Potential and problems in ultrasound-responsive drug delivery systems

Ultrasound is an important local stimulus for triggering drug release at the target tissue. Ultrasound-responsive drug delivery systems (URDDS) have become an important research focus in targeted therapy. URDDS include many different formulations, such as microbubbles, nanobubbles, nanodroplets, liposomes, emulsions, and micelles. Drugs that can be loaded into URDDS include small molecules, biomacromolecules, and inorganic substances. Fields of clinical application include anticancer therapy, treatment of ischemic myocardium, induction of an immune response, cartilage tissue engineering, transdermal drug delivery, treatment of Huntington’s disease, thrombolysis, and disruption of the blood–brain barrier. This review focuses on recent advances in URDDS, and discusses their formulations, clinical application, and problems, as well as a perspective on their potential use in the future.

[1]  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.

[2]  S. Nazzal,et al.  In vitro phonophoresis: effect of ultrasound intensity and mode at high frequency on NSAIDs transport across cellulose and rabbit skin membranes. , 2008, Die Pharmazie.

[3]  A. McHale,et al.  Exploiting ultrasound-mediated effects in delivering targeted, site-specific cancer therapy. , 2010, Cancer letters.

[4]  Nico de Jong,et al.  High-speed optical observations of contrast agent destruction. , 2005, Ultrasound in medicine & biology.

[5]  Robert Langer,et al.  Prediction of steady-state skin permeabilities of polar and nonpolar permeants across excised pig skin based on measurements of transient diffusion: characterization of hydration effects on the skin porous pathway. , 2002, Journal of pharmaceutical sciences.

[6]  Ying-zheng Zhao,et al.  Phospholipid-based ultrasonic microbubbles for loading protein and ultrasound-triggered release , 2009, Drug development and industrial pharmacy.

[7]  Chrit T. W. Moonen,et al.  Evaluation of the Temporal Window for Drug Delivery Following Ultrasound-Mediated Membrane Permeability Enhancement , 2011, Molecular Imaging and Biology.

[8]  C. Yoon,et al.  Ultrasound-mediated gene delivery , 2010, Expert opinion on drug delivery.

[9]  N. Jong,et al.  Ultrasound microbubble induced endothelial cell permeability. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[10]  J. Shea,et al.  Ultrasonic nanotherapy of pancreatic cancer: lessons from ultrasound imaging. , 2010, Molecular pharmaceutics.

[11]  S. Kitamura,et al.  Nonviral delivery of siRNA into mesenchymal stem cells by a combination of ultrasound and microbubbles. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[12]  Samir Mitragotri,et al.  Interactions of inertial cavitation bubbles with stratum corneum lipid bilayers during low-frequency sonophoresis. , 2003, Biophysical journal.

[13]  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.

[14]  Ryuichi Morishita,et al.  Local Delivery of Plasmid DNA Into Rat Carotid Artery Using Ultrasound , 2002, Circulation.

[15]  Penetration pathways induced by low-frequency sonophoresis with physical and chemical enhancers: iron oxide nanoparticles versus lanthanum nitrates. , 2010, The Journal of investigative dermatology.

[16]  Eleanor Stride,et al.  Dissolution of coated microbubbles: The effect of nanoparticles and surfactant concentration , 2012 .

[17]  James L. Thomas,et al.  Ultrasound mediates the release of curcumin from microemulsions. , 2008, Langmuir : the ACS journal of surfaces and colloids.

[18]  Haiqiang Jin,et al.  Ultrasound-triggered thrombolysis using urokinase-loaded nanogels. , 2012, International journal of pharmaceutics.

[19]  Gregory T. Clement,et al.  The feasibility of noninvasive image‐guided treatments of brain disorders by focused ultrasound , 2004 .

[20]  C. Moonen,et al.  Ultrasound-mediated intracellular drug delivery using microbubbles and temperature-sensitive liposomes. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[21]  Peter Alken,et al.  High intensity focused ultrasound as noninvasive therapy for multilocal renal cell carcinoma: case study and review of the literature. , 2002, The Journal of urology.

[22]  Yan Zhang,et al.  Improving the cardio protective effect of aFGF in ischemic myocardium with ultrasound-mediated cavitation of heparin modified microbubbles: preliminary experiment , 2012, Journal of drug targeting.

[23]  R. Langer,et al.  Transport pathways and enhancement mechanisms within localized and non-localized transport regions in skin treated with low-frequency sonophoresis and sodium lauryl sulfate. , 2010, Journal of pharmaceutical sciences.

[24]  Mu-Yi Hua,et al.  Blood-brain barrier disruption with focused ultrasound enhances delivery of chemotherapeutic drugs for glioblastoma treatment. , 2010, Radiology.

[25]  Robert Langer,et al.  Effects of ultrasound and sodium lauryl sulfate on the transdermal delivery of hydrophilic permeants: Comparative in vitro studies with full-thickness and split-thickness pig and human skin. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[26]  V. Torchilin Targeted pharmaceutical nanocarriers for cancer therapy and imaging , 2007, The AAPS Journal.

[27]  Isao Sakaida,et al.  Usefulness of Sonazoid contrast-enhanced ultrasonography for hepatocellular carcinoma: comparison with pathological diagnosis and superparamagnetic iron oxide magnetic resonance images , 2009, Journal of Gastroenterology.

[28]  Natalia Vykhodtseva,et al.  Progress and problems in the application of focused ultrasound for blood-brain barrier disruption. , 2008, Ultrasonics.

[29]  N. Rapoport Combined cancer therapy by micellar-encapsulated drug and ultrasound. , 2004, International journal of pharmaceutics.

[30]  A. Brayman,et al.  A comparison of the fragmentation thresholds and inertial cavitation doses of different ultrasound contrast agents. , 2003, The Journal of the Acoustical Society of America.

[31]  E. Unger,et al.  Local drug and gene delivery through microbubbles. , 2001, Progress in cardiovascular diseases.

[32]  S. Nazzal,et al.  Effect of gel composition and phonophoresis on the transdermal delivery of ibuprofen: In vitro and in vivo evaluation , 2011, Pharmaceutical development and technology.

[33]  Ying-zheng Zhao,et al.  Comparing encapsulation efficiency and ultrasound-triggered release for protein between phospholipid-based microbubbles and liposomes , 2009, Journal of microencapsulation.

[34]  Zhigang Wang,et al.  Ultrasound triggered drug release from 10-hydroxycamptothecin-loaded phospholipid microbubbles for targeted tumor therapy in mice. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[35]  Zhigang Wang,et al.  Enhanced homing of mesenchymal stem cells to the ischemic myocardium by ultrasound-targeted microbubble destruction. , 2012, Ultrasonics.

[36]  Fabian Kiessling,et al.  Theranostic nanomedicine. , 2020, Accounts of chemical research.

[37]  Y. Negishi,et al.  Delivery of siRNA into the cytoplasm by liposomal bubbles and ultrasound. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[38]  John C Chappell,et al.  Targeted delivery of nanoparticles bearing fibroblast growth factor-2 by ultrasonic microbubble destruction for therapeutic arteriogenesis. , 2008, Small.

[39]  B. Angelsen,et al.  Effect of ultrasound parameters on the release of liposomal calcein. , 2012, Ultrasound in medicine & biology.

[40]  M. Machluf,et al.  Therapeutic ultrasound optimization for gene delivery: a key factor achieving nuclear DNA localization. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[41]  Morton W. Miller,et al.  Biological and environmental factors affecting ultrasound-induced hemolysis in vitro: 2. Medium dissolved gas (pO2) content. , 2003, Ultrasound in medicine & biology.

[42]  Ying-zheng Zhao,et al.  Experiment on enhancing antitumor effect of intravenous epirubicin hydrochloride by acoustic cavitation in situ combined with phospholipid-based microbubbles , 2011, Cancer Chemotherapy and Pharmacology.

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

[44]  Ji-hye Lee,et al.  Anti-hyperalgesic and anti-inflammatory effects of Ketorolac Tromethamine gel using pulsed ultrasound in inflamed rats , 2008, Archives of pharmacal research.

[45]  Y. Tabuchi,et al.  Inhibition of DNA-dependent protein kinase promotes ultrasound-induced cell death including apoptosis in human leukemia cells. , 2012, Cancer letters.

[46]  K. Hong,et al.  Perfluorodecalin/[InGaP/ZnS quantum dots] nanoemulsions as 19F MR/optical imaging nanoprobes for the labeling of phagocytic and nonphagocytic immune cells. , 2010, Biomaterials.

[47]  S. Nakagawa,et al.  Cancer gene therapy by IL-12 gene delivery using liposomal bubbles and tumoral ultrasound exposure. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[48]  M. Ashokkumar,et al.  Acoustic bubble sizes, coalescence, and sonochemical activity in aqueous electrolyte solutions saturated with different gases. , 2010, Langmuir : the ACS journal of surfaces and colloids.

[49]  W. Pardridge Advances in cell biology of blood-brain barrier transport. , 1991, Seminars in cell biology.

[50]  Akira Ito,et al.  High intensity focused ultrasound lithotripsy with cavitating microbubbles , 2009, Medical & Biological Engineering & Computing.

[51]  Wen-Zhi Chen,et al.  Extracorporeal High Intensity Focused Ultrasound Ablation in the Treatment of Patients with Large Hepatocellular Carcinoma , 2004, Annals of Surgical Oncology.

[52]  X. B. Zhou,et al.  Platelet-targeted microbubbles inhibit re-occlusion after thrombolysis with transcutaneous ultrasound and microbubbles. , 2011, Ultrasonics.

[53]  Gary P. Martin,et al.  Dermal and Transdermal Drug Delivery Systems: Current and Future Prospects , 2006, Drug delivery.

[54]  Zhen Xu,et al.  A new strategy to enhance cavitational tissue erosion using a high-intensity, initiating sequence , 2006, IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control.

[55]  Jun-ichiro Jo,et al.  An ultrasound-responsive nano delivery system of tissue-type plasminogen activator for thrombolytic therapy. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[56]  K. Hynynen,et al.  Focused ultrasound for targeted delivery of siRNA and efficient knockdown of Htt expression. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[57]  Wen-zhi Chen,et al.  [High intensity focused ultrasound in the treatment of primary malignant bone tumor]. , 2002, Zhonghua zhong liu za zhi [Chinese journal of oncology].

[58]  Isabelle Tardy,et al.  BR55: A Lipopeptide-Based VEGFR2-Targeted Ultrasound Contrast Agent for Molecular Imaging of Angiogenesis , 2010, Investigative radiology.

[59]  Mingxi Wan,et al.  The inception of cavitation bubble clouds induced by high-intensity focused ultrasound. , 2006, Ultrasonics.

[60]  J. Patrie,et al.  Real-time measurement of renal blood flow in healthy subjects using contrast-enhanced ultrasound. , 2009, American journal of physiology. Renal physiology.

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

[62]  M. Averkiou,et al.  Investigation of microbubble response to long pulses used in ultrasound-enhanced drug delivery. , 2012, Ultrasound in medicine & biology.

[63]  Y. Kalia,et al.  Skin permeability enhancement by low frequency sonophoresis: lipid extraction and transport pathways. , 2003, Journal of pharmaceutical sciences.

[64]  Paul S. Sheeran,et al.  Decafluorobutane as a phase-change contrast agent for low-energy extravascular ultrasonic imaging. , 2011, Ultrasound in medicine & biology.

[65]  Nili Grossman,et al.  Bubble growth within the skin by rectified diffusion might play a significant role in sonophoresis. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[66]  Samir Mitragotri,et al.  An experimental and theoretical analysis of ultrasound-induced permeabilization of cell membranes. , 2003, Biophysical journal.

[67]  W. Gaertner Frequency Dependence of Ultrasonic Cavitation , 1954 .

[68]  J G Miller,et al.  Contrast Echocardiography: Current and Future Applications , 2000 .

[69]  M. Atobe,et al.  Elucidation of the transport pathway in hairless rat skin enhanced by low-frequency sonophoresis based on the solute-water transport relationship and confocal microscopy. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[70]  M. Prausnitz,et al.  Changes in cell morphology due to plasma membrane wounding by acoustic cavitation. , 2010, Ultrasound in medicine & biology.

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

[72]  Nico de Jong,et al.  Ultrasound and Microbubble-Targeted Delivery of Macromolecules Is Regulated by Induction of Endocytosis and Pore Formation , 2009, Circulation research.

[73]  Krista M. Durney,et al.  Microbubbles as biocompatible porogens for hydrogel scaffolds. , 2012, Acta biomaterialia.

[74]  M. Suematsu,et al.  Mechanism of Hepatic Parenchyma-Specific Contrast of Microbubble-Based Contrast Agent for Ultrasonography: Microscopic Studies in Rat Liver , 2007, Investigative Radiology.

[75]  Shahram Vaezy,et al.  An image-guided high intensity focused ultrasound device for uterine fibroids treatment. , 2002, Medical physics.

[76]  Lawrence A Crum,et al.  Inertial cavitation dose and hemolysis produced in vitro with or without Optison. , 2003, Ultrasound in medicine & biology.

[77]  R. Vandenbroucke,et al.  Ultrasound exposure of lipoplex loaded microbubbles facilitates direct cytoplasmic entry of the lipoplexes. , 2009, Molecular pharmaceutics.

[78]  N. Rapoport,et al.  Acoustic activation of drug delivery from polymeric micelles: effect of pulsed ultrasound. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[79]  S. Esener,et al.  A novel nested liposome drug delivery vehicle capable of ultrasound triggered release of its payload. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[80]  Mark Borden,et al.  Ultrasound microbubble contrast agents: fundamentals and application to gene and drug delivery. , 2007, Annual review of biomedical engineering.

[81]  Natalia Vykhodtseva,et al.  Temporary disruption of the blood-brain barrier by use of ultrasound and microbubbles: safety and efficacy evaluation in rhesus macaques. , 2012, Cancer research.

[82]  Jie Tang,et al.  Phospholipids-based microbubbles sonoporation pore size and reseal of cell membrane cultured in vitro. , 2008, Journal of drug targeting.

[83]  L. Curiel,et al.  Local recurrence of prostate cancer after external beam radiotherapy: early experience of salvage therapy using high-intensity focused ultrasonography. , 2004, Urology.

[84]  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.

[85]  C. Cain,et al.  Noninvasive thrombolysis using pulsed ultrasound cavitation therapy - histotripsy. , 2009, Ultrasound in medicine & biology.

[86]  P. Bussat,et al.  Gas-filled microbubble-mediated delivery of antigen and the induction of immune responses. , 2012, Biomaterials.

[87]  Ultrasound activated nano-encapsulated targeted drug delivery and tumour cell poration. , 2012, Advances in experimental medicine and biology.

[88]  J. Chapelon,et al.  Treatment of localised prostate cancer with transrectal high intensity focused ultrasound. , 1999, European journal of ultrasound : official journal of the European Federation of Societies for Ultrasound in Medicine and Biology.

[89]  D. Christensen,et al.  Ultrasound-triggered drug targeting of tumors in vitro and in vivo. , 2004, Ultrasonics.

[90]  原田 慶美 Ultrasound activation of TiO₂ in melanoma tumors , 2011 .

[91]  Fabian Kiessling,et al.  Iron oxide nanoparticle-containing microbubble composites as contrast agents for MR and ultrasound dual-modality imaging. , 2011, Biomaterials.

[92]  Paul Campbell,et al.  DNA Double-Strand Breaks Induced by Cavitational Mechanical Effects of Ultrasound in Cancer Cell Lines , 2012, PloS one.

[93]  Roy W. Martin,et al.  Liver Hemostasis With High‐Intensity Ultrasound , 2004, Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine.

[94]  Peter T C So,et al.  Dual-channel two-photon microscopy study of transdermal transport in skin treated with low-frequency ultrasound and a chemical enhancer. , 2007, The Journal of investigative dermatology.

[95]  Nathaniel Katz,et al.  Two-minute skin anesthesia through ultrasound pretreatment and iontophoretic delivery of a topical anesthetic: a feasibility study. , 2008, Pain medicine.

[96]  Wenying Zhou,et al.  Ultrasound-triggered drug release and enhanced anticancer effect of doxorubicin-loaded poly(D,L-lactide-co-glycolide)-methoxy-poly(ethylene glycol) nanodroplets. , 2011, Ultrasound in medicine & biology.

[97]  K. Rainsford Profile and mechanisms of gastrointestinal and other side effects of nonsteroidal anti-inflammatory drugs (NSAIDs). , 1999, The American journal of medicine.

[98]  J. Shea,et al.  Controlled and targeted tumor chemotherapy by ultrasound-activated nanoemulsions/microbubbles. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[99]  Ying-zheng Zhao,et al.  Using acoustic cavitation to enhance chemotherapy of DOX liposomes: experiment in vitro and in vivo , 2012, Drug development and industrial pharmacy.

[100]  Samir Mitragotri,et al.  Sonophoresis: a 50-year journey. , 2004, Drug discovery today.

[101]  Joseph Kost,et al.  Ultrasound triggered release of cisplatin from liposomes in murine tumors. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[102]  Mickael Tanter,et al.  Numerical prediction of frequency dependent 3D maps of mechanical index thresholds in ultrasonic brain therapy , 2010, 2010 IEEE International Ultrasonics Symposium.

[103]  Ying-zheng Zhao,et al.  Factors that affect the efficiency of antisense oligodeoxyribonucleotide transfection by insonated gas-filled lipid microbubbles , 2008 .

[104]  J. Kost,et al.  The importance of microjet vs shock wave formation in sonophoresis. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[105]  Samir Mitragotri,et al.  Transdermal Drug Delivery Using Low-Frequency Sonophoresis , 2004, Pharmaceutical Research.

[106]  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.

[107]  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.

[108]  Nico de Jong,et al.  Sonoporation from jetting cavitation bubbles. , 2006, Biophysical journal.

[109]  Juan Tu,et al.  Inertial cavitation dose produced in ex vivo rabbit ear arteries with Optison by 1-MHz pulsed ultrasound. , 2006, Ultrasound in medicine & biology.

[110]  Robert Langer,et al.  Ultrasound-mediated transdermal drug delivery: mechanisms, scope, and emerging trends. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[111]  S. Meairs,et al.  Elucidating the mechanisms behind sonoporation with adeno-associated virus-loaded microbubbles. , 2011, Molecular pharmaceutics.

[112]  K. Maruyama,et al.  Progress in the development of ultrasound-mediated gene delivery systems utilizing nano- and microbubbles. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[113]  A. del Pozo,et al.  Use of ultrasound to prepare lipid emulsions of lorazepam for intravenous injection. , 2001, International journal of pharmaceutics.

[114]  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.

[115]  Eric J Topol,et al.  Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy , 2003, The Lancet.

[116]  Xiang Li,et al.  Preparation of nanobubbles for ultrasound imaging and intracelluar drug delivery. , 2010, International journal of pharmaceutics.

[117]  D. Kobayashi,et al.  Acoustic cavitation as an enhancing mechanism of low-frequency sonophoresis for transdermal drug delivery. , 2009, Biological & pharmaceutical bulletin.

[118]  K. Hynynen,et al.  Use of ultrasound pulses combined with Definity for targeted blood-brain barrier disruption: a feasibility study. , 2007, Ultrasound in Medicine and Biology.

[119]  Brian P. Timko,et al.  Remotely Triggerable Drug Delivery Systems , 2010, Advanced materials.

[120]  C. Yeh,et al.  Effects of acoustic insonation parameters on ultrasound contrast agent destruction. , 2008, Ultrasound in medicine & biology.

[121]  Chien Ting Chin,et al.  Focused ultrasound-induced stimulation of microbubbles augments site-targeted engraftment of mesenchymal stem cells after acute myocardial infarction. , 2009, Journal of molecular and cellular cardiology.

[122]  H. Klocker,et al.  Microbubble-enhanced ultrasound to deliver an antisense oligodeoxynucleotide targeting the human androgen receptor into prostate tumours , 2006, The Journal of Steroid Biochemistry and Molecular Biology.

[123]  Wen-zhi Chen,et al.  A randomised clinical trial of high-intensity focused ultrasound ablation for the treatment of patients with localised breast cancer , 2003, British Journal of Cancer.