Mechanical Force-Triggered Drug Delivery.

Advanced drug delivery systems (DDS) enhance treatment efficacy of different therapeutics in a dosage, spatial, and/or temporal controlled manner. To date, numerous chemical- or physical-based stimuli-responsive formulations or devices for controlled drug release have been developed. Among them, the emerging mechanical force-based stimulus offers a convenient and robust controlled drug release platform and has attracted increasing attention. The relevant DDS can be activated to promote drug release by different types of mechanical stimuli, including compressive force, tensile force, and shear force as well as indirect formats, remotely triggered by ultrasound and magnetic field. In this review, we provide an overview of recent advances in mechanically activated DDS. The opportunities and challenges regarding clinical translations are also discussed.

[1]  Daniel G. Anderson,et al.  Ultrasound-mediated gastrointestinal drug delivery , 2015, Science Translational Medicine.

[2]  Jonathan T. Sutton,et al.  Ultrasound-mediated drug delivery for cardiovascular disease , 2013, Expert opinion on drug delivery.

[3]  David J. Mooney,et al.  Controlled Drug Delivery from Polymers by Mechanical Signals , 2001 .

[4]  David J. Mooney,et al.  Active scaffolds for on-demand drug and cell delivery , 2010, Proceedings of the National Academy of Sciences.

[5]  Raeed H. Chowdhury,et al.  Epidermal Electronics , 2011, Science.

[6]  Patrick Couvreur,et al.  Stimuli-responsive nanocarriers for drug delivery. , 2013, Nature materials.

[7]  Samir Mitragotri,et al.  Platelet-like Nanoparticles: Mimicking Shape, Flexibility, and Surface Biology of Platelets To Target Vascular Injuries , 2014, ACS nano.

[8]  Omid C Farokhzad,et al.  pH-Responsive nanoparticles for drug delivery. , 2010, Molecular pharmaceutics.

[9]  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.

[10]  Samuel Sanchez,et al.  Catalytic Janus motors on microfluidic chip: deterministic motion for targeted cargo delivery. , 2012, ACS nano.

[11]  M. Ziskin,et al.  International recommendations and guidelines for the safe use of diagnostic ultrasound in medicine. , 2000, Ultrasound in medicine & biology.

[12]  T. Budtova,et al.  Kinetics of shear-induced gel deswelling/solvent release. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[13]  Nico de Jong,et al.  "Compression-only" behavior of phospholipid-coated contrast bubbles. , 2007, Ultrasound in medicine & biology.

[14]  R. McCarley.  Redox-responsive delivery systems. , 2012, Annual review of analytical chemistry.

[15]  N. Jong,et al.  Biodegradable polymeric microcapsules for selective ultrasound-triggered drug release , 2011 .

[16]  Bartosz A Grzybowski,et al.  Controlled pH stability and adjustable cellular uptake of mixed-charge nanoparticles. , 2013, Journal of the American Chemical Society.

[17]  N. Rapoport.  Physical stimuli-responsive polymeric micelles for anti-cancer drug delivery , 2007 .

[18]  Chih-Kuang Yeh,et al.  Concurrent blood-brain barrier opening and local drug delivery using drug-carrying microbubbles and focused ultrasound for brain glioma treatment. , 2012, Biomaterials.

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

[20]  M. Muhammed,et al.  Injectable Superparamagnetic Ferrogels for Controlled Release of Hydrophobic Drugs , 2009 .

[21]  T. Yen,et al.  Antiangiogenic-targeting drug-loaded microbubbles combined with focused ultrasound for glioma treatment. , 2013, Biomaterials.

[22]  Feng-Yi Yang,et al.  Focused ultrasound and interleukin-4 receptor-targeted liposomal doxorubicin for enhanced targeted drug delivery and antitumor effect in glioblastoma multiforme. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[23]  C. Yeh,et al.  Targeted tumor theranostics using folate-conjugated and camptothecin-loaded acoustic nanodroplets in a mouse xenograft model. , 2015, Biomaterials.

[24]  Joseph Hemmerlé,et al.  Layer-by-Layer Enzymatic Platform for Stretched-Induced Reactive Release , 2012 .

[25]  Zhiguang Wu,et al.  Self-propelled polymer-based multilayer nanorockets for transportation and drug release. , 2013, Angewandte Chemie.

[26]  Jon Dobson,et al.  Magnetic micro- and nano-particle-based targeting for drug and gene delivery. , 2006, Nanomedicine.

[27]  M. Melancon,et al.  Cancer theranostics with near-infrared light-activatable multimodal nanoparticles. , 2011, Accounts of chemical research.

[28]  Samir Mitragotri,et al.  Impact of particle elasticity on particle‐based drug delivery systems☆ , 2017, Advanced drug delivery reviews.

[29]  Paul A Dayton,et al.  Ultrasound radiation force enables targeted deposition of model drug carriers loaded on microbubbles. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[30]  Sébastien Lecommandoux,et al.  Magnetic responsive polymer composite materials. , 2013, Chemical Society reviews.

[31]  Sam Emaminejad,et al.  Fully integrated wearable sensor arrays for multiplexed in situ perspiration analysis , 2016, Nature.

[32]  Xiaoqi Sun,et al.  Multifunctional Theranostic Red Blood Cells For Magnetic‐Field‐Enhanced in vivo Combination Therapy of Cancer , 2014, Advanced materials.

[33]  Elena Aznar,et al.  Enzyme-responsive intracellular controlled release using nanometric silica mesoporous supports capped with "saccharides". , 2010, ACS nano.

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

[35]  Unyong Jeong,et al.  A Strain‐Regulated, Refillable Elastic Patch for Controlled Release , 2016 .

[36]  M. Tabrizian,et al.  Liposome technology for cardiovascular disease treatment and diagnosis , 2012, Expert opinion on drug delivery.

[37]  Miklós Zrínyi,et al.  Deformation of ferrogels induced by nonuniform magnetic fields , 1996 .

[38]  S. Mitragotri,et al.  A mechanistic study of ultrasonically-enhanced transdermal drug delivery. , 1995, Journal of pharmaceutical sciences.

[39]  Fei Li,et al.  A Force to Be Reckoned With: A Review of Synthetic Microswimmers Powered by Ultrasound. , 2015, Small.

[40]  The shear stress of busting blood clots. , 2012, The New England journal of medicine.

[41]  J. Karp,et al.  Nanocarriers as an Emerging Platform for Cancer Therapy , 2022 .

[42]  Younan Xia,et al.  Strain-controlled release of molecules from arrayed microcapsules supported on an elastomer substrate. , 2011, Angewandte Chemie.

[43]  S. Mitragotri,et al.  Current status and future potential of transdermal drug delivery , 2004, Nature Reviews Drug Discovery.

[44]  Fabian Kiessling,et al.  Recent advances in molecular, multimodal and theranostic ultrasound imaging. , 2014, Advanced drug delivery reviews.

[45]  G. Ranieri,et al.  Novel pH sensitive ferrogels as new approach in cancer treatment: Effect of the magnetic field on swelling and drug delivery. , 2015, Colloids and surfaces. B, Biointerfaces.

[46]  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.

[47]  Emanuel Fleige,et al.  Stimuli-responsive polymeric nanocarriers for the controlled transport of active compounds: concepts and applications. , 2012, Advanced drug delivery reviews.

[48]  D. Ku,et al.  Fluid mechanics of vascular systems, diseases, and thrombosis. , 1999, Annual review of biomedical engineering.

[49]  Gary Friedman,et al.  Magnetic targeting for site-specific drug delivery: applications and clinical potential. , 2009, Expert opinion on drug delivery.

[50]  B. Angelsen,et al.  Ultrasound-enhanced drug delivery in prostate cancer xenografts by nanoparticles stabilizing microbubbles. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[51]  Zhigang Wang,et al.  Antitumor Effect of Docetaxel‐Loaded Lipid Microbubbles Combined With Ultrasound‐Targeted Microbubble Activation on VX2 Rabbit Liver Tumors , 2010, Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine.

[52]  Enzo Terreno,et al.  Image guided therapy: the advent of theranostic agents. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[53]  Nicholas A Peppas,et al.  Micro- and nanotechnologies for intelligent and responsive biomaterial-based medical systems. , 2009, Advanced drug delivery reviews.

[54]  Mitchell T. Ong,et al.  Force-induced activation of covalent bonds in mechanoresponsive polymeric materials , 2009, Nature.

[55]  Carl T.F. Ross,et al.  Mechanical Engineering Principles , 2002 .

[56]  David J Mooney,et al.  On-demand drug delivery from local depots. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[57]  Quanyin Hu,et al.  Enzyme-responsive nanomaterials for controlled drug delivery. , 2014, Nanoscale.

[58]  Carmen C. Mayorga-Martinez,et al.  Nano/micromotors in (bio)chemical science applications. , 2014, Chemical reviews.

[59]  Ghaleb A Husseini,et al.  Micelles and nanoparticles for ultrasonic drug and gene delivery. , 2008, Advanced drug delivery reviews.

[60]  Wei Gao,et al.  Functionalized ultrasound-propelled magnetically guided nanomotors: toward practical biomedical applications. , 2013, ACS nano.

[61]  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.

[62]  Benjamin C. Tang,et al.  Managing diabetes with nanomedicine: challenges and opportunities , 2014, Nature Reviews Drug Discovery.

[63]  Zaverio M. Ruggeri,et al.  Platelets in atherothrombosis , 2002, Nature Medicine.

[64]  Jeffrey W. Smith,et al.  Platelet Mimetic Particles for Targeting Thrombi in Flowing Blood , 2012, Advanced materials.

[65]  Samir Mitragotri,et al.  Materials for Drug Delivery: Innovative Solutions to Address Complex Biological Hurdles , 2012, Advanced materials.

[66]  Li Tang,et al.  Chain-shattering polymeric therapeutics with on-demand drug-release capability. , 2013, Angewandte Chemie.

[67]  Leticia Hosta-Rigau,et al.  Shear stress and its effect on the interaction of myoblast cells with nanosized drug delivery vehicles. , 2013, Molecular pharmaceutics.

[68]  S. Yusuf,et al.  Controversies in cardiovascular medicine Why are we failing to implement effective therapies in cardiovascular disease ? , 2013 .

[69]  Hesheng Xia,et al.  High intensity focused ultrasound and redox dual responsive polymer micelles. , 2010, Chemical communications.

[70]  Zhen Gu,et al.  Ultrasound‐Triggered Regulation of Blood Glucose Levels Using Injectable Nano‐Network , 2014, Advanced healthcare materials.

[71]  Zhen Gu,et al.  Hypoxia-Sensitive Materials for Biomedical Applications , 2016, Annals of Biomedical Engineering.

[72]  Kai Yang,et al.  Magnetic Targeting Enhanced Theranostic Strategy Based on Multimodal Imaging for Selective Ablation of Cancer , 2014 .

[73]  James L. Thomas,et al.  PEG−Lipids and Oligo(ethylene glycol) Surfactants Enhance the Ultrasonic Permeabilizability of Liposomes , 2003 .

[74]  Huanyu Cheng,et al.  Bioresorbable silicon electronic sensors for the brain , 2016, Nature.

[75]  Zhigang Wang,et al.  Ultrasound-mediated destruction of paclitaxel and oxygen loaded lipid microbubbles for combination therapy in ovarian cancer xenografts. , 2015, Cancer letters.

[76]  Younan Xia,et al.  A temperature-sensitive drug release system based on phase-change materials. , 2010, Angewandte Chemie.

[77]  Zhen Gu,et al.  Stimuli-responsive nanomaterials for therapeutic protein delivery. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[78]  R. Langer,et al.  Enhancing the transdermal delivery of rigid nanoparticles using the simultaneous application of ultrasound and sodium lauryl sulfate. , 2011, Biomaterials.

[79]  Angela C Cruciano,et al.  Redox-triggered contents release from liposomes. , 2008, Journal of the American Chemical Society.

[80]  T. Budtova,et al.  Delivery of fullerene-containing complexes via microgel swelling and shear-induced release. , 2010, International journal of pharmaceutics.

[81]  Bolin Liu,et al.  Mesoporous silica nanoparticles as a breast-cancer targeting ultrasound contrast agent. , 2014, Colloids and surfaces. B, Biointerfaces.

[82]  Jesse V Jokerst,et al.  Molecular imaging with theranostic nanoparticles. , 2011, Accounts of chemical research.

[83]  K. Tanaka,et al.  Gene delivery by combination of novel liposomal bubbles with perfluoropropane and ultrasound. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[84]  E. Lavik,et al.  Leveraging Shear Stress to Bust Clots with Nanoparticles , 2012, Science.

[85]  San-Yuan Chen,et al.  Study on controlled drug permeation of magnetic-sensitive ferrogels: effect of Fe3O4 and PVA. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[86]  Chih-Kuang Yeh,et al.  Aptamer-conjugated and drug-loaded acoustic droplets for ultrasound theranosis. , 2012, Biomaterials.

[87]  Robert Langer,et al.  A vector-free microfluidic platform for intracellular delivery , 2013, Proceedings of the National Academy of Sciences.

[88]  Robert Langer,et al.  First-in-Human Testing of a Wirelessly Controlled Drug Delivery Microchip , 2012, Science Translational Medicine.

[89]  Ick Chan Kwon,et al.  Echogenic nanoparticles for ultrasound technologies: Evolution from diagnostic imaging modality to multimodal theranostic agent , 2014 .

[90]  Zhen Gu,et al.  ATP-Responsive Drug Delivery Systems , 2016, Expert opinion on drug delivery.

[91]  Jun Ge,et al.  Drug release from electric-field-responsive nanoparticles. , 2012, ACS nano.

[92]  Benjamin C. Tang,et al.  Glucose-responsive microgels integrated with enzyme nanocapsules for closed-loop insulin delivery. , 2013, ACS nano.

[93]  A. Pandit,et al.  Standardization of models and methods used to assess nanoparticles in cardiovascular applications. , 2011, Small.

[94]  Dipak K. Sarker.  Engineering of nanoemulsions for drug delivery. , 2005, Current drug delivery.

[95]  S. D. De Smedt,et al.  Crucial factors and emerging concepts in ultrasound-triggered drug delivery. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[96]  D. Ku,et al.  Wall shear over high degree stenoses pertinent to atherothrombosis. , 2010, Journal of biomechanics.

[97]  R. Langer,et al.  pH-responsive supramolecular polymer gel as an enteric elastomer for use in gastric devices , 2015, Nature materials.

[98]  D. Ingber,et al.  Shear-Activated Nanotherapeutics for Drug Targeting to Obstructed Blood Vessels , 2012, Science.

[99]  C T W Moonen,et al.  Understanding ultrasound induced sonoporation: definitions and underlying mechanisms. , 2014, Advanced drug delivery reviews.

[100]  P. Davies,et al.  Flow-mediated endothelial mechanotransduction. , 1995, Physiological reviews.

[101]  B. Werner,et al.  Prolonged survival upon ultrasound-enhanced doxorubicin delivery in two syngenic glioblastoma mouse models. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[102]  Zhixiang Tong,et al.  Hyaluronic acid-based hydrogels containing covalently integrated drug depots: implication for controlling inflammation in mechanically stressed tissues. , 2013, Biomacromolecules.

[103]  Xing-Jie Liang,et al.  pH-sensitive nano-systems for drug delivery in cancer therapy. , 2014, Biotechnology advances.

[104]  B. Ratner,et al.  Self-assembled molecular structures as ultrasonically-responsive barrier membranes for pulsatile drug delivery. , 2001, Journal of biomedical materials research.

[105]  Jonathan S. Dordick,et al.  Radio-Wave Heating of Iron Oxide Nanoparticles Can Regulate Plasma Glucose in Mice , 2012, Science.

[106]  Jonah A Kaplan,et al.  Stretch-Induced Drug Delivery from Superhydrophobic Polymer Composites: Use of Crack Propagation Failure Modes for Controlling Release Rates. , 2016, Angewandte Chemie.

[107]  Kinam Park,et al.  Environment-sensitive hydrogels for drug delivery. , 2001, Advanced drug delivery reviews.

[108]  S. Roels,et al.  Coupling of drug containing liposomes to microbubbles improves ultrasound triggered drug delivery in mice. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[109]  J. Willmann,et al.  Ultrasound-guided delivery of microRNA loaded nanoparticles into cancer. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[110]  S. Mitragotri,et al.  Low-frequency sonophoresis: current status and future prospects. , 2008, Advanced drug delivery reviews.

[111]  Samir Mitragotri,et al.  Polymer particles that switch shape in response to a stimulus , 2010, Proceedings of the National Academy of Sciences.

[112]  Philippe Lavalle,et al.  Stretch-induced biodegradation of polyelectrolyte multilayer films for drug release. , 2012, Langmuir : the ACS journal of surfaces and colloids.

[113]  C. Alexander,et al.  Stimuli responsive polymers for biomedical applications. , 2005, Chemical Society reviews.

[114]  Daniel G. Anderson,et al.  Engineering synthetically modified insulin for glucose-responsive diabetes therapy , 2015, Expert review of endocrinology & metabolism.

[115]  D O Cosgrove,et al.  Microbubble contrast agents: a new era in ultrasound , 2001, BMJ : British Medical Journal.

[116]  Zhuang Liu,et al.  PEG-functionalized iron oxide nanoclusters loaded with chlorin e6 for targeted, NIR light induced, photodynamic therapy. , 2013, Biomaterials.

[117]  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.

[118]  S Otto,et al.  Dissolution of multicomponent microbubbles in the bloodstream: 2. Experiment. , 1998, Ultrasound in medicine & biology.

[119]  A. Hoffman,et al.  Bioconjugates of intelligent polymers and recognition proteins for use in diagnostics and affinity separations. , 2000, Clinical chemistry.

[120]  Joseph Hemmerlé,et al.  Mechanically responding nanovalves based on polyelectrolyte multilayers. , 2007, Nano letters.

[121]  E. Unger,et al.  Gas-filled liposomes as echocardiographic contrast agents in rabbits with myocardial infarcts. , 1993, Investigative radiology.

[122]  H. Grüll,et al.  Ultrasound-mediated gene delivery of naked plasmid DNA in skeletal muscles: a case for bolus injections. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[123]  Shaoling Huang,et al.  Echogenic liposome compositions for increased retention of ultrasound reflectivity at physiologic temperature. , 2008, Journal of pharmaceutical sciences.

[124]  K. Nguyen,et al.  Biodegradable nanoparticles mimicking platelet binding as a targeted and controlled drug delivery system. , 2012, International journal of pharmaceutics.

[125]  J Kost,et al.  Low‐Frequency Sonophoresis: A Noninvasive Method of Drug Delivery and Diagnostics , 2000, Biotechnology progress.

[126]  J B Fowlkes,et al.  Acoustic droplet vaporization for therapeutic and diagnostic applications. , 2000, Ultrasound in medicine & biology.

[127]  Kazunori Kataoka,et al.  Current state, achievements, and future prospects of polymeric micelles as nanocarriers for drug and gene delivery. , 2006, Pharmacology & therapeutics.

[128]  Wei Gao,et al.  Turning erythrocytes into functional micromotors. , 2014, ACS nano.

[129]  Zhen Gu,et al.  Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery , 2015, Proceedings of the National Academy of Sciences.

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

[131]  T. Abribat,et al.  The rise and rise of drug delivery , 2005, Nature Reviews Drug Discovery.

[132]  Michael R Hamblin,et al.  Physical energy for drug delivery; poration, concentration and activation. , 2014, Advanced drug delivery reviews.

[133]  M. Runge,et al.  Redox signaling in cardiovascular health and disease. , 2013, Free radical biology & medicine.

[134]  Victor Frenkel,et al.  Ultrasound mediated delivery of drugs and genes to solid tumors. , 2008, Advanced drug delivery reviews.

[135]  V. Muzykantov,et al.  Flow shear stress differentially regulates endothelial uptake of nanocarriers targeted to distinct epitopes of PECAM-1. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[136]  Wei Wang,et al.  Autonomous motion of metallic microrods propelled by ultrasound. , 2012, ACS nano.

[137]  Allister F. McGuire,et al.  A skin-inspired organic digital mechanoreceptor , 2015, Science.

[138]  Kazuo Maruyama,et al.  Systemic delivery systems of angiogenic gene by novel bubble liposomes containing cationic lipid and ultrasound exposure. , 2012, Molecular pharmaceutics.

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

[140]  Nico P E Vermeulen,et al.  Enzyme-Catalyzed Activation of Anticancer Prodrugs , 2004, Pharmacological Reviews.

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

[142]  Zhen Gu,et al.  Recent advances of cocktail chemotherapy by combination drug delivery systems. , 2016, Advanced drug delivery reviews.

[143]  Qiaobing Xu,et al.  Reactive oxygen species-responsive protein modification and its intracellular delivery for targeted cancer therapy. , 2014, Angewandte Chemie.

[144]  Jiahua Zhu,et al.  Mechano-Responsive Hydrogels Crosslinked by Block Copolymer Micelles. , 2012, Soft matter.

[145]  Y. Tabata,et al.  Ultrasound enhances in vivo tumor expression of plasmid DNA by PEG-introduced cationized dextran. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[146]  V. Muzykantov,et al.  Acute and chronic shear stress differently regulate endothelial internalization of nanocarriers targeted to platelet-endothelial cell adhesion molecule-1. , 2012, ACS nano.

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

[148]  S. Alper,et al.  Hemodynamic shear stress and its role in atherosclerosis. , 1999, JAMA.

[149]  Christopher W. Bielawski,et al.  Methods for activating and characterizing mechanically responsive polymers. , 2013, Chemical Society reviews.

[150]  S. Guido,et al.  Dynamic flow behaviour of surfactant vesicles under shear flow: role of a multilamellar microstructure , 2013 .

[151]  Samir Mitragotri,et al.  Healing sound: the use of ultrasound in drug delivery and other therapeutic applications , 2005, Nature Reviews Drug Discovery.

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

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

[154]  Timothy L. Routh,et al.  Function of an Implanted Tissue Glucose Sensor for More than 1 Year in Animals , 2010, Science Translational Medicine.

[155]  Kinam Park.  Controlled drug delivery systems: past forward and future back. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[156]  Mary M. Caruso,et al.  Mechanically-induced chemical changes in polymeric materials. , 2009, Chemical reviews.

[157]  T. Budtova,et al.  Shear-induced solvent release from gel particles: application to drug-delivery systems. , 2002, International journal of pharmaceutics.

[158]  P. Grayburn,et al.  Cardiovascular drug delivery with ultrasound and microbubbles. , 2014, Advanced drug delivery reviews.

[159]  Zhefu Chen,et al.  Organization of glucose-responsive systems and their properties. , 2011, Chemical reviews.

[160]  A. Beaudoin,et al.  Analysis of shear stress and hemodynamic factors in a model of coronary artery stenosis and thrombosis. , 1993, The American journal of physiology.

[161]  J. Kuszak,et al.  Development of inherently echogenic liposomes as an ultrasonic contrast agent. , 1996, Journal of pharmaceutical sciences.

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

[163]  K. Sharma,et al.  Targeted renal therapies through microbubbles and ultrasound. , 2010, Advanced drug delivery reviews.

[164]  Yanyan Cao,et al.  Catalytic nanomotors: autonomous movement of striped nanorods. , 2004, Journal of the American Chemical Society.

[165]  Filiz Kuralay,et al.  Ultrasound-propelled nanoporous gold wire for efficient drug loading and release. , 2014, Small.

[166]  A. Kolozsvary,et al.  Increased tumor cures using combined radiosurgery and BCNU in the treatment of 9l glioma in the rat brain. , 2000, International journal of radiation oncology, biology, physics.

[167]  Guanghui Ma,et al.  Co-Assembly of Heparin and Polypeptide Hybrid Nanoparticles for Biomimetic Delivery and Anti-Thrombus Therapy. , 2016, Small.

[168]  W. Pitt,et al.  Ultrasonic gene and drug delivery using eLiposomes. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[169]  Ayusman Sen,et al.  Fantastic voyage: designing self-powered nanorobots. , 2012, Angewandte Chemie.

[170]  C. Yeh,et al.  Superparamagnetic iron oxide and drug complex-embedded acoustic droplets for ultrasound targeted theranosis. , 2013, Biomaterials.

[171]  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.

[172]  Keng-Shiang Huang,et al.  Anti-inflammatory effect with high intensity focused ultrasound-mediated pulsatile delivery of diclofenac. , 2012, Biomaterials.

[173]  Zhen Gu,et al.  Spatiotemporal drug delivery using laser-generated-focused ultrasound system. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[174]  Joseph Kost,et al.  Ultrasound mediated transdermal drug delivery. , 2014, Advanced drug delivery reviews.

[175]  Jonathan A. Kopechek,et al.  Triggered Drug Release from Superhydrophobic Meshes using High‐Intensity Focused Ultrasound , 2013, Advanced healthcare materials.

[176]  Paul S. Sheeran,et al.  Targeted drug delivery with focus ultrasound-induced blood-brain barrier opening Using acoustically-activated nanodroplets , 2013, 2013 IEEE International Ultrasonics Symposium (IUS).

[177]  J. Kost,et al.  Ultrasound-enhanced polymer degradation and release of incorporated substances. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[178]  Robert Langer,et al.  Emerging Frontiers in Drug Delivery , 2016 .

[179]  Vassilis Sboros,et al.  Response of contrast agents to ultrasound. , 2008, Advanced drug delivery reviews.

[180]  R. Langer,et al.  Enzymatically controlled drug delivery. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[181]  S. Mitragotri,et al.  Transdermal Delivery of Heparin and Low-Molecular Weight Heparin Using Low-Frequency Ultrasound , 2001, Pharmaceutical Research.

[182]  Wei Wang,et al.  Acoustic propulsion of nanorod motors inside living cells. , 2014, Angewandte Chemie.

[183]  Inga Cicenaite,et al.  Composition of PLGA and PEI/DNA nanoparticles improves ultrasound-mediated gene delivery in solid tumors in vivo. , 2008, Cancer letters.

[184]  Brian D. MacCraith,et al.  Nanoparticle-based drug delivery: case studies for cancer and cardiovascular applications , 2011, Cellular and Molecular Life Sciences.

[185]  R. Langer,et al.  A physical mechanism to explain the delivery of chemical penetration enhancers into skin during transdermal sonophoresis - Insight into the observed synergism. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[186]  Linhong Deng,et al.  Magnetically Triggered Reversible Controlled Drug Delivery from Microfabricated Polymeric Multireservoir Devices , 2009 .

[187]  R. Vandenbroucke,et al.  mRNA-Lipoplex loaded microbubble contrast agents for ultrasound-assisted transfection of dendritic cells. , 2011, Biomaterials.

[188]  T. Cloughesy,et al.  Pharmacological blood-brain barrier modification for selective drug delivery , 1995, Journal of Neuro-Oncology.

[189]  Y. Bae,et al.  Thermosensitive sol-gel reversible hydrogels. , 2002, Advanced drug delivery reviews.

[190]  A. Klibanov,et al.  Nucleic acid delivery with microbubbles and ultrasound. , 2014, Advanced drug delivery reviews.

[191]  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.

[192]  P. Dayton,et al.  Experimental and theoretical evaluation of microbubble behavior: effect of transmitted phase and bubble size , 2000, IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control.

[193]  Dean-Mo Liu,et al.  Core/Single‐Crystal‐Shell Nanospheres for Controlled Drug Release via a Magnetically Triggered Rupturing Mechanism , 2008, Advanced materials.

[194]  Katherine W Ferrara,et al.  Lipid-shelled vehicles: engineering for ultrasound molecular imaging and drug delivery. , 2009, Accounts of chemical research.

[195]  Zhigang Suo,et al.  Ultrasound-triggered disruption and self-healing of reversibly cross-linked hydrogels for drug delivery and enhanced chemotherapy , 2014, Proceedings of the National Academy of Sciences.

[196]  Y. Negishi,et al.  Delivery of an Angiogenic Gene into Ischemic Muscle by Novel Bubble Liposomes Followed by Ultrasound Exposure , 2011, Pharmaceutical Research.

[197]  D. Kohane,et al.  HYDROGELS IN DRUG DELIVERY: PROGRESS AND CHALLENGES , 2008 .

[198]  V. Torchilin.  Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery , 2014, Nature Reviews Drug Discovery.

[199]  B. M. Wohl,et al.  Interaction between drug delivery vehicles and cells under the effect of shear stress. , 2015, Biomicrofluidics.

[200]  Kullervo Hynynen,et al.  Ultrasound for drug and gene delivery to the brain. , 2008, Advanced drug delivery reviews.

[201]  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.

[202]  Ai-Ho Liao,et al.  Ultrasound-aided microbubbles facilitate the delivery of drugs to the inner ear via the round window membrane. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[203]  O. De Wever,et al.  Targeted liposome-loaded microbubbles for cell-specific ultrasound-triggered drug delivery. , 2013, Small.

[204]  Constance B. Bailey,et al.  Mechanobiochemistry: harnessing biomacromolecules for force-responsive materials , 2013 .

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

[206]  J. Leroux,et al.  pH-sensitive vesicles, polymeric micelles, and nanospheres prepared with polycarboxylates. , 2012, Advanced drug delivery reviews.

[207]  Ralf Seip,et al.  Ultrasound-triggered release of materials entrapped in microbubble-liposome constructs: a tool for targeted drug delivery. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[208]  Zhen Gu,et al.  Cocoon-Like Self-Degradable DNA Nanoclew for Anticancer Drug Delivery , 2014, Journal of the American Chemical Society.

[209]  Stephen Meairs,et al.  Self-assembled liposome-loaded microbubbles: The missing link for safe and efficient ultrasound triggered drug-delivery. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[210]  Tayyaba Hasan,et al.  Development and applications of photo-triggered theranostic agents. , 2010, Advanced drug delivery reviews.

[211]  C. Prestidge,et al.  Perspective and potential of oral lipid-based delivery to optimize pharmacological therapies against cardiovascular diseases. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[212]  Nico de Jong,et al.  Acoustic behavior of microbubbles and implications for drug delivery. , 2014, Advanced drug delivery reviews.

[213]  Dean-Mo Liu,et al.  Magnetic-sensitive behavior of intelligent ferrogels for controlled release of drug. , 2006, Langmuir : the ACS journal of surfaces and colloids.

[214]  S. Biswas,et al.  Hypoxia-targeted siRNA delivery. , 2014, Angewandte Chemie.

[215]  Katsuhiko Ariga,et al.  β-Cyclodextrin-crosslinked alginate gel for patient-controlled drug delivery systems: regulation of host-guest interactions with mechanical stimuli. , 2013, Journal of materials chemistry. B.

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

[217]  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.

[218]  A. Sabnis,et al.  Shear-regulated uptake of nanoparticles by endothelial cells and development of endothelial-targeting nanoparticles. , 2009, Journal of biomedical materials research. Part A.

[219]  Douglas L. Miller,et al.  Ultrasound-enhanced transfection activity of HPMA-stabilized DNA polyplexes with prolonged plasma circulation. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[220]  A. J. Tavares,et al.  Analysis of nanoparticle delivery to tumours , 2016 .

[221]  S. Jacobo,et al.  Composites of polymeric gels and magnetic nanoparticles: Preparation and drug release behavior , 2007 .

[222]  H. Xia,et al.  High intensity focused ultrasound-responsive release behavior of PLA-b-PEG copolymer micelles. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[223]  B. Müller,et al.  Shear-stress sensitive lenticular vesicles for targeted drug delivery. , 2012, Nature nanotechnology.

[224]  Jinming Hu,et al.  Enzyme-responsive polymeric assemblies, nanoparticles and hydrogels. , 2012, Chemical Society reviews.

[225]  Yixiao Zhang,et al.  Real-Time Monitoring of ATP-Responsive Drug Release Using Mesoporous-Silica-Coated Multicolor Upconversion Nanoparticles. , 2015, ACS nano.

[226]  William D. Callister,et al.  Materials Science and Engineering: An Introduction , 1985 .

[227]  Frank Caruso,et al.  Engineering and evaluating drug delivery particles in microfluidic devices. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[228]  Raimo Hartmann,et al.  Adenosine Triphosphate-Triggered Release of Macromolecular and Nanoparticle Loads from Aptamer/DNA-Cross-Linked Microcapsules. , 2015, ACS nano.

[229]  Andrew J Boydston,et al.  Successive mechanochemical activation and small molecule release in an elastomeric material. , 2014, Journal of the American Chemical Society.

[230]  Katsuhiko Ariga,et al.  Mechanical Control of Nanomaterials and Nanosystems , 2012 .

[231]  S. Mitragotri,et al.  Ultrasound-mediated transdermal protein delivery , 1995, Science.

[232]  C. Alexiou,et al.  Nano-biomaterials for cardiovascular applications: Clinical perspective. , 2016, Journal of controlled release : official journal of the Controlled Release Society.

[233]  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.

[234]  Alexander L. Klibanov,et al.  Microbubbles in ultrasound-triggered drug and gene delivery. , 2008, Advanced drug delivery reviews.

[235]  S. Mitragotri,et al.  Ultrasound-induced cavitation: applications in drug and gene delivery , 2006, Expert opinion on drug delivery.

[236]  Zhen Gu,et al.  ATP-triggered anticancer drug delivery , 2014, Nature Communications.

[237]  M. Brandl,et al.  Ultrasound-mediated destabilization and drug release from liposomes comprising dioleoylphosphatidylethanolamine. , 2011, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[238]  Nathan McDannold,et al.  Ultrasound-mediated blood-brain barrier disruption for targeted drug delivery in the central nervous system. , 2014, Advanced drug delivery reviews.

[239]  B. Teo,et al.  Cell response to PEGylated poly(dopamine) coated liposomes considering shear stress. , 2013, Biochimica et biophysica acta.

[240]  Mark Borden,et al.  State-of-the-art materials for ultrasound-triggered drug delivery. , 2014, Advanced drug delivery reviews.

[241]  Deborah Vela,et al.  Ultrasound-enhanced delivery of targeted echogenic liposomes in a novel ex vivo mouse aorta model. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[242]  Michael R Hamblin,et al.  Smart micro/nanoparticles in stimulus-responsive drug/gene delivery systems. , 2016, Chemical Society reviews.

[243]  G. Khomutov,et al.  Nanocomposite Microcontainers with High Ultrasound Sensitivity , 2010 .

[244]  Robert Langer,et al.  Impact of nanotechnology on drug delivery. , 2009, ACS nano.

[245]  K. Hynynen,et al.  Noninvasive MR imaging-guided focal opening of the blood-brain barrier in rabbits. , 2001, Radiology.

[246]  Zhen Gu,et al.  Emerging micro- and nanotechnology based synthetic approaches for insulin delivery. , 2014, Chemical Society reviews.

[247]  Lawrence A. Crum,et al.  Applications of high-intensity focused ultrasound in medicine: Spotlight on neurological applications , 2007 .

[248]  Arnan Mitchell,et al.  A shear gradient–dependent platelet aggregation mechanism drives thrombus formation , 2009, Nature Medicine.

[249]  Hirokazu Miyoshi,et al.  Encapsulated ultrasound microbubbles: therapeutic application in drug/gene delivery. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[250]  D. Pioletti,et al.  Controlled release from a mechanically-stimulated thermosensitive self-heating composite hydrogel. , 2014, Biomaterials.

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

[252]  Y. Barenholz.  Nanomedicine: Shake up the drug containers. , 2012, Nature nanotechnology.

[253]  Mitsuru Hashida,et al.  Ultrasound induced cancer immunotherapy. , 2014, Advanced drug delivery reviews.

[254]  D. J. Phillips,et al.  Redox-sensitive materials for drug delivery: targeting the correct intracellular environment, tuning release rates, and appropriate predictive systems. , 2014, Antioxidants & redox signaling.

[255]  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.

[256]  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.

[257]  Joseph Hemmerlé,et al.  Mechanotransductive surfaces for reversible biocatalysis activation. , 2009, Nature materials.

[258]  Shao-ling Huang,et al.  Liposomes in ultrasonic drug and gene delivery. , 2008, Advanced drug delivery reviews.

[259]  Howard A. Stone,et al.  Gas-core triple emulsions for ultrasound triggered release , 2013 .

[260]  Zhen Gu,et al.  Stretch-Triggered Drug Delivery from Wearable Elastomer Films Containing Therapeutic Depots. , 2015, ACS nano.

[261]  David J. Mooney,et al.  Controlled growth factor release from synthetic extracellular matrices , 2000, Nature.

[262]  T. Mallouk,et al.  Powering nanorobots. , 2009, Scientific American.

[263]  S. Mitragotri.  Devices for overcoming biological barriers: the use of physical forces to disrupt the barriers. , 2013, Advanced drug delivery reviews.

[264]  Dean Ho,et al.  Cancer Nanomedicine: From Drug Delivery to Imaging , 2013, Science Translational Medicine.

[265]  Ayusman Sen,et al.  Catalytic motors for transport of colloidal cargo. , 2008, Nano letters.

[266]  P. Cullis,et al.  Drug Delivery Systems: Entering the Mainstream , 2004, Science.

[267]  S. Murdan.  Electro-responsive drug delivery from hydrogels. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[268]  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.

[269]  D. Belnap,et al.  Encapsulating nanoemulsions inside eLiposomes for ultrasonic drug delivery. , 2012, Langmuir : the ACS journal of surfaces and colloids.