More info
  • ReceivedFeb 25, 2021
  • AcceptedJun 27, 2021
  • PublishedAug 25, 2021


Funded by

the National Natural Science Foundation of China(31971169,81822022,81771846,81571810)

the Beijing Natural Science Foundation(7182180)

the National Key Research and Development Program of China(2018YFC0116003,2016YFA0201400)

Beijing Talents Foundation(2018000021223ZK48)

and Peking University Third Hospital(BYSYZD2019018,jyzc2018-02,BYSY2015023)


This work was supported by the National Natural Science Foundation of China (31971169, 81822022, 81771846, 81571810), the Beijing Natural Science Foundation (7182180), National Key Research and Development Program of China (2018YFC0116003, 2016YFA0201400), Beijing Talents Foundation (2018000021223ZK48), and Peking University Third Hospital (BYSYZD2019018, jyzc2018-02, BYSY2015023).

Interest statement

The author(s) declare that they have no conflict of interest.


[1] Ahmadi F., McLoughlin I.V., Chauhan S., ter-Haar G.. Bio-effects and safety of low-intensity, low-frequency ultrasonic exposure. Prog Biophys Mol Biol, 2012, 108: 119-138 CrossRef PubMed Google Scholar

[2] Aryal M., Vykhodtseva N., Zhang Y.Z., Park J., McDannold N.. Multiple treatments with liposomal doxorubicin and ultrasound-induced disruption of blood-tumor and blood-brain barriers improve outcomes in a rat glioma model. J Control Release, 2013, 169: 103-111 CrossRef PubMed Google Scholar

[3] Bekeredjian R., Kroll R.D., Fein E., Tinkov S., Coester C., Winter G., Katus H.A., Kulaksiz H.. Ultrasound targeted microbubble destruction increases capillary permeability in hepatomas. Ultrasound Med Biol, 2007, 33: 1592-1598 CrossRef PubMed Google Scholar

[4] Bioley G., Lassus A., Bussat P., Terrettaz J., Tranquart F., Corthésy B.. Gas-filled microbubble-mediated delivery of antigen and the induction of immune responses. Biomaterials, 2012, 33: 5935-5946 CrossRef PubMed Google Scholar

[5] Böhmer M.R., Chlon C.H.T., Raju B.I., Chin C.T., Shevchenko T., Klibanov A.L.. Focused ultrasound and microbubbles for enhanced extravasation. J Control Release, 2010, 148: 18-24 CrossRef PubMed Google Scholar

[6] Boissenot T., Bordat A., Fattal E., Tsapis N.. Ultrasound-triggered drug delivery for cancer treatment using drug delivery systems: From theoretical considerations to practical applications. J Control Release, 2016, 241: 144-163 CrossRef PubMed Google Scholar

[7] Carpentier A., Canney M., Vignot A., Reina V., Beccaria K., Horodyckid C., Karachi C., Leclercq D., Lafon C., Chapelon J.Y., et al. Clinical trial of blood-brain barrier disruption by pulsed ultrasound. Sci Transl Med, 2016, 8: 343re2 CrossRef PubMed Google Scholar

[8] Chen Y., Liang Y., Jiang P., Li F., Yu B., Yan F.. Lipid/PLGA hybrid microbubbles as a versatile platform for noninvasive image-guided targeted drug delivery. ACS Appl Mater Interfaces, 2019, 11: 41842-41852 CrossRef PubMed Google Scholar

[9] Ciancia S., Cafarelli A., Zahoranova A., Menciassi A., Ricotti L.. Pulsatile drug delivery system triggered by acoustic radiation force. Front Bioeng Biotechnol, 2020, 8: 317 CrossRef PubMed Google Scholar

[10] Dasgupta A., Liu M., Ojha T., Storm G., Kiessling F., Lammers T.. Ultrasound-mediated drug delivery to the brain: Principles, progress and prospects. Drug Discov Today Technol, 2016, 20: 41-48 CrossRef PubMed Google Scholar

[11] Dayton P.A., Allen J.S., Ferrara K.W.. The magnitude of radiation force on ultrasound contrast agents. J Acoust Soc Am, 2002, 112: 2183-2192 CrossRef PubMed ADS Google Scholar

[12] Dayton P.A., Morgan K.E., Klibanov A.L., Brandenburger G.H., Ferrara K.W.. Optical and acoustical observations of the effects of ultrasound on contrast agents. IEEE Trans Ultrason Ferroelect Freq Contr, 1999, 46: 220-232 CrossRef PubMed Google Scholar

[13] de Smet M., Heijman E., Langereis S., Hijnen N.M., Grüll H.. Magnetic resonance imaging of high intensity focused ultrasound mediated drug delivery from temperature-sensitive liposomes: An in vivo proof-of-concept study. J Control Release, 2011, 150: 102-110 CrossRef PubMed Google Scholar

[14] Deng Z., Yan F., Jin Q., Li F., Wu J., Liu X., Zheng H.. Reversal of multidrug resistance phenotype in human breast cancer cells using doxorubicin-liposome-microbubble complexes assisted by ultrasound. J Control Release, 2014, 174: 109-116 CrossRef PubMed Google Scholar

[15] Dewey W.C., Diederich C.J., Dewhirst M.W.. Hyperthermia classic commentary: ‘Arrhenius relationships from the molecule and cell to the clinic’ by William Dewey, Int. J. Hyperthermia, 10: 457–483, 1994. Int J Hyperthermia, 2009, 25: 21-24 CrossRef PubMed Google Scholar

[16] Didenko Y.T., McNamara William B. I., Suslick K.S.. Effect of noble gases on sonoluminescence temperatures during multibubble cavitation. Phys Rev Lett, 2000a, 84: 777-780 CrossRef PubMed ADS Google Scholar

[17] Didenko Y.T., McNamara William B. I., Suslick K.S.. Molecular emission from single-bubble sonoluminescence. Nature, 2000b, 407: 877-879 CrossRef PubMed ADS Google Scholar

[18] Dromi S., Frenkel V., Luk A., Traughber B., Angstadt M., Bur M., Poff J., Xie J., Libutti S.K., Li K.C.P., et al. Pulsed-high intensity focused ultrasound and low temperature-sensitive liposomes for enhanced targeted drug delivery and antitumor effect. Clin Cancer Res, 2007, 13: 2722-2727 CrossRef PubMed Google Scholar

[19] Duco, W., Grosso, V., Zaccari, D., and Soltermann, A.T. (2016). Generation of ROS mediated by mechanical waves (ultrasound) and its possible applications. Methods 109, 141–148. Google Scholar

[20] Eisenbrey J.R., Soulen M.C., Wheatley M.A.. Delivery of encapsulated doxorubicin by ultrasound-mediated size reduction of drug-loaded polymer contrast agents. IEEE Trans Biomed Eng, 2010, 57: 24-28 CrossRef PubMed Google Scholar

[21] Frenkel V.. Ultrasound mediated delivery of drugs and genes to solid tumors. Adv Drug Deliv Rev, 2008, 60: 1193-1208 CrossRef PubMed Google Scholar

[22] Frenkel V., Kimmel E., Iger Y.. Ultrasound-induced intercellular space widening in fish epidermis. Ultrasound Med Biol, 2000, 26: 473-480 CrossRef Google Scholar

[23] Ge G., Wu H., Xiong F., Zhang Y., Guo Z., Bian Z., Xu J., Gu C., Gu N., Chen X., et al. The cytotoxicity evaluation of magnetic iron oxide nanoparticles on human aortic endothelial cells. Nanoscale Res Lett, 2013, 8: 215 CrossRef PubMed ADS Google Scholar

[24] Ge H.Y., Miao L.Y., Xiong L.L., Yan F., Zheng C.S., Wang J.R., Jia J.W., Cui L.G., Chen W.. High-intensity focused ultrasound treatment of late-stage pancreatic body carcinoma: Optimal tumor depth for safe ablation. Ultrasound Med Biol, 2014, 40: 947-955 CrossRef PubMed Google Scholar

[25] Geers B., Dewitte H., De Smedt S.C., Lentacker I.. Crucial factors and emerging concepts in ultrasound-triggered drug delivery. J Control Release, 2012, 164: 248-255 CrossRef PubMed Google Scholar

[26] Geers B., De Wever O., Demeester J., Bracke M., De Smedt S.C., Lentacker I.. Targeted liposome-loaded microbubbles for cell-specific ultrasound-triggered drug delivery. Small, 2013, 9: 4027-4035 CrossRef PubMed Google Scholar

[27] Gray M.D., Lyon P.C., Mannaris C., Folkes L.K., Stratford M., Campo L., Chung D.Y.F., Scott S., Anderson M., Goldin R., et al. Focused ultrasound hyperthermia for targeted drug release from thermosensitive liposomes: results from a phase I trial. Radiology, 2019, 291: 232-238 CrossRef PubMed Google Scholar

[28] Greenleaf W.J., Bolander M.E., Sarkar G., Goldring M.B., Greenleaf J.F.. Artificial cavitation nuclei significantly enhance acoustically induced cell transfection. Ultrasound Med Biol, 1998, 24: 587-595 CrossRef Google Scholar

[29] Grüll H., Langereis S.. Hyperthermia-triggered drug delivery from temperature-sensitive liposomes using MRI-guided high intensity focused ultrasound. J Control Release, 2012, 161: 317-327 CrossRef PubMed Google Scholar

[30] Hernot S., Klibanov A.L.. Microbubbles in ultrasound-triggered drug and gene delivery. Adv Drug Deliv Rev, 2008, 60: 1153-1166 CrossRef PubMed Google Scholar

[31] Hijnen N., Kneepkens E., de Smet M., Langereis S., Heijman E., Grüll H.. Thermal combination therapies for local drug delivery by magnetic resonance-guided high-intensity focused ultrasound. Proc Natl Acad Sci USA, 2017, 114: E4802-E4811 CrossRef PubMed ADS Google Scholar

[32] Hua X., Liu P., Gao Y.H., Tan K.B., Zhou L.N., Liu Z., Li X., Zhou S.W., Gao Y.J.. Construction of thrombus-targeted microbubbles carrying tissue plasminogen activator and their in vitro thrombolysis efficacy: A primary research. J Thromb Thrombolysis, 2010, 30: 29-35 CrossRef PubMed Google Scholar

[33] Jain A., Tiwari A., Verma A., Jain S.K.. Ultrasound-based triggered drug delivery to tumors. Drug Deliv Transl Res, 2018, 8: 150-164 CrossRef PubMed Google Scholar

[34] Jung S.E., Cho S.H., Jang J.H., Han J.Y.. High-intensity focused ultrasound ablation in hepatic and pancreatic cancer: Complications. Abdom Imag, 2011, 36: 185-195 CrossRef PubMed Google Scholar

[35] Kang J., Wu X., Wang Z., Ran H., Xu C., Wu J., Wang Z., Zhang Y.. Antitumor effect of docetaxel-loaded lipid microbubbles combined with ultrasound-targeted microbubble activation on VX2 rabbit liver tumors. J Ultrasound Med, 2010, 29: 61-70 CrossRef PubMed Google Scholar

[36] Kiesel H., Renz A., Hasselbach F.. Observation of Hanbury Brown-Twiss anticorrelations for free electrons. Nature, 2002, 418: 392-394 CrossRef PubMed ADS Google Scholar

[37] Kilroy J.P., Klibanov A.L., Wamhoff B.R., Hossack J.A.. Intravascular ultrasound catheter to enhance microbubble-based drug delivery via acoustic radiation force. IEEE Trans Ultrason Ferroelect Freq Contr, 2012, 59: 2156-2166 CrossRef PubMed Google Scholar

[38] Kopechek J.A., Carson A.R., McTiernan C.F., Chen X., Hasjim B., Lavery L., Sen M., Grandis J.R., Villanueva F.S.. Ultrasound targeted microbubble destruction-mediated delivery of a transcription factor decoy inhibits STAT3 signaling and tumor growth. Theranostics, 2015, 5: 1378-1387 CrossRef PubMed Google Scholar

[39] Kotopoulis S., Dimcevski G., Helge Gilja O., Hoem D., Postema M.. Treatment of human pancreatic cancer using combined ultrasound, microbubbles, and gemcitabine: A clinical case study. Med Phys, 2013, 40: 072902 CrossRef PubMed ADS Google Scholar

[40] Kwekkeboom R.F.J., Sluijter J.P.G., van Middelaar B.J., Metz C.H., Brans M.A., Kamp O., Paulus W.J., Musters R.J.P.. Increased local delivery of antagomir therapeutics to the rodent myocardium using ultrasound and microbubbles. J Control Release, 2016, 222: 18-31 CrossRef PubMed Google Scholar

[41] Lefor A.T., Makohon S., Ackerman N.B.. The effects of hyperthermia on vascular permeability in experimental liver metastasis. J Surg Oncol, 1985, 28: 297-300 CrossRef PubMed Google Scholar

[42] Lentacker I., De Cock I., Deckers R., De Smedt S.C., Moonen C.T.W.. Understanding ultrasound induced sonoporation: Definitions and underlying mechanisms. Adv Drug Deliver Rev, 2014, 72: 49-64 CrossRef PubMed Google Scholar

[43] Li P., Zheng Y., Ran H., Tan J., Lin Y., Zhang Q., Ren J., Wang Z.. Ultrasound triggered drug release from 10-hydroxy-camptothecin-loaded phospholipid microbubbles for targeted tumor therapy in mice. J Control Release, 2012, 162: 349-354 CrossRef PubMed Google Scholar

[44] Liang X., Gao J., Jiang L., Luo J., Jing L., Li X., Jin Y., Dai Z.. Nanohybrid liposomal cerasomes with good physiological stability and rapid temperature responsiveness for high intensity focused ultrasound triggered local chemotherapy of cancer. ACS Nano, 2015, 9: 1280-1293 CrossRef PubMed Google Scholar

[45] Lin C.Y., Lin Y.C., Huang C.Y., Wu S.R., Chen C.M., Liu H.L.. Ultrasound-responsive neurotrophic factor-loaded microbubble- liposome complex: Preclinical investigation for Parkinson’s disease treatment. J Control Release, 2020, 321: 519-528 CrossRef PubMed Google Scholar

[46] Liu J., Chen Y., Wang G., Jin Q., Sun Z., Lv Q., Wang J., Yang Y., Zhang L., Xie M.. Improving acute cardiac transplantation rejection therapy using ultrasound-targeted FK506-loaded microbubbles in rats. Biomater Sci, 2019, 7: 3729-3740 CrossRef PubMed Google Scholar

[47] Lum A.F.H., Borden M.A., Dayton P.A., Kruse D.E., Simon S.I., Ferrara K.W.. Ultrasound radiation force enables targeted deposition of model drug carriers loaded on microbubbles. J Control Release, 2006, 111: 128-134 CrossRef PubMed Google Scholar

[48] Ma X., Yao M., Shi J., Li X., Gao Y., Luo Q., Hou R., Liang X., Wang F.. High intensity focused ultrasound-responsive and ultrastable cerasomal perfluorocarbon nanodroplets for alleviating tumor multidrug resistance and epithelial-mesenchymal transition. ACS Nano, 2020, 14: 15904-15918 CrossRef PubMed Google Scholar

[49] Meijering B.D.M., Juffermans L.J.M., van Wamel A., Henning R.H., Zuhorn I.S., Emmer M., Versteilen A.M.G., Paulus W.J., van Gilst W.H., Kooiman K., et al. Ultrasound and microbubble-targeted delivery of macromolecules is regulated by induction of endocytosis and pore formation. Circ Res, 2009, 104: 679-687 CrossRef PubMed Google Scholar

[50] Mozafari M., Shimoda M., Urbanska A.M., Laurent S.. Ultrasound-targeted microbubble destruction: Toward a new strategy for diabetes treatment. Drug Discov Today, 2016, 21: 540-543 CrossRef PubMed Google Scholar

[51] Mura S., Nicolas J., Couvreur P.. Stimuli-responsive nanocarriers for drug delivery. Nat Mater, 2013, 12: 991-1003 CrossRef ADS Google Scholar

[52] Oerlemans C., Deckers R., Storm G., Hennink W.E., Nijsen J.F.W.. Evidence for a new mechanism behind HIFU-triggered release from liposomes. J Control Release, 2013, 168: 327-333 CrossRef PubMed Google Scholar

[53] Palmeri M.L., McAleavey S.A., Fong K.L., Trahey G.E., Nightingale K.R.. Dynamic mechanical response of elastic spherical inclusions to impulsive acoustic radiation force excitation. IEEE Trans Ultrason Ferroelect Freq Contr, 2006, 53: 2065-2079 CrossRef PubMed Google Scholar

[54] Park S.M., Kim M.S., Park S.J., Park E.S., Choi K.S., Kim Y.S., Kim H.R.. Novel temperature-triggered liposome with high stability: Formulation, in vitro evaluation, and in vivo study combined with high-intensity focused ultrasound (HIFU). J Control Release, 2013, 170: 373-379 CrossRef PubMed Google Scholar

[55] Paulides M.M., Dobsicek Trefna H., Curto S., Rodrigues D.B.. Recent technological advancements in radiofrequency- and microwave-mediated hyperthermia for enhancing drug delivery. Adv Drug Deliv Rev, 2020, 163–164: 3-18 CrossRef Google Scholar

[56] Pitt W.G., Husseini G.A., Staples B.J.. Ultrasonic drug delivery—A general review. Expert Opin Drug Deliv, 2004, 1: 37-56 CrossRef PubMed Google Scholar

[57] Poon R.T., Borys N.. Lyso-thermosensitive liposomal doxorubicin: An adjuvant to increase the cure rate of radiofrequency ablation in liver cancer. Future Oncol, 2011, 7: 937-945 CrossRef PubMed Google Scholar

[58] Price R.J., Skyba D.M., Kaul S., Skalak T.C.. Delivery of colloidal particles and red blood cells to tissue through microvessel ruptures created by targeted microbubble destruction with ultrasound. Circulation, 1998, 98: 1264-1267 CrossRef PubMed Google Scholar

[59] Rich M.C., Sherwood J., Bartley A.F., Whitsitt Q.A., Lee M., Willoughby W.R., Dobrunz L.E., Bao Y., Lubin F.D., Bolding M.. Focused ultrasound blood brain barrier opening mediated delivery of MRI-visible albumin nanoclusters to the rat brain for localized drug delivery with temporal control. J Control Release, 2020, 324: 172-180 CrossRef PubMed Google Scholar

[60] Sirsi S.R., Borden M.A.. Microbubble compositions, properties and biomedical applications. Bubble Sci Eng Tech, 2009, 1: 3-17 CrossRef PubMed Google Scholar

[61] Snipstad S., Sulheim E., de Lange Davies C., Moonen C., Storm G., Kiessling F., Schmid R., Lammers T.. Sonopermeation to improve drug delivery to tumors: From fundamental understanding to clinical translation. Expert Opin Drug Deliv, 2018, 15: 1249-1261 CrossRef PubMed Google Scholar

[62] Song, C.W. (1984). Effect of local hyperthermia on blood flow and microenvironment: A review. Cancer Res 44, 4721s–4730s. Google Scholar

[63] Song C.W., Kang M.S., Rhee J.G., Levitt S.H.. Effect of hyperthermia on vascular function in normal and neoplastic tissues. Ann NY Acad Sci, 1980, 335: 35-47 CrossRef PubMed ADS Google Scholar

[64] Song K.H., Fan A.C., Brlansky J.T., Trudeau T., Gutierrez-Hartmann A., Calvisi M.L., Borden M.A.. High efficiency molecular delivery with sequential low-energy sonoporation bursts. Theranostics, 2015, 5: 1419-1427 CrossRef PubMed Google Scholar

[65] Tian Y., Liu Z., Tan H., Hou J., Wen X., Yang F., Cheng W.. New aspects of ultrasound-mediated targeted delivery and therapy for cancer. Int J Nanomed, 2020, 15: 401-418 CrossRef PubMed Google Scholar

[66] Ting C.Y., Fan C.H., Liu H.L., Huang C.Y., Hsieh H.Y., Yen T.C., Wei K.C., Yeh C.K.. Concurrent blood-brain barrier opening and local drug delivery using drug-carrying microbubbles and focused ultrasound for brain glioma treatment. Biomaterials, 2012, 33: 704-712 CrossRef PubMed Google Scholar

[67] Tinkov S., Coester C., Serba S., Geis N.A., Katus H.A., Winter G., Bekeredjian R.. New doxorubicin-loaded phospholipid microbubbles for targeted tumor therapy: In-vivo characterization. J Control Release, 2010, 148: 368-372 CrossRef PubMed Google Scholar

[68] Unger E.C., McCreery T.P., Sweitzer R.H., Shen D.K., Wu G.L.. In vitro studies of a new thrombus-specific ultrasound contrast agent. Am J Cardiol, 1998, 81: 58G-61G CrossRef Google Scholar

[69] Wang P., Sun L., Sun S., Xu M., Zhang L., Zhang J., Gao L., Chen Q., Liang X.. Research advances in ultrasound imaging for tumor in situ. Adv Ultrasound Diagn Ther, 2020, 4: 169 CrossRef Google Scholar

[70] Wood B.J., Poon R.T., Locklin J.K., Dreher M.R., Ng K.K., Eugeni M., Seidel G., Dromi S., Neeman Z., Kolf M., et al. Phase I study of heat-deployed liposomal doxorubicin during radiofrequency ablation for hepatic malignancies. J Vasc Interv Rad, 2012, 23: 248-255.e7 CrossRef PubMed Google Scholar

[71] Wu S.K., Chiang C.F., Hsu Y.H., Lin T.H., Liou H.C., Fu W.M., Lin W.L.. Short-time focused ultrasound hyperthermia enhances liposomal doxorubicin delivery and antitumor efficacy for brain metastasis of breast cancer. Int J Nanomed, 2014, 9: 4485 CrossRef PubMed Google Scholar

[72] Xie F., Gao S., Wu J., Lof J., Radio S., Vignon F., Shi W., Powers J., Unger E., Everbach E.C., et al. Diagnostic ultrasound induced inertial cavitation to non-invasively restore coronary and microvascular flow in acute myocardial infarction. PLoS ONE, 2013, 8: e69780 CrossRef PubMed ADS Google Scholar

[73] Yang H., Sun Y., Wei J., Xu L., Tang Y., Yang L., Zhang X., Lu Y.. The effects of ultrasound-targeted microbubble destruction (UTMD) carrying IL-8 monoclonal antibody on the inflammatory responses and stability of atherosclerotic plaques. Biomed Pharmacother, 2019, 118: 109161 CrossRef PubMed Google Scholar

[74] Yang Y., Mu J., Xing B.. Photoactivated drug delivery and bioimaging. WIREs Nanomed Nanobiotechnol, 2017, 9: e1408 CrossRef PubMed Google Scholar

[75] Yudina A., Lepetit-Coiffé M., Moonen C.T.W.. Evaluation of the temporal window for drug delivery following ultrasound-mediated membrane permeability enhancement. Mol Imag Biol, 2011, 13: 239-249 CrossRef PubMed Google Scholar

[76] Zagar T.M., Vujaskovic Z., Formenti S., Rugo H., Muggia F., O’Connor B., Myerson R., Stauffer P., Hsu I.C., Diederich C., et al. Two phase I dose-escalation/pharmacokinetics studies of low temperature liposomal doxorubicin (LTLD) and mild local hyperthermia in heavily pretreated patients with local regionally recurrent breast cancer. Int J Hyperthermia, 2014, 30: 285-294 CrossRef PubMed Google Scholar

[77] Zhang L., Sun Z., Ren P., You M., Zhang J., Fang L., Wang J., Chen Y., Yan F., Zheng H., et al. Localized delivery of shRNA against PHD2 protects the heart from acute myocardial infarction through ultrasound-targeted cationic microbubble destruction. Theranostics, 2017, 7: 51-66 CrossRef PubMed Google Scholar

[78] Zhao W., Zhao Y., Wang Q., Liu T., Sun J., Zhang R.. Remote light-responsive nanocarriers for controlled drug delivery: advances and perspectives. Small, 2019, 15: 1903060 CrossRef PubMed Google Scholar

[79] Zhao Y., Tavares A.C., Gauthier M.A.. Nano-engineered electro-responsive drug delivery systems. J Mater Chem B, 2016, 4: 3019-3030 CrossRef PubMed Google Scholar

  • Figure 1

    (Color online) History of the application of ultrasound-induced biophysical effects in controlled drug delivery.

  • Figure 2

    Mechanisms underlying ultrasound-induced thermal effects for drug delivery. A, Thermal effects on cells and tissues can enhance drug delivery (from Boissenot et al., 2016). B, Schematic of high-intensity focused ultrasound-induced thermal effects on drug release in thermo-responsive drug delivery systems (from de Smet et al., 2011).

  • Figure 3

    The application of ultrasound-triggered drug delivery based on thermal effects. A, Schematic of PFC combined with HIFU resulting in DOX and oxygen release in response to ultrasound. B, Tumors ultrasound imaging before, 5, and 10 min after M-HIFU demonstrating oxygen release. C, 4T1 cells viability detected by CCK-8 assay after different treatments. D, Changes in tumor volume of implanted 4T1 cells in response to different treatments (from Ma et al., 2020).

  • Figure 4

    The mechanism of ultrasound-induced cavitation effects for drug delivery. A, Ultrasound-induced cavitation effects increase permeabilization of drug carries to enhance drug delivery (from Chen et al., 2019). B, Different effects involve in affecting the permeability of cell membrane to enhance drug delivery (from Lentacker et al., 2014).

  • Figure 5

    The application of ultrasound-triggered drug delivery based on cavitation effects. A, Schematic illustration for the structure of FK506-MBs and the therapeutic process using UTMD in vivo. B, Survival time of cardiac grafts. Mean survival was significantly longer in the FK506-MB+UTMD group (16.00 d±0.89 d) compared to the PBS group (6.66 d±1.36 d) and FK506 group (12.83 d±1.17 d;n=6) (from Liu et al., 2019).

  • Figure 6

    Mechanism underlying ultrasound-induced ARF for drug delivery. A, ARF can push drug carriers against tumor blood vessel walls (from Tian et al., 2020). B, ARF opens the intercellular space between endothelial cells to enhance drug delivery (from Dasgupta et al., 2016).

  • Figure 7

    (Color online) Summary of recent advances and future research directions for ultrasound-triggered drug delivery.

  • Table 1   Advantages and disadvantages of different external stimuli

    External stimuli





    Spatiotemporal control, low cost

    Limited penetration (depth of penetration: 0.3–0.8 cm)

    (Zhao et al., 2019)

    Electric field

    Spatiotemporal control

    Surgical implantation required, low penetration, sensitive to surrounding medium

    (Zhao et al., 2016)

    Magnetic field

    Spatiotemporal control, noninvasiveness,high penetration

    Cytotoxicity due to accumulation of magnetic particles, high cost

    (Ge et al., 2013)


    Spatiotemporal control, high penetration(depth of penetration: 0.1–10 cm), low cost

    Technically challenging targeting of moving organs, high reflection of air and bone

    (Boissenot et al., 2016)

  • Table 2   Ultrasound-triggered drug delivery based on thermal effectsa)


    Type of liposome(composition/molar ratio)

    US parameters

    Tumor model



    Intensity/peaknegative pressure/power/voltage

    PRF (Hz)



    Dromi* 2007(Dromi et al., 2007)


    1 MHz

    ISATA=1300 W cm−2



    2 min

    Breast cancer

    LTSL combined with mild hyperthermia induced by ultrasound enhanced

    drug delivery andreduced tumor volume

    Hijnen* 2017(Hijnen et al., 2017)

    LTSLs (DPPC:HSPC:Chol:DPPE-PEG2000=50:25:15:3, molar ratio)

    1.44 MHz

    35 W



    15 min


    HIFU combined with LTSL led to deeper cellularuptake and higher DOX concentrations in theinterstitial space

    Wu* 2014(Wu et al., 2014)

    LTSLs (DPPC:MPPC:DSPE-PEG-2000=90:10:4, molar ratio)

    500 kHz

    0.97 MPa



    10 min

    Brain metastasis of breast cancer

    LTSL combined with mild hyperthermia induced by ultrasound increased DOX delivery to brain tumors and inhibited tumor growth

    Gray# 2019(Gray et al., 2019)


    90:10:4, molar ratio)

    0.96 MHz

    50–140 W



    60 min

    Patients withliver tumor

    Demonstrated safety and feasibility of lyso-thermosensitive liposome combined with focused ultrasound for drugdelivery

    Park* 2013(Park et al., 2013)

    STLs (DPPC:DSPE-PEG-2000:cholesterol:modified ELP=55:2:15:0.4125,molar ratio)

    1 MHz

    12 W, ISATA=1,981.6 W cm−2



    15 min for each spot, 4 spots


    Tumor regression at 2 d with combined STLS and mild hyperthermia induced by ultrasound

    Liang* 2015(Liang et al., 2015)

    HTSCs (CFL:DPPC:MSPC:DSPE-PEG-2000=43.25:43.25:9.7:3.8, molar ratio)

    0.5 MHz

    190 mV



    5 min

    Breast cancer

    HTSCs combined with mild hyperthermia induced by ultrasound enhanced drug delivery and reduced tumor volume

    PRF, pulse repetition frequency; NA, not available; *, preclinical studies; #, clinical studies.

  • Table 3   Ultrasound-triggered drug delivery based on cavitation effectsa)


    Type of microbubble(composition/molar orquality ratio)

    Approaches ofdelivery

    US parameters

    Disease model



    Intensity/peak negativepressure

    PRF (Hz)

    Duty cycle


    Aryal* 2013(Aryal et al., 2013)

    Lipid MB (Definity)


    690 kHz

    0.55–0.81 MPa



    60 s

    Glioblastoma tumor

    DOX delivery via combination of US and microbubbles increased mean survival

    Xie* 2013(Xie et al., 2013)

    Lipid MB (MRX 801)


    1.6 MHz

    MI=2 or 1



    30 min

    Acute myocardial infarction

    Microvascular reflow was increased via combination of tissue plasminogen activator with microbubbles and ultrasound

    Kotopoulis# 2013(Kotopoulis et al., 2013)

    Lipid MB (Sonovue)


    1.9 MHz

    0.27 MPa




    Pancreatic cancer

    Gemcitabine delivery via combination of US and microbubbles decreased tumor size and increased the quality of life of patients with pancreatic cancer

    Carpentier# 2016(Carpentier et al., 2016)

    Lipid MB (Sonovue)


    1.05 MHz

    0.5–1.1 MPa



    2.5 min



    Combination of microbubbles withultrasound was safe for BBB-disruption and had potential to optimizechemotherapy delivery

    Hua* 2010(Hua et al., 2010)

    Lipid MB

    (DPPC; DSPC; D-glucose; AT-PEG)


    2 MHz

    1.8 W cm−2



    10 min


    Drug-loaded microbubbles combined with ultrasound resulted in greaterthrombolysis with lower doses

    Kang* 2010(Kang et al., 2010)

    Lipid MB (DPPC:DPPE:DDPA=5 mg: 2 mg:1 mg)


    3,000 kHz

    2 W cm−2



    6 min

    Liver tumor

    Docetaxel-loaded microbubbles combined with US inhibited liver tumor growth and promoted apoptosis

    Tinkov* 2010(Tinkov et al., 2010)

    Lipid MB (DPPC:DPPG:DPPE-PEG2000=1.74 mg: 0.45 mg: 0.08 mg)


    1.3 MHz

    1.2 MPa





    Pancreatic cancer

    DOX-loaded microbubbles combined with US increased DOX delivery and inhibited tumor growth

    Eisenbrey* 2010(Eisenbrey et al., 2010)

    Polymer MB (PLA:camphor=0.5 g: 0.05 g)


    5 MHz




    20 min

    Liver tumor

    Combination of DOX-loadedmicrobubbles and US resulted indecreased hepatic delivery of DOX but increased DOX delivery to tumor tissues

    Ting* 2012(Ting et al., 2012)

    Lipid MB (DPPC: DSPE-PEG-2000=19:1, molar ratio)


    1 MHz

    0.7 MPa




    Glioblastoma multiforme

    1,3-bis(2-chloroethyl)-1- nitrosourea (BCNU)-loaded microbubbles with US controlled tumor progression andimproved mean survival

    Li* 2012(Li et al., 2012)

    Lipid MB (DPPC:DPPA:DPPE-PEG2000=47:10:5, molar ratio)


    1 MHz

    2 W cm−2



    6 min

    Liver tumor

    10-hydroxycamptothecin-loaded microbubbles combined with US resulted in higher drug accumulation and increased tumor inhibition compared with 10-hydroxycamptothecin-loaded microbubbles or 10-hydroxycamptothecin

    Deng* 2014(Deng et al., 2014)

    Lipid MB (DSPC:DSPE-PEG2000:DSPE-PEG2000-biotin=9:0.5:0.5, molar ratio)


    1 MHz

    1.65 W cm−2



    15 s

    Breast cancer

    Drug delivery, cell uptake, and decreased drug efflux with DOX liposome-loaded-microbubbles plus US leading toincreased cytotoxicity

    Liu* 2019(Liu et al., 2019)

    Lipid MB (DSPC:DSPE-PEG2000=9:1, molar ratio)


    1 MHz

    2 W cm−2



    2 min

    transplanted heart

    Enhanced drug delivery, decreased graft rejection, and improved survival

    PRF, pulse repetition frequency; NA, not available; *, preclinical studies; #, clinical studies.

  • Table 4   Summary of effects induced by ultrasound for drug delivery

    Type of effects

    Type of applicable drug delivery systems

    Characteristics of ultrasound parameters

    Current status

    Thermal effects

    Thermosensitive liposomes

    Prolonged duration of ultrasound(predominantly greater than 5 min)

    One clinical study (Gray et al., 2019)

    Cavitation effects


    Shorter duty cycle and duration of ultrasound

    Two clinical studies (Carpentier et al., 2016; Kotopoulis et al., 2013)



    Low negative pressure

    Preclinical studies (Ciancia et al., 2020; Kilroy et al., 2012)


Contact and support