves, including cavitation, streaming and hyperthermia, and how those interactions can promote drug release and tissue uptake. We then discuss the rational design of some state-of-the-art materials for ultrasound-triggered drug delivery and review recent progress for each drug carrier, focusing on the delivery of chemotherapeutic agents such as doxorubicin. These materials include nanocarrier formulations, such as liposomes and micelles, designed specifically for ultrasound-triggered drug release, as well as microbubbles, microbubble-nanocarrier hybrids, microbubble-seeded hydrogels and phase-change agents.

[1]  C. Arvanitis,et al.  Cavitation-enhanced extravasation for drug delivery. , 2011, Ultrasound in medicine & biology.

[2]  R V Shohet,et al.  Targeting of VEGF-mediated angiogenesis to rat myocardium using ultrasonic destruction of microbubbles , 2005, Gene Therapy.

[3]  T. Leighton The Acoustic Bubble , 1994 .

[4]  E. Stride,et al.  Understanding the Structure and Mechanism of Formation of a New Magnetic Microbubble Formulation , 2012, Theranostics.

[5]  Mark A. Borden,et al.  Lung Surfactant Microbubbles Increase Lipophilic Drug Payload for Ultrasound-Targeted Delivery , 2013, Theranostics.

[6]  James L. Thomas,et al.  Factors affecting responsivity of unilamellar liposomes to 20 kHz ultrasound. , 2004, Langmuir : the ACS journal of surfaces and colloids.

[7]  K. Tachibana,et al.  Enhanced cytotoxic effect of Ara-C by low intensity ultrasound to HL-60 cells. , 2000, Cancer letters.

[8]  C. Lafon,et al.  In vivo monitoring of liposomal release in tumours following ultrasound stimulation. , 2013, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[9]  Douglas A Christensen,et al.  Ultrasonic release of doxorubicin from Pluronic P105 micelles stabilized with an interpenetrating network of N,N-diethylacrylamide. , 2002, Journal of controlled release : official journal of the Controlled Release Society.

[10]  P. Dayton,et al.  Microbubble tunneling in gel phantoms. , 2009, The Journal of the Acoustical Society of America.

[11]  Junru Wu,et al.  Ultrasound, cavitation bubbles and their interaction with cells. , 2008, Advanced drug delivery reviews.

[12]  R. Langer,et al.  A microcomposite hydrogel for repeated on-demand ultrasound-triggered drug delivery. , 2010, Biomaterials.

[13]  N. Rapoport Stabilization and activation of Pluronic micelles for tumor-targeted drug delivery , 1999 .

[14]  Xuegong Shi,et al.  Quantitative investigation of acoustic streaming in blood. , 2002, The Journal of the Acoustical Society of America.

[15]  Hairong Zheng,et al.  Dynamic microPET imaging of ultrasound contrast agents and lipid delivery. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[16]  Paul A Dayton,et al.  The magnitude of radiation force on ultrasound contrast agents. , 2002, The Journal of the Acoustical Society of America.

[17]  G. G. Stokes "J." , 1890, The New Yale Book of Quotations.

[18]  J. Hubbell,et al.  Investigating the acoustic release of doxorubicin from targeted micelles. , 2013, Colloids and surfaces. B, Biointerfaces.

[19]  C. Lafon,et al.  Validation of an acoustic cavitation dose with hydroxyl radical production generated by inertial cavitation in pulsed mode: application to in vitro drug release from liposomes. , 2011, Ultrasonics sonochemistry.

[20]  R L Magin,et al.  Liposomes and local hyperthermia: selective delivery of methotrexate to heated tumors. , 1979, Science.

[21]  R. Brasseur,et al.  A comparative model membrane study on structural effects of membrane-active positively charged anti-tumor drugs. , 1988, Biochimica et biophysica acta.

[22]  Joseph Kost,et al.  Controlling liposomal drug release with low frequency ultrasound: mechanism and feasibility. , 2007, Langmuir : the ACS journal of surfaces and colloids.

[23]  Francis A. Duck,et al.  A Review of Therapeutic Ultrasound: Biophysical Effects , 2010 .

[24]  Hesheng Xia,et al.  High-frequency ultrasound-responsive block copolymer micelle. , 2009, Langmuir : the ACS journal of surfaces and colloids.

[25]  J. G. Abbott,et al.  Rationale and derivation of MI and TI--a review. , 1999, Ultrasound in medicine & biology.

[26]  R. Lappalainen,et al.  Monitoring of swelling of hydrophilic polymer matrix tablets by ultrasound techniques. , 2011, International journal of pharmaceutics.

[27]  Joe Barfett,et al.  Encapsulated calcium carbonate suspensions: A drug delivery vehicle sensitive to ultrasound disruption , 2006, McGill journal of medicine : MJM : an international forum for the advancement of medical sciences by students.

[28]  David M Belnap,et al.  Ultrasound sensitive eLiposomes containing doxorubicin for drug targeting therapy. , 2014, Nanomedicine : nanotechnology, biology, and medicine.

[29]  Xin Liu,et al.  Ultrasound-mediated tumor imaging and nanotherapy using drug loaded, block copolymer stabilized perfluorocarbon nanoemulsions. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[30]  K. Miyake,et al.  Plasma membrane disruption underlies injury of the corneal endothelium by ultrasound. , 1999, Experimental eye research.

[31]  Mark A. Borden,et al.  Advances in Ultrasound Mediated Gene Therapy Using Microbubble Contrast Agents , 2012, Theranostics.

[32]  Sadik Esener,et al.  Acoustic droplet vaporization and propulsion of perfluorocarbon-loaded microbullets for targeted tissue penetration and deformation. , 2012, Angewandte Chemie.

[33]  D. Christensen,et al.  The role of cavitation in acoustically activated drug delivery. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[34]  Jun Fang,et al.  The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. , 2011, Advanced drug delivery reviews.

[35]  P. Pagel,et al.  Potential Adverse Ultrasound-related Biological Effects: A Critical Review , 2011, Anesthesiology.

[36]  G. Winter,et al.  New doxorubicin-loaded phospholipid microbubbles for targeted tumor therapy: in-vivo characterization. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[37]  N. Rapoport Ultrasound-mediated micellar drug delivery , 2012, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[38]  Meng-Xing Tang,et al.  Theoretical and experimental characterisation of magnetic microbubbles. , 2012, Ultrasound in medicine & biology.

[39]  A. Babataheri,et al.  Ultrasound internal tattooing. , 2011, Medical physics.

[40]  F. Bordi,et al.  Ultrasound well below the intensity threshold of cavitation can promote efficient uptake of small drug model molecules in fibroblast cells , 2013, Drug delivery.

[41]  Paul L. Carson,et al.  Delivery of Water-Soluble Drugs Using Acoustically Triggered Perfluorocarbon Double Emulsions , 2010, Pharmaceutical Research.

[42]  Paul S. Sheeran,et al.  Phase-shift perfluorocarbon agents enhance high intensity focused ultrasound thermal delivery with reduced near-field heating. , 2013, The Journal of the Acoustical Society of America.

[43]  Hairong Zheng,et al.  Acoustically-active microbubbles conjugated to liposomes: characterization of a proposed drug delivery vehicle. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[44]  Paul A Dayton,et al.  Formulation and acoustic studies of a new phase-shift agent for diagnostic and therapeutic ultrasound. , 2011, Langmuir : the ACS journal of surfaces and colloids.

[45]  Weixiang Song,et al.  Doxorubicin loaded superparamagnetic PLGA-iron oxide multifunctional microbubbles for dual-mode US/MR imaging and therapy of metastasis in lymph nodes. , 2013, Biomaterials.

[46]  Suzanne M D'Addio,et al.  Controlling drug nanoparticle formation by rapid precipitation. , 2011, Advanced drug delivery reviews.

[47]  P. Dayton,et al.  A method for radiation-force localized drug delivery using gas-filled lipospheres , 2004, IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control.

[48]  J. R. Tacker,et al.  Delivery of antitumor drug to bladder cancer by use of phase transition liposomes and hyperthermia. , 1982, The Journal of urology.

[49]  S. Wrenn,et al.  Coencapsulation of lipid microbubbles within polymer microcapsules for contrast applications , 2011 .

[50]  Lawrence A. Crum,et al.  Nucleation and stabilization of microbubbles in liquids , 1982 .

[51]  Ari Partanen,et al.  Reduction of peak acoustic pressure and shaping of heated region by use of multifoci sonications in MR-guided high-intensity focused ultrasound mediated mild hyperthermia. , 2012, Medical physics.

[52]  H. Azhari Basics of Biomedical Ultrasound for Engineers , 2010 .

[53]  J. Mari,et al.  Feasibility study of cavitation-induced liposomal doxorubicin release in an AT2 Dunning rat tumor model , 2012, Journal of drug targeting.

[54]  Kinam Park,et al.  Polymeric micelles and alternative nanonized delivery vehicles for poorly soluble drugs. , 2013, International journal of pharmaceutics.

[55]  W. Pitt,et al.  Ultrasonic activated drug delivery from Pluronic P-105 micelles. , 1997, Cancer letters.

[56]  G. Haar,et al.  The effect of ultrasound on the cytoxicity of adriamycin , 1990 .

[57]  M. Mokhtari-Dizaji,et al.  Effect of local dual frequency sonication on drug distribution from polymeric nanomicelles. , 2011, Ultrasonics sonochemistry.

[58]  N. Rapoport,et al.  Phase-shift, stimuli-responsive perfluorocarbon nanodroplets for drug delivery to cancer. , 2012, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[59]  Koichi Ogawa,et al.  Induction of cell-membrane porosity by ultrasound , 1999, The Lancet.

[60]  Oliver D Kripfgans,et al.  Acoustic droplet vaporization for enhancement of thermal ablation by high intensity focused ultrasound. , 2011, Academic radiology.

[61]  D. Christensen,et al.  Drug delivery in pluronic micelles: effect of high-frequency ultrasound on drug release from micelles and intracellular uptake. , 2002, Journal of controlled release : official journal of the Controlled Release Society.

[62]  Claudia Kuntner,et al.  Guidance for Methods Descriptions Used in Preclinical Imaging Papers , 2013, Molecular imaging.

[63]  M. Wheatley,et al.  Development and optimization of a doxorubicin loaded poly(lactic acid) contrast agent for ultrasound directed drug delivery. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[64]  Susan M. Schultz,et al.  Disposition of ultrasound sensitive polymeric drug carrier in a rat hepatocellular carcinoma model. , 2011, Academic radiology.

[65]  Zhong-gao Gao,et al.  Multifunctional nanoparticles for combining ultrasonic tumor imaging and targeted chemotherapy. , 2007, Journal of the National Cancer Institute.

[66]  Georg Schmitz,et al.  Bubble dynamics involved in ultrasonic imaging , 2006, Expert review of molecular diagnostics.

[67]  R. Deckers,et al.  Evidence for a new mechanism behind HIFU-triggered release from liposomes. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[68]  H. Stahlberg,et al.  An optical and microPET assessment of thermally-sensitive liposome biodistribution in the Met-1 tumor model: Importance of formulation. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[69]  Jonathan A. Kopechek,et al.  Accumulation of phase-shift nanoemulsions to enhance MR-guided ultrasound-mediated tumor ablation in vivo. , 2013, Journal of healthcare engineering.

[70]  J. Fowlkes,et al.  Treatment of murine tumors using acoustic droplet vaporization-enhanced high intensity focused ultrasound , 2013, Physics in medicine and biology.

[71]  角田 聖 Sonoporation using microbubble BR14 promotes pDNA/siRNA transduction to murine heart , 2006 .

[72]  W. Pitt,et al.  Ultrasonic drug delivery – a general review , 2004, Expert opinion on drug delivery.

[73]  K Hynynen,et al.  Ultrasound technology for hyperthermia. , 1999, Ultrasound in medicine & biology.

[74]  Katherine W Ferrara,et al.  Therapeutic effects of paclitaxel-containing ultrasound contrast agents. , 2006, Ultrasound in medicine & biology.

[75]  A. Gabizon Pegylated Liposomal Doxorubicin: Metamorphosis of an Old Drug into a New Form of Chemotherapy , 2001, Cancer investigation.

[76]  J. Kost,et al.  Ultrasound, liposomes, and drug delivery: principles for using ultrasound to control the release of drugs from liposomes. , 2009, Chemistry and physics of lipids.

[77]  Ronald A. Roy,et al.  Applications of Acoustics and Cavitation to Noninvasive Therapy and Drug Delivery , 2008 .

[78]  P. Cullis,et al.  Liposomal drug delivery systems: from concept to clinical applications. , 2013, Advanced drug delivery reviews.

[79]  HONG CHEN,et al.  Preliminary observations on the spatial correlation between short-burst microbubble oscillations and vascular bioeffects. , 2012, Ultrasound in medicine & biology.

[80]  Paul S. Sheeran,et al.  Design of ultrasonically-activatable nanoparticles using low boiling point perfluorocarbons. , 2012, Biomaterials.

[81]  Miss A.O. Penney (b) , 1974, The New Yale Book of Quotations.

[82]  S. Libutti,et al.  Pulsed-High Intensity Focused Ultrasound and Low Temperature–Sensitive Liposomes for Enhanced Targeted Drug Delivery and Antitumor Effect , 2007, Clinical Cancer Research.

[83]  W. Pitt,et al.  The use of ultrasound and micelles in cancer treatment. , 2008, Journal of nanoscience and nanotechnology.

[84]  M. Brandl,et al.  Distearoylphosphatidylethanolamine-based liposomes for ultrasound-mediated drug delivery. , 2010, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[85]  Ying-zheng Zhao,et al.  Preparation and antitumor activity of bFGF-mediated active targeting doxorubicin microbubbles , 2013, Drug development and industrial pharmacy.

[86]  Eleanor Stride,et al.  Magnetic targeting and ultrasound mediated drug delivery: Benefits, limitations and combination , 2012, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[87]  B. de Kruijff,et al.  Comparable interaction of doxorubicin with various acidic phospholipids results in changes of lipid order and dynamics. , 1990, Biochimica et biophysica acta.

[88]  Douglas L. Miller,et al.  Transfection of a reporter plasmid into cultured cells by sonoporation in vitro. , 1997, Ultrasound in medicine & biology.

[89]  G. Hahn,et al.  Hyperthermia induces doxorubicin release from long-circulating liposomes and enhances their anti-tumor efficacy. , 1994, International journal of radiation oncology, biology, physics.

[90]  Jacob D. Dove,et al.  Enhanced photoacoustic response with plasmonic nanoparticle-templated microbubbles , 2013 .

[91]  Bruno Quesson,et al.  Magnetic resonance temperature imaging for guidance of thermotherapy , 2000, Journal of magnetic resonance imaging : JMRI.

[92]  T. Yen,et al.  SPIO-conjugated, doxorubicin-loaded microbubbles for concurrent MRI and focused-ultrasound enhanced brain-tumor drug delivery. , 2013, Biomaterials.

[93]  Diane Dalecki,et al.  Mechanical bioeffects of ultrasound. , 2004, Annual review of biomedical engineering.

[94]  S. Shoham,et al.  Intramembrane cavitation as a unifying mechanism for ultrasound-induced bioeffects , 2011, Proceedings of the National Academy of Sciences.

[95]  Paul A. Dayton,et al.  Optical observation of lipid- and polymer-shelled ultrasound microbubble contrast agents , 2004 .

[96]  John R. Eisenbrey,et al.  Delivery of Encapsulated Doxorubicin by Ultrasound-Mediated Size Reduction of Drug-Loaded Polymer Contrast Agents , 2010, IEEE Transactions on Biomedical Engineering.

[97]  M Halliwell A tutorial on ultrasonic physics and imaging techniques , 2010, Proceedings of the Institution of Mechanical Engineers. Part H, Journal of engineering in medicine.

[98]  Timothy J. Mason,et al.  The use of a microbubble agent to enhance rabbit liver destruction using high intensity focused ultrasound , 2006 .

[99]  N. Rapoport,et al.  Doxorubicin as a molecular nanotheranostic agent: effect of doxorubicin encapsulation in micelles or nanoemulsions on the ultrasound-mediated intracellular delivery and nuclear trafficking. , 2010, Molecular pharmaceutics.

[100]  A. Bouakaz,et al.  Acoustic microstreaming around an encapsulated particle. , 2010, The Journal of the Acoustical Society of America.

[101]  D. Christensen,et al.  Factors affecting acoustically triggered release of drugs from polymeric micelles. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[102]  Ying-zheng Zhao,et al.  Characterization and anti-tumor activity of chemical conjugation of doxorubicin in polymeric micelles (DOX-P) in vitro. , 2011, Cancer letters.

[103]  J. Pérez-Gil LIPID-PROTEIN INTERACTIONS OF HYDROPHOBIC PROTEINS SP-B AND SP-C IN LUNG SURFACTANT ASSEMBLY AND DYNAMICS , 2001, Pediatric pathology & molecular medicine.

[104]  D Needham,et al.  A new temperature-sensitive liposome for use with mild hyperthermia: characterization and testing in a human tumor xenograft model. , 2000, Cancer research.

[105]  E. Stride,et al.  Enhancement of microbubble mediated gene delivery by simultaneous exposure to ultrasonic and magnetic fields , 2008 .

[106]  Wayne Kreider,et al.  Blood vessel deformations on microsecond time scales by ultrasonic cavitation. , 2011, Physical review letters.

[107]  Yue Zhao,et al.  Investigation of a new thermosensitive block copolymer micelle: hydrolysis, disruption, and release. , 2008, Langmuir : the ACS journal of surfaces and colloids.

[108]  Kullervo Hynynen,et al.  Overview of Therapeutic Ultrasound Applications and Safety Considerations , 2012, Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine.

[109]  A. Kabalnov,et al.  Dissolution of multicomponent microbubbles in the bloodstream: 1. Theory. , 1998, Ultrasound in medicine & biology.

[110]  M. Dewhirst,et al.  Efficacy of liposomes and hyperthermia in a human tumor xenograft model: importance of triggered drug release. , 2000, Cancer research.

[111]  Stefaan C De Smedt,et al.  Design and evaluation of doxorubicin-containing microbubbles for ultrasound-triggered doxorubicin delivery: cytotoxicity and mechanisms involved. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[112]  Y Wu,et al.  Acoustically active lipospheres containing paclitaxel: a new therapeutic ultrasound contrast agent. , 1998, Investigative radiology.

[113]  Yoichiro Matsumoto,et al.  Use of a microbubble agent to increase the effects of high intensity focused ultrasound on liver tissue , 2005, European Radiology.

[114]  Katherine W Ferrara,et al.  Ultrasound contrast microbubbles in imaging and therapy: physical principles and engineering , 2009, Physics in medicine and biology.

[115]  Mark Borden,et al.  Microbubble Compositions, Properties and Biomedical Applications. , 2009, Bubble science engineering and technology.

[116]  P. Dayton,et al.  In Vivo Demonstration of Cancer Molecular Imaging with Ultrasound Radiation Force and Buried-Ligand Microbubbles , 2013, Molecular imaging.

[117]  S. Kawakami,et al.  Optimization of tumor-selective targeting by basic fibroblast growth factor-binding peptide grafted PEGylated liposomes. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[118]  Yanzhong Zhang,et al.  Ultrasound-modulated shape memory and payload release effects in a biodegradable cylindrical rod made of chitosan-functionalized PLGA microspheres. , 2013, Biomacromolecules.

[119]  Paul A Dayton,et al.  Phase-change contrast agents for imaging and therapy. , 2012, Current pharmaceutical design.

[120]  R. Guy,et al.  Ultrasound-mediated gene delivery: influence of contrast agent on transfection. , 2007, Bioconjugate chemistry.

[121]  Douglas A Christensen,et al.  Drug-loaded nano/microbubbles for combining ultrasonography and targeted chemotherapy. , 2008, Ultrasonics.

[122]  Chris J Diederich,et al.  Thermal ablation and high-temperature thermal therapy: Overview of technology and clinical implementation , 2005, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[123]  J. Bai,et al.  A microbubble agent improves the therapeutic efficiency of high intensity focused ultrasound: a rabbit kidney study , 2004, Urological Research.

[124]  Niek N. Sanders,et al.  Drug loaded microbubble design for ultrasound triggered delivery , 2009 .

[125]  J. Herron,et al.  Micellar delivery of doxorubicin and its paramagnetic analog, ruboxyl, to HL-60 cells: effect of micelle structure and ultrasound on the intracellular drug uptake. , 1999, Journal of controlled release : official journal of the Controlled Release Society.

[126]  Douglas L. Miller Overview of experimental studies of biological effects of medical ultrasound caused by gas body activation and inertial cavitation. , 2007, Progress in biophysics and molecular biology.

[127]  Bradford J. Wood,et al.  Comparison of Conventional Chemotherapy, Stealth Liposomes and Temperature-Sensitive Liposomes in a Mathematical Model , 2012, PloS one.