From Wikipedia, the free encyclopedia
(Redirected from Microbubbles)

Microbubbles (MBs) are bubbles smaller than one hundredth of a millimetre in diameter, but larger than one micrometre. They have widespread application in industry, medicine,[1] life science,[2] and food technology.[3] The composition of the bubble shell and filling material determine important design features such as buoyancy, crush strength, thermal conductivity, and acoustic properties.

They are used in medical diagnostics as a contrast agent for ultrasound imaging.[4] The gas-filled microbubbles, typically air or perfluorocarbon, oscillate, and vibrate if a sonic energy field is applied and may reflect ultrasound waves. This distinguishes the microbubbles from surrounding tissues. Because gas bubbles in liquid lack stability and would therefore quickly dissolve, microbubbles are typically encapsulated by shells. The shell is made from elastic, viscoelastic, or viscous material. Common shell materials are lipid, albumin, and protein. Materials having a hydrophilic outer layer to interact with the bloodstream and a hydrophobic inner layer to house the gas molecules are thermodynamically stable. Air, sulfur hexafluoride, and perfluorocarbon gases all can serve as the composition of the MB interior. Microbubbles with one or more incompressible liquid or solid cores surrounded by gas are referred to as microscopic or endoskeletal antibubbles. For increased stability and persistence in the bloodstream, gases with high molecular weight as well as low solubility in the blood are attractive candidates for MB gas cores.[5]

Microbubbles may be used for drug delivery,[6] biofilm removal,[7] membrane cleaning[8][9] /biofilm control and water/waste water treatment purposes.[10] They are also produced by the movement of a ship’s hull through water, creating a bubble layer; this may interfere with the use of sonar because of the tendency of the layer to absorb or reflect sound waves.[11]

Acoustic response[edit]

Contrast in ultrasound imaging relies on the difference in acoustic impedance, a function of both the speed of the ultrasound wave and the density of the tissues,[12] between tissues or regions of interest.[5] As the sound waves induced by ultrasound interact with a tissue interface, some of the waves are reflected back to the transducer. The larger the difference, the more waves are reflected, and the higher the signal to noise ratio. Hence, MBs, which have a core with a density orders of magnitude lower than and compress more readily than the surrounding tissues and blood, afford high contrast in imaging.[5]

Therapeutic application[edit]

Physical Response[edit]

When exposed to ultrasound, MBs oscillate in response to the incoming pressure waves in one of two ways. With lower pressures, higher frequencies, and larger MB diameter, MBs oscillate, or cavitate, stably.[5]  This causes microstreaming near the surrounding vasculature and tissues, inducing shear stresses that can create pores on the endothelial layer.[13] This pore formation enhances endocytosis and permeability.[13] At lower frequencies, higher pressures, and lower microbubble diameter, MBs oscillate inertially; they expand and contract violently, ultimately leading to microbubble collapse.[14] This phenomenon can create mechanical stresses and microjets along the vascular wall, which has been shown to disrupt tight cellular junctions as well as induce cellular permeability.[13] Extremely high pressures cause small vessel destruction, but the pressure can be tuned to only create transient pores in vivo.[5][14] MB destruction serves as a desirable method for drug delivery vehicles. The resulting force from destruction can dislodge the therapeutic payload present on the microbubble and simultaneously sensitize the surrounding cells for drug uptake.[14]

Drug Delivery[edit]

MBs can serve as drug delivery vehicles in a variety of methods. The most notable of these include: (1) incorporating a lipophilic drug to the lipid monolayer, (2) attaching nanoparticles and liposomes to the microbubble surface, (3) enveloping the microbubble within a larger liposome, and (4) electrostatically bonding nucleic acids to the MB surface.[5][15][16][17]

I. Lipophilic Drugs[edit]

MBs can facilitate the local targeting of hydrophobic drugs through the incorporation of these agents into the MB lipid shell.[18][19][20][21][22][23][24][25] This encapsulation technique reduces systemic toxicity,  increases drug localization, and improves the solubility of hydrophobic drugs.[19] For increased localization, a targeting ligand can be appended to the exterior of the MB.[20][21][23][24][25] This improves treatment efficacy.[21] One drawback of the lipid-encapsulated MB as a drug delivery vehicle is its low payload efficacy. To combat this, an oil shell can be incorporated to the interior of the lipid monolayer to enhance payload efficacy.[26]

II. Nanoparticle and Liposome Attachment[edit]

Attachment of liposomes[27][28][29][30] or nanoparticles [13][31][32][33][34] to the exterior of the lipid MB has also been explored to increase MB payload. Upon MB destruction with ultrasound, these smaller particles can extravasate into the tumor tissue. Furthermore, through attachment of these particles to MBs as opposed to co-injection, the drug is confined to the blood stream instead of accumulating in healthy tissues, and the treatment is relegated to the location of ultrasound therapy.[29] This MB modification is particularly attractive for Doxil, a lipid formulation of Doxorubicin already in clinical use.[29] An analysis of nanoparticle infiltration due to MB destruction indicates that higher pressures are necessary for vascular permeability and likely improves treatment by promoting local fluid movement and enhancing endocytosis.[13]

III. Microbubble Loading Inside Liposome[edit]

Another novel acoustically responsive MB system is the direct encapsulation of MBs inside of a liposome. Theses systems circulate longer in the body than MBs alone do, as this packaging method prevents the MB from dissolving in the blood stream.[35] Hydrophilic drugs persist in the aqueous media inside the liposome, while hydrophobic drugs congregate in the lipid bilayer.[35][36] It has been shown in vitro that macrophages do not engulf these particles.[36]

IV. Gene Delivery through Electrostatic Interactions   [edit]

MBs also serve a non-viral vector for gene transfection through electrostatic bonds between a positively charged MB outer shell and negatively charged nucleic acids. The transient pores formed by microbubble collapse allow the genetic material to pass into the target cells in a safer and more specific manner than current treatment methods.[37] MBs have been used to deliver microRNAs,[38][39] plasmids,[40] small interfering RNA,[41] and messenger RNA.[42][43]

Disadvantages of Microbubbles for Drug Delivery[edit]

  • MBs do not extravasate easily due to their large size, and hence their effects are relegated to the vasculature. Nanodroplets, perfluorocarbon liquid droplets surrounded by a lipid shell that vaporize due to an ultrasound pulse, offer a small diameter to promote extravasation and afford an alternative to MBs.
  • MBs have short half-lives on the order of minutes in circulation, which limits the treatment time.
  • MBs are filtered by the liver and spleen, and any drug conjugation would then also potentially pose a toxicity threat to these organs, should the MBs not have already released their cargo.
  • Drug conjugations to MBs are complicated for translation, and these formulations would be difficult to scale up for widespread use.
  • There can be a small amount hemorrhage into brain tissue when microbubbles are used to disrupt the blood brain barrier, though this is thought to be reversible.[citation needed]

Unique Applications of Microbubbles for Therapeutic Application[edit]

MBs used for drug delivery not only serve as drug vehicles but also as a means to permeate otherwise impenetrable barriers, specifically the blood brain barrier, and to alter the tumor microenvironment.

I. Blood Brain Barrier Disruption[edit]

The brain is protected by tight junctions in the endothelial cell wall in the capillaries, known as the blood-brain barrier (BBB).[44] The BBB strictly regulates what passes into the brain from the blood, and while this function is highly desirable in healthy individuals, it also poses a barrier for therapeutics to enter the brain for cancer patients. Ultrasound was shown to disrupt the blood brain barrier in the mid 20th century,[45] and in the early 2000’s, MBs were shown to assist in a temporary permeabilization.[46] Since then, ultrasound and MB therapy has been used to deliver therapeutics to the brain. As BBB disruption with ultrasound and MB treatment has shown to be a safe and promising treatment pre-clinically, two clinical trials are testing delivery of doxorubicin[47] and carboplatin[48] with MBs to increase drug concentration locally.

II. Immunotherapy[edit]

In addition to permeating the blood brain barrier, ultrasound and MB therapy can alter the tumor environment and serve as an immunotherapeutic treatment.[49] High-intensity focused ultrasound (HIFU) alone triggers an immune response, speculated to be through facilitating the release of tumor antigens for immune cell recognition, activating antigen-presenting cells and promoting their infiltration, combatting tumor immunosuppression, and promoting a Th1 cell response.[50][51] Typically, HIFU is used for thermal ablation of tumors. Low-intensity focused ultrasound (LIFU) in combination with MBs has also shown to stimulate immunostimulatory effects, inhibiting tumor growth and increasing endogenous leukocyte infiltration.[50][52] Furthermore, lowering the acoustic power required for HIFU yields a safer treatment for the patient, as well as diminished treatment time.[53] Though the treatment itself shows potential, a combinatorial treatment is speculated to be required for a complete treatment. Ultrasound and MB treatment without additional drugs impeded the growth of small tumors but required a combinatorial drug treatment to affect medium-sized tumor growth.[54] With their immune stimulating mechanism, ultrasound and MBs offer a unique ability to prime or enhance immunotherapies for more effective cancer treatment.


  1. ^ Rodríguez-Rodríguez, Javier; Sevilla, Alejandro; Martínez-Bazán, Carlos; Gordillo, José Manuel (3 January 2015). "Generation of Microbubbles with Applications to Industry and Medicine". Annual Review of Fluid Mechanics. 47 (1): 405–429. doi:10.1146/annurev-fluid-010814-014658. ISSN 0066-4189. Retrieved 28 March 2023.
  2. ^ Zeng, Wenlong; Yue, Xiuli; Dai, Zhifei (19 October 2022). "Ultrasound contrast agents from microbubbles to biogenic gas vesicles". Medical Review. doi:10.1515/mr-2022-0020. ISSN 2749-9642. Retrieved 28 March 2023.
  3. ^ Lu, Jiakai; Jones, Owen G.; Yan, Weixin; Corvalan, Carlos M. (27 March 2023). "Microbubbles in Food Technology". Annual Review of Food Science and Technology. 14 (1): 495–515. doi:10.1146/annurev-food-052720-113207. ISSN 1941-1413. Retrieved 28 March 2023.
  4. ^ Blomley, Martin J K; Cooke, Jennifer C; Unger, Evan C; Monaghan, Mark J; Cosgrove, David O (2001). "Science, medicine, and the future: Microbubble contrast agents: A new era in ultrasound". BMJ. 322 (7296): 1222–5. doi:10.1136/bmj.322.7296.1222. PMC 1120332. PMID 11358777.
  5. ^ a b c d e f Martin, K. Heath; Dayton, Paul A. (July 2013). "Current status and prospects for microbubbles in ultrasound theranostics: Current status and prospects for microbubbles". Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology. 5 (4): 329–345. doi:10.1002/wnan.1219. PMC 3822900. PMID 23504911.
  6. ^ Sirsi, Shashank; Borden, Mark (2009). "Microbubble compositions, properties and biomedical applications". Bubble Science, Engineering & Technology. 1 (1–2): 3–17. doi:10.1179/175889709X446507. PMC 2889676. PMID 20574549.
  7. ^ Mukumoto, Mio; Ohshima, Tomoko; Ozaki, Miwa; Konishi, Hirokazu; Maeda, Nobuko; Nakamura, Yoshiki (2012). "Effect of microbubbled water on the removal of a biofilm attached to orthodontic appliances — an in vitro study". Dental Materials Journal. 31 (5): 821–7. doi:10.4012/dmj.2012-091. PMID 23037846.
  8. ^ Agarwal, Ashutosh; Ng, Wun Jern; Liu, Yu (January 1, 2013). "Cleaning of biologically fouled membranes with self-collapsing microbubbles". Biofouling. 29 (1): 69–76. doi:10.1080/08927014.2012.746319. PMID 23194437. S2CID 19107010 – via Taylor and Francis+NEJM.
  9. ^ Agarwal, Ashutosh; Ng, Wun Jern; Liu, Yu, (2012). "Cleaning of biologically fouled membranes with self-collapsing microbubbles". Biofouling 29 (1): 69-76. doi:10.1080/08927014.2012.746319[permanent dead link]
  10. ^ Agarwal, Ashutosh; Ng, Wun Jern; Liu, Yu (2011). "Principle and applications of microbubble and nanobubble technology for water treatment". Chemosphere. 84 (9): 1175–80. Bibcode:2011Chmsp..84.1175A. doi:10.1016/j.chemosphere.2011.05.054. PMID 21689840.
  11. ^ Griffiths, Brian; Sabto, Michele (25 June 2012). "Quiet on board please: science underway". ECOS.
  12. ^ Cikes, Maja; D’hooge, Jan; Solomon, Scott D. (2019), "Physical Principles of Ultrasound and Generation of Images", Essential Echocardiography, Elsevier, pp. 1–15.e1, doi:10.1016/b978-0-323-39226-6.00001-1, ISBN 978-0-323-39226-6, S2CID 67264821
  13. ^ a b c d e Snipstad, Sofie; Berg, Sigrid; Mørch, Ýrr; Bjørkøy, Astrid; Sulheim, Einar; Hansen, Rune; Grimstad, Ingeborg; van Wamel, Annemieke; Maaland, Astri F.; Torp, Sverre H.; Davies, Catharina de Lange (November 2017). "Ultrasound Improves the Delivery and Therapeutic Effect of Nanoparticle-Stabilized Microbubbles in Breast Cancer Xenografts". Ultrasound in Medicine & Biology. 43 (11): 2651–2669. doi:10.1016/j.ultrasmedbio.2017.06.029. PMID 28781149.
  14. ^ a b c Hernot, Sophie; Klibanov, Alexander L. (June 2008). "Microbubbles in ultrasound-triggered drug and gene delivery". Advanced Drug Delivery Reviews. 60 (10): 1153–1166. doi:10.1016/j.addr.2008.03.005. PMC 2720159. PMID 18486268.
  15. ^ Klibanov, Alexander L. (March 2006). "Microbubble Contrast Agents: Targeted Ultrasound Imaging and Ultrasound-Assisted Drug-Delivery Applications". Investigative Radiology. 41 (3): 354–362. doi:10.1097/01.rli.0000199292.88189.0f. ISSN 0020-9996. PMID 16481920. S2CID 27546582.
  16. ^ Ibsen, Stuart; Schutt; Esener (May 2013). "Microbubble-mediated ultrasound therapy: a review of its potential in cancer treatment". Drug Design, Development and Therapy. 7: 375–88. doi:10.2147/DDDT.S31564. ISSN 1177-8881. PMC 3650568. PMID 23667309.
  17. ^ Mullick Chowdhury, Sayan; Lee, Taehwa; Willmann, Jürgen K. (2017-07-01). "Ultrasound-guided drug delivery in cancer". Ultrasonography. 36 (3): 171–184. doi:10.14366/usg.17021. ISSN 2288-5919. PMC 5494871. PMID 28607323.
  18. ^ Tinkov, Steliyan; Coester, Conrad; Serba, Susanne; Geis, Nicolas A.; Katus, Hugo A.; Winter, Gerhard; Bekeredjian, Raffi (December 2010). "New doxorubicin-loaded phospholipid microbubbles for targeted tumor therapy: In-vivo characterization". Journal of Controlled Release. 148 (3): 368–372. doi:10.1016/j.jconrel.2010.09.004. PMID 20868711.
  19. ^ a b Ren, Shu-Ting; Liao, Yi-Ran; Kang, Xiao-Ning; Li, Yi-Ping; Zhang, Hui; Ai, Hong; Sun, Qiang; Jing, Jing; Zhao, Xing-Hua; Tan, Li-Fang; Shen, Xin-Liang (June 2013). "The Antitumor Effect of a New Docetaxel-Loaded Microbubble Combined with Low-Frequency Ultrasound In Vitro: Preparation and Parameter Analysis". Pharmaceutical Research. 30 (6): 1574–1585. doi:10.1007/s11095-013-0996-5. ISSN 0724-8741. PMID 23417512. S2CID 18668573.
  20. ^ a b Liu, Hongxia; Chang, Shufang; Sun, Jiangchuan; Zhu, Shenyin; Pu, Caixiu; Zhu, Yi; Wang, Zhigang; Xu, Ronald X. (2014-01-06). "Ultrasound-Mediated Destruction of LHRHa-Targeted and Paclitaxel-Loaded Lipid Microbubbles Induces Proliferation Inhibition and Apoptosis in Ovarian Cancer Cells". Molecular Pharmaceutics. 11 (1): 40–48. doi:10.1021/mp4005244. ISSN 1543-8384. PMC 3903397. PMID 24266423.
  21. ^ a b c Pu, Caixiu; Chang, Shufang; Sun, Jiangchuan; Zhu, Shenyin; Liu, Hongxia; Zhu, Yi; Wang, Zhigang; Xu, Ronald X. (2014-01-06). "Ultrasound-Mediated Destruction of LHRHa-Targeted and Paclitaxel-Loaded Lipid Microbubbles for the Treatment of Intraperitoneal Ovarian Cancer Xenografts". Molecular Pharmaceutics. 11 (1): 49–58. doi:10.1021/mp400523h. ISSN 1543-8384. PMC 3899929. PMID 24237050.
  22. ^ Kang, Juan; Wu, Xiaoling; Wang, Zhigang; Ran, Haitao; Xu, Chuanshan; Wu, Jinfeng; Wang, Zhaoxia; Zhang, Yong (January 2010). "Antitumor Effect of Docetaxel-Loaded Lipid Microbubbles Combined With Ultrasound-Targeted Microbubble Activation on VX2 Rabbit Liver Tumors". Journal of Ultrasound in Medicine. 29 (1): 61–70. doi:10.7863/jum.2010.29.1.61. PMID 20040776. S2CID 35510004.
  23. ^ a b Li, Yan; Huang, Wenqi; Li, Chunyan; Huang, Xiaoteng (2018). "Indocyanine green conjugated lipid microbubbles as an ultrasound-responsive drug delivery system for dual-imaging guided tumor-targeted therapy". RSC Advances. 8 (58): 33198–33207. Bibcode:2018RSCAd...833198L. doi:10.1039/C8RA03193B. ISSN 2046-2069. PMC 9086377. PMID 35548112.
  24. ^ a b Su, Jilian; Wang, Junmei; Luo, Jiamin; Li, Haili (August 2019). "Ultrasound-mediated destruction of vascular endothelial growth factor (VEGF) targeted and paclitaxel loaded microbubbles for inhibition of human breast cancer cell MCF-7 proliferation". Molecular and Cellular Probes. 46: 101415. doi:10.1016/j.mcp.2019.06.005. PMID 31228519. S2CID 195298987.
  25. ^ a b Li, Tiankuan; Hu, Zhongqian; Wang, Chao; Yang, Jian; Zeng, Chuhui; Fan, Rui; Guo, Jinhe (2020). "PD-L1-targeted microbubbles loaded with docetaxel produce a synergistic effect for the treatment of lung cancer under ultrasound irradiation". Biomaterials Science. 8 (5): 1418–1430. doi:10.1039/C9BM01575B. ISSN 2047-4830. PMID 31942578.
  26. ^ Unger, Evan C.; McCREERY, Thomas P.; Sweitzer, Robert H.; Caldwell, Veronica E.; Wu, Yunqiu (December 1998). "Acoustically Active Lipospheres Containing Paclitaxel: A New Therapeutic Ultrasound Contrast Agent". Investigative Radiology. 33 (12): 886–892. doi:10.1097/00004424-199812000-00007. ISSN 0020-9996. PMID 9851823.
  27. ^ Escoffre, J.; Mannaris, C.; Geers, B.; Novell, A.; Lentacker, I.; Averkiou, M.; Bouakaz, A. (January 2013). "Doxorubicin liposome-loaded microbubbles for contrast imaging and ultrasound-triggered drug delivery". IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control. 60 (1): 78–87. doi:10.1109/TUFFC.2013.2539. ISSN 0885-3010. PMID 23287915. S2CID 5540324.
  28. ^ Deng, Zhiting; Yan, Fei; Jin, Qiaofeng; Li, Fei; Wu, Junru; Liu, Xin; Zheng, Hairong (January 2014). "Reversal of multidrug resistance phenotype in human breast cancer cells using doxorubicin-liposome–microbubble complexes assisted by ultrasound". Journal of Controlled Release. 174: 109–116. doi:10.1016/j.jconrel.2013.11.018. PMID 24287101.
  29. ^ a b c Lentacker, Ine; Geers, Bart; Demeester, Joseph; De Smedt, Stefaan C; Sanders, Niek N (January 2010). "Design and Evaluation of Doxorubicin-containing Microbubbles for Ultrasound-triggered Doxorubicin Delivery: Cytotoxicity and Mechanisms Involved". Molecular Therapy. 18 (1): 101–108. doi:10.1038/mt.2009.160. PMC 2839231. PMID 19623162.
  30. ^ Lentacker, Ine; Geers, Bart; Demeester, Jo; De Smedt, Stefaan C.; Sanders, Niek N. (November 2010). "Tumor cell killing efficiency of doxorubicin loaded microbubbles after ultrasound exposure". Journal of Controlled Release. 148 (1): e113–e114. doi:10.1016/j.jconrel.2010.07.085. PMID 21529584.
  31. ^ Gong, Yuping; Wang, Zhigang; Dong, Guifang; Sun, Yang; Wang, Xi; Rong, Yue; Li, Maoping; Wang, Dong; Ran, Haitao (2014-11-04). "Low-intensity focused ultrasound mediated localized drug delivery for liver tumors in rabbits". Drug Delivery. 23 (7): 2280–2289. doi:10.3109/10717544.2014.972528. ISSN 1071-7544. PMID 25367869. S2CID 41067520.
  32. ^ Lee; Moon; Han; Lee; Kim; Lee; Ha; Kim; Chung (2019-04-24). "Antitumor Effects of Intra-Arterial Delivery of Albumin-Doxorubicin Nanoparticle Conjugated Microbubbles Combined with Ultrasound-Targeted Microbubble Activation on VX2 Rabbit Liver Tumors". Cancers. 11 (4): 581. doi:10.3390/cancers11040581. ISSN 2072-6694. PMC 6521081. PMID 31022951.
  33. ^ Ha, Shin-Woo; Hwang, Kihwan; Jin, Jun; Cho, Ae-Sin; Kim, Tae Yoon; Hwang, Sung Il; Lee, Hak Jong; Kim, Chae-Yong (2019-05-24). "Ultrasound-sensitizing nanoparticle complex for overcoming the blood-brain barrier: an effective drug delivery system". International Journal of Nanomedicine. 14: 3743–3752. doi:10.2147/ijn.s193258. PMC 6539164. PMID 31213800.
  34. ^ Liufu, Chun; Li, Yue; Tu, Jiawei; Zhang, Hui; Yu, Jinsui; Wang, Yi; Huang, Pintong; Chen, Zhiyi (2019-11-15). "Echogenic PEGylated PEI-Loaded Microbubble As Efficient Gene Delivery System". International Journal of Nanomedicine. 14: 8923–8941. doi:10.2147/ijn.s217338. PMC 6863126. PMID 31814720.
  35. ^ a b Wrenn, Steven; Dicker, Stephen; Small, Eleanor; Mleczko, Michal (September 2009). "Controlling cavitation for controlled release". 2009 IEEE International Ultrasonics Symposium. Rome: IEEE: 104–107. doi:10.1109/ULTSYM.2009.5442045. ISBN 978-1-4244-4389-5. S2CID 34883820.
  36. ^ a b Ibsen, Stuart; Benchimol, Michael; Simberg, Dmitri; Schutt, Carolyn; Steiner, Jason; Esener, Sadik (November 2011). "A novel nested liposome drug delivery vehicle capable of ultrasound triggered release of its payload". Journal of Controlled Release. 155 (3): 358–366. doi:10.1016/j.jconrel.2011.06.032. PMC 3196035. PMID 21745505.
  37. ^ Rychak, Joshua J.; Klibanov, Alexander L. (June 2014). "Nucleic acid delivery with microbubbles and ultrasound". Advanced Drug Delivery Reviews. 72: 82–93. doi:10.1016/j.addr.2014.01.009. PMC 4204336. PMID 24486388.
  38. ^ Meng, Lingwu; Yuan, Shaofei; Zhu, Linjia; ShangGuan, Zongxiao; Zhao, Renguo (2019-09-13). "Ultrasound-microbubbles-mediated microRNA-449a inhibits lung cancer cell growth via the regulation of Notch1". OncoTargets and Therapy. 12: 7437–7450. doi:10.2147/ott.s217021. PMC 6752164. PMID 31686849.
  39. ^ Wang, Xiaowei; Searle, Amy; Hohmann, Jan David; Liu, Leo; Abraham, Meike; Palasubramaniam, Jathushan; Lim, Bock; Yao, Yu; Wallert, Maria; Yu, Eefang; Chen, Yung; Peter, Karlheinz (July 2017). "Dual-Targeted Theranostic Delivery of miRs Arrests Abdominal Aortic Aneurysm Development". Molecular Therapy. 26 (4): 1056–1065. doi:10.1016/j.ymthe.2018.02.010. PMC 6080135. PMID 29525742.
  40. ^ Cai, Junhong; Huang, Sizhe; Yi, Yuping; Bao, Shan (May 2019). "Ultrasound microbubble-mediated CRISPR/Cas9 knockout of C-erbB-2 in HEC-1A cells". Journal of International Medical Research. 47 (5): 2199–2206. doi:10.1177/0300060519840890. ISSN 0300-0605. PMC 6567764. PMID 30983484.
  41. ^ Zhao, Ranran; Liang, Xiaolong; Zhao, Bo; Chen, Min; Liu, Renfa; Sun, Sujuan; Yue, Xiuli; Wang, Shumin (August 2018). "Ultrasound assisted gene and photodynamic synergistic therapy with multifunctional FOXA1-siRNA loaded porphyrin microbubbles for enhancing therapeutic efficacy for breast cancer". Biomaterials. 173: 58–70. doi:10.1016/j.biomaterials.2018.04.054. PMID 29758547. S2CID 206080519.
  42. ^ Abraham, Meike; Peter, Karlheinz; Michel, Tatjana; Wendel, Hans; Krajewski, Stefanie; Wang, Xiaowei (April 2017). "Nanoliposomes for safe and efficient therapeutic mRNA delivery: A step toward nanotheranostics in inflammatory and cardiovascular diseases as well as cancer". Nanotheranostics. 1 (2): 154–165. doi:10.7150/ntno.19449. PMC 5646717. PMID 29071184.
  43. ^ Michel, Tatjana; Luft, Daniel; Abraham, Meike; Reinhardt, Sabina; Medinal, Martha; Kurz, Julia; Schaller, Martin; Avci-Adali, Meltem; Schlensak, Christian; Peter, Karlheinz; Wendel, Hans; Wang, Xiaowei; Krajewski, Stefanie (July 2017). "Cationic Nanoliposomes Meet mRNA: Efficient Delivery of Modified mRNA Using Hemocompatible and Stable Vectors for Therapeutic Applications". Molecular Therapy Nucleic Acids. 8: 459–468. doi:10.1016/j.omtn.2017.07.013. PMC 5545769. PMID 28918045.
  44. ^ Abbott, N. Joan; Patabendige, Adjanie A.K.; Dolman, Diana E.M.; Yusof, Siti R.; Begley, David J. (January 2010). "Structure and function of the blood–brain barrier". Neurobiology of Disease. 37 (1): 13–25. doi:10.1016/j.nbd.2009.07.030. PMID 19664713. S2CID 14753395.
  45. ^ Bakay, L. (1956-11-01). "Ultrasonically Produced Changes in the Blood-Brain Barrier". Archives of Neurology and Psychiatry. 76 (5): 457–67. doi:10.1001/archneurpsyc.1956.02330290001001. ISSN 0096-6754. PMID 13371961.
  46. ^ Hynynen, Kullervo; McDannold, Nathan; Vykhodtseva, Natalia; Jolesz, Ferenc A. (September 2001). "Noninvasive MR Imaging–guided Focal Opening of the Blood-Brain Barrier in Rabbits". Radiology. 220 (3): 640–646. doi:10.1148/radiol.2202001804. ISSN 0033-8419. PMID 11526261.
  47. ^ "A Study to Evaluate the Safety and Feasibility of Blood-Brain Barrier Disruption Using Transcranial MRI-Guided Focused Ultrasound With Intravenous Ultrasound Contrast Agents in the Treatment of Brain Tumours With Doxorubicin". January 23, 2020 – via clinicaltrials.gov. {{cite journal}}: Cite journal requires |journal= (help)
  48. ^ "A Study to Evaluate the Safety of Transient Opening of the Blood-Brain Barrier by Low Intensity Pulsed Ultrasound With the SonoCloud Implantable Device in Patients With Recurrent Glioblastoma Before Chemotherapy Administration". October 10, 2018 – via clinicaltrials.gov. {{cite journal}}: Cite journal requires |journal= (help)
  49. ^ Escoffre, Jean-Michel; Deckers, Roel; Bos, Clemens; Moonen, Chrit (2016), Escoffre, Jean-Michel; Bouakaz, Ayache (eds.), "Bubble-Assisted Ultrasound: Application in Immunotherapy and Vaccination", Therapeutic Ultrasound, Springer International Publishing, vol. 880, pp. 243–261, doi:10.1007/978-3-319-22536-4_14, ISBN 978-3-319-22535-7, PMID 26486342
  50. ^ a b Liu, Hao-Li; Hsieh, Han-Yi; Lu, Li-An; Kang, Chiao-Wen; Wu, Ming-Fang; Lin, Chun-Yen (2012). "Low-pressure pulsed focused ultrasound with microbubbles promotes an anticancer immunological response". Journal of Translational Medicine. 10 (1): 221. doi:10.1186/1479-5876-10-221. ISSN 1479-5876. PMC 3543346. PMID 23140567.
  51. ^ Shi, Guilian; Zhong, Mingchuan; Ye, Fuli; Zhang, Xiaoming (November 2019). "Low-frequency HIFU induced cancer immunotherapy: tempting challenges and potential opportunities". Cancer Biology & Medicine. 16 (4): 714–728. doi:10.20892/j.issn.2095-3941.2019.0232. ISSN 2095-3941. PMC 6936245. PMID 31908890.
  52. ^ Sta Maria, Naomi S.; Barnes, Samuel R.; Weist, Michael R.; Colcher, David; Raubitschek, Andrew A.; Jacobs, Russell E. (2015-11-10). Mondelli, Mario U. (ed.). "Low Dose Focused Ultrasound Induces Enhanced Tumor Accumulation of Natural Killer Cells". PLOS ONE. 10 (11): e0142767. Bibcode:2015PLoSO..1042767S. doi:10.1371/journal.pone.0142767. ISSN 1932-6203. PMC 4640510. PMID 26556731.
  53. ^ Suzuki, Ryo; Oda, Yusuke; Omata, Daiki; Nishiie, Norihito; Koshima, Risa; Shiono, Yasuyuki; Sawaguchi, Yoshikazu; Unga, Johan; Naoi, Tomoyuki; Negishi, Yoichi; Kawakami, Shigeru (March 2016). "Tumor growth suppression by the combination of nanobubbles and ultrasound". Cancer Science. 107 (3): 217–223. doi:10.1111/cas.12867. PMC 4814255. PMID 26707839.
  54. ^ Lin, Win-Li; Lin, Chung-Yin; Tseng, Hsiao-Ching; Shiu, Heng-Ruei; Wu, Ming-Fang (April 2012). "Ultrasound sonication with microbubbles disrupts blood vessels and enhances tumor treatments of anticancer nanodrug". International Journal of Nanomedicine. 7: 2143–52. doi:10.2147/IJN.S29514. ISSN 1178-2013. PMC 3356217. PMID 22619550.

External links[edit]