Nanobubbles: Fundamentals and recent drug delivery applications
Keywords:
anticancer, cavitation, diagnostic tool, nanobubble, ultrasound imagingAbstract
The emerging branch in pharmaceutical sciences known as pharmaceutical nanotechnology presents new tools, opportunities and scope, which are expected to have significant applications, in disease diagnostics and therapeutics. There is a growing interest in nanobubble (NB) technology because of its wide range of potential applications in theranostics and targeted drug delivery including anticancer drug delivery, antibiotic delivery, gene delivery etc. Nanobubbles could offer several features in anticancer drug delivery, improving cellular uptake of chemotherapy drugs into cancer cell lines. Nanobubbles opened a new field of ultrasound imaging and were used as a diagnostic method. Generally, the delivery of drugs to organs and tissues is affected by two main ultrasound effects including the cavitation and sonoporation effects. This review describes the history of nanobubble, nomenclature, stability of nanobubble, physicochemical properties, characterization of nanobubble, method of preparation and applications. This article aims at highlighting the most recent and promising research trends including oxygen nanobubble, silica nanobubble and pluronicnanobubble and enlist the various drug delivery approaches involving the application of nanobubbles.
Downloads
References
Abdalkader, R., Kawakami, S., Unga, J., Higuchi, Y., Suzuki, R., Maruyama, K., Yamashita, F., &Hashida, M. (2017). The development of mechanically formed stable nanobubbles intended for sonoporation-mediated gene transfection. Drug Delivery, 24(1), 320–327. https://doi.org/10.1080/10717544.2016.1250139
Alheshibri, M., Qian, J., Jehannin, M., & Craig, V. S. J. (2016).A History of Nanobubbles.In Langmuir (Vol. 32, Issue 43, pp. 11086–11100).American Chemical Society.https://doi.org/10.1021/acs.langmuir.6b02489
Arai, N., Koishi, T., &Ebisuzaki, T. (2017).Theory of nanobubble formation and induced force in nanochannels. Physical Review E, 96(4).https://doi.org/10.1103/PhysRevE.96.042802
Bhandari, P., Novikova, G., Goergen, C. J., &Irudayaraj, J. (2018a). Ultrasound beam steering of oxygen nanobubbles for enhanced bladder cancer therapy. Scientific Reports, 8(1).https://doi.org/10.1038/s41598-018-20363-8
Bhandari, P., Novikova, G., Goergen, C. J., &Irudayaraj, J. (2018b). Ultrasound beam steering of oxygen nanobubbles for enhanced bladder cancer therapy. Scientific Reports, 8(1).https://doi.org/10.1038/s41598-018-20363-8
Brutin D. (2015).Droplet Wetting and Evaporation: From Pure to Complex Fluids. Droplet Wetting and Evaporation.Academic Press: 2015; p 464 .https://www.researchgate.net/publication/277275149
Bosca, F., Bielecki, P. A., Exner, A. A., & Barge, A. (2018).Porphyrin-Loaded Pluronic Nanobubbles: A New US-Activated Agent for Future Theranostic Applications. Bioconjugate Chemistry, 29(2), 234–240. https://doi.org/10.1021/acs.bioconjchem.7b00732
Cavalli, R., Bisazza, A., Giustetto, P., Civra, A., Lembo, D., Trotta, G., Guiot, C., &Trotta, M. (2009).Preparation and characterization of dextran nanobubbles for oxygen delivery.International Journal of Pharmaceutics, 381(2), 160–165. https://doi.org/10.1016/j.ijpharm.2009.07.010
Cavalli, R., Bisazza, A., &Lembo, D. (2013). Micro- and nanobubbles: A versatile non-viral platform for gene delivery. In International Journal of Pharmaceutics (Vol. 456, Issue 2, pp. 437–445). Elsevier B.V. https://doi.org/10.1016/j.ijpharm.2013.08.041
Cavalli, R., Bisazza, A., Trotta, M., Argenziano, M., Civra, A., Donalisio, M., &Lembo, D. (2012a). New chitosan nanobubbles for ultrasound-mediated gene delivery: Preparation and in vitro characterization. International Journal of Nanomedicine, 7, 3309–3318. https://doi.org/10.2147/IJN.S30912
Cavalli, R., Bisazza, A., Trotta, M., Argenziano, M., Civra, A., Donalisio, M., &Lembo, D. (2012b). New chitosan nanobubbles for ultrasound-mediated gene delivery: Preparation and in vitro characterization. International Journal of Nanomedicine, 7, 3309–3318. https://doi.org/10.2147/IJN.S30912
Cavalli, R., Soster, M., &Argenziano, M. (2016a). Nanobubbles: A promising efficienft tool for therapeutic delivery. In Therapeutic Delivery (Vol. 7, Issue 2, pp. 117–138). Future Science Ltd. https://doi.org/10.4155/tde.15.92
Cavalli, R., Soster, M., &Argenziano, M. (2016b). Nanobubbles: A promising efficienft tool for therapeutic delivery. In Therapeutic Delivery (Vol. 7, Issue 2, pp. 117–138). Future Science Ltd. https://doi.org/10.4155/tde.15.92
Chandan, R., & Banerjee, R. (2018a). Pro-apoptotic liposomes-nanobubble conjugate synergistic with paclitaxel: A platform for ultrasound responsive image-guided drug delivery. Scientific Reports, 8(1).https://doi.org/10.1038/s41598-018-21084-8
Chandan, R., & Banerjee, R. (2018b). Pro-apoptotic liposomes-nanobubble conjugate synergistic with paclitaxel: A platform for ultrasound responsive image-guided drug delivery. Scientific Reports, 8(1).https://doi.org/10.1038/s41598-018-21084-8
Delalande, A., Postema, M., Mignet, N., Midoux, P., &Pichon, C. (2012). Ultrasound and microbubble-assisted gene delivery: Recent advances and ongoing challenges. In Therapeutic Delivery (Vol. 3, Issue 10, pp. 1199–1215).https://doi.org/10.4155/tde.12.100
Dhanaliwala, A. H., Dixon, A. J., Lin, D., Chen, J. L., Klibanov, A. L., &Hossack, J. A. (2015). In vivo imaging of microfluidic-produced microbubbles.Biomedical Microdevices, 17(1), 1–12. https://doi.org/10.1007/s10544-014-9914-9
Hobbs, S. K., Monsky, W. L., Yuan, F., Gregory Roberts, W., Griffith, L., Torchilin, V. P., & Jain, R. K. (1998). Regulation of transport pathways in tumor vessels: Role of tumor type and microenvironment. In Medical Sciences (Vol. 95).www.pnas.org.
Horie, S., Watanabe, Y., Chen, R., Mori, S., Matsumura, Y., & Kodama, T. (2010a).Development of localized gene delivery using a dual-intensity ultrasound system in the bladder.Ultrasound in Medicine and Biology, 36(11), 1867–1875. https://doi.org/10.1016/j.ultrasmedbio.2010.07.015
Horie, S., Watanabe, Y., Chen, R., Mori, S., Matsumura, Y., & Kodama, T. (2010b).Development of localized gene delivery using a dual-intensity ultrasound system in the bladder.Ultrasound in Medicine and Biology, 36(11), 1867–1875. https://doi.org/10.1016/j.ultrasmedbio.2010.07.015
Huynh, E., Rajora, M. A., & Zheng, G. (2016).Multimodal micro, nano, and size conversion ultrasound agents for imaging and therapy. In Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology (Vol. 8, Issue 6, pp. 796–813). Wiley-Blackwell.https://doi.org/10.1002/wnan.1398
Hwang, T. L., Lin, Y. K., Chi, C. H., Huang, T. H., & Fang, J. Y. (2009). Development and evaluation of perfluorocarbon nanobubbles for apomorphine delivery.Journal of Pharmaceutical Sciences, 98(10), 3735–3747. https://doi.org/10.1002/jps.21687
Jiang, Q., Hao, S., Xiao, X., Yao, J., Ou, B., Zhao, Z., Liu, F., Pan, X., Luo, B., &Zhi, H. (2016). Production and characterization of a novel long-acting Herceptin-targeted nanobubble contrast agent specific for Her-2-positive breast cancers. Breast Cancer, 23(3), 445–455. https://doi.org/10.1007/s12282-014-0581-8
Khan, M. S., Hwang, J., Lee, K., Choi, Y., Kim, K., Koo, H. J., Hong, J. W., & Choi, J. (2018). Oxygen-carrying micro/nanobubbles: Composition, synthesis techniques and potential prospects in photo-triggered theranostics. In Molecules (Vol. 23, Issue 9). MDPI AG. https://doi.org/10.3390/molecules23092210
Kobayashi, H., Maeda, S., Kashiwa, M., & Fujita, T. (2014). Measurement and identification of ultrafine bubbles by resonant mass measurement method.International Conference on Optical Particle Characterization (OPC 2014), 9232, 92320S.https://doi.org/10.1117/12.2064811
Krafft, M. P., Fainerman, V. B., & Miller, R. (2015). Modeling of the effect of fluorocarbon gases on the properties of phospholipid monolayers and the adsorption dynamics of their aqueous solutions or dispersions. Colloid and Polymer Science, 293(11), 3091–3097.
Krupka, T. M., Solorio, L., Wilson, R. E., Wu, H., Azar, N., &Exner, A. A. (2010a).Formulation and characterization of echogenic lipid-pluronic nanobubbles.Molecular Pharmaceutics, 7(1), 49–59. https://doi.org/10.1021/mp9001816
Krupka, T. M., Solorio, L., Wilson, R. E., Wu, H., Azar, N., &Exner, A. A. (2010b).Formulation and characterization of echogenic lipid-pluronic nanobubbles.Molecular Pharmaceutics, 7(1), 49–59. https://doi.org/10.1021/mp9001816
Lee, M., Lee, E. Y., Lee, D., & Park, B. J. (2015). Stabilization and fabrication of microbubbles: applications for medical purposes and functional materials. Soft Matter, 11(11), 2067–2079. https://doi.org/10.1039/c5sm00113g
Liu, J., Zhang, B., Li, M., Zhou, M., Li, F., Huang, X., Pan, M., Xue, L., & Yan, F. (2017a).Preparation and characterization of a novel silicon-modified nanobubble.PLoS ONE, 12(5).https://doi.org/10.1371/journal.pone.0178031
Liu, J., Zhang, B., Li, M., Zhou, M., Li, F., Huang, X., Pan, M., Xue, L., & Yan, F. (2017b).Preparation and characterization of a novel silicon-modified nanobubble.PLoS ONE, 12(5).https://doi.org/10.1371/journal.pone.0178031
Lukianova-Hleb, E. Y., Ren, X., Townley, D., Wu, X., Kupferman, M. E., &Lapotko, D. O. (2012).Plasmonic nanobubbles rapidly detect and destroy drug-resistant tumors. Theranostics, 2(10), 976–987. https://doi.org/10.7150/thno.5116
Marxer, E. E. J., Brüßler, J., Becker, A., Schümmelfeder, J., Schubert, R., Nimsky, C., &Bakowsky, U. (2011). Development and characterization of new nanoscaled ultrasound active lipid dispersions as contrast agents. European Journal of Pharmaceutics and Biopharmaceutics, 77(3), 430–437. https://doi.org/10.1016/j.ejpb.2010.12.007
May, D. J., Allen, J. S., & Ferrara, K. W. (2002).Dynamics and Fragmentation of Thick-Shelled Microbubbles. In 1400 ieee transactions on ultrasonics, ferroelectrics, and frequency control (Vol. 49, Issue 10).
Meng, M., Gao, J., Wu, C., Zhou, X., Zang, X., Lin, X., Liu, H., Wang, C., Su, H., Liu, K., Wang, Y., Xue, X., & Wu, J. (2016). Doxorubicin nanobubble for combining ultrasonography and targeted chemotherapy of rabbit with VX2 liver tumor.Tumor Biology, 37(7), 8673–8680.https://doi.org/10.1007/s13277-015-4525-5
Miller, D. L., Pislaru, S. v, & Greenleaf, J. F. (2002).Sonoporation: Mechanical DNA Delivery by Ultrasonic Cavitation. In Somatic Cell and Molecular Genetics (Vol. 27, Issue 6).
Nguyen, A. T., &Wrenn, S. P. (2014).Acoustically active liposome-nanobubble complexes for enhanced ultrasonic imaging and ultrasound-triggered drug delivery.Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, 6(3), 316–325. https://doi.org/10.1002/wnan.1255
Nishimura, K., Fumoto, S., Fuchigami, Y., Hagimori, M., Maruyama, K., & Kawakami, S. (2017a). Effective intraperitoneal gene transfection system using nanobubbles and ultrasound irradiation.Drug Delivery, 24(1), 737–744. https://doi.org/10.1080/10717544.2017.1319433
Nishimura, K., Fumoto, S., Fuchigami, Y., Hagimori, M., Maruyama, K., & Kawakami, S. (2017b). Effective intraperitoneal gene transfection system using nanobubbles and ultrasound irradiation.Drug Delivery, 24(1), 737–744. https://doi.org/10.1080/10717544.2017.1319433
Oeffinger, B. E., & Wheatley, M. A. (2004a). Development and characterization of a nano-scale contrast agent. Ultrasonics, 42(1–9), 343–347. https://doi.org/10.1016/j.ultras.2003.11.011
Oeffinger, B. E., & Wheatley, M. A. (2004b). Development and characterization of a nano-scale contrast agent. Ultrasonics, 42(1–9), 343–347. https://doi.org/10.1016/j.ultras.2003.11.011
Ooss, S. A., Frizzell, L. A., & Dunn, F. (1979). ULTRASONIC ABSORPTION AND ATTENUATION IN MAMMALIAN TISSUES.In Ultrasound in Med. &Biol (Vol. 5).Pergamon Press Ltd.
Owen, J., McEwan, C., Nesbitt, H., Bovornchutichai, P., Averre, R., Borden, M., McHale, A. P., Callan, J. F., & Stride, E. (2016).Reducing tumour hypoxia via oral administration of oxygen nanobubbles.PLoS ONE, 11(12).https://doi.org/10.1371/journal.pone.0168088
Perera, R. H., Solorio, L., Wu, H., Gangolli, M., Silverman, E., Hernandez, C., Peiris, P. M., Broome, A. M., & Exner, A. A. (2014). Nanobubble ultrasound contrast agents for enhanced delivery of thermal sensitizer to tumors undergoing radiofrequency ablation. Pharmaceutical Research, 31(6), 1407–1417. https://doi.org/10.1007/s11095-013-1100-x
Shri Devi, S. D. K., Ashokkumar, N., Bhagyalakshmi, K., Alagarsamy, S., Vinayaka, K. S., & Sathish, S. (2022). Multifunctional management of gold nanoparticles for improved applications. International Journal of Health Sciences, 6(S5), 4130–4145. https://doi.org/10.53730/ijhs.v6nS5.9528
Song, W., Luo, Y., Zhao, Y., Liu, X., Zhao, J., Luo, J., Zhang, Q., Ran, H., Wang, Z., & Guo, D. (2017). Magnetic nanobubbles with potential for targeted drug delivery and trimodal imaging in breast cancer: An in vitro study. Nanomedicine, 12(9), 991–1009.https://doi.org/10.2217/nnm-2017-0027
Stride, E., & Edirisinghe, M. (2008). Novel microbubble preparation technologies. Soft Matter, 4(12), 2350–2359. https://doi.org/10.1039/b809517p
Sun, Y., Xie, G., Peng, Y., Xia, W., & Sha, J. (2016). Stability theories of nanobubbles at solid-liquid interface: A review. In Colloids and Surfaces A: Physicochemical and Engineering Aspects (Vol. 495, pp. 176–186). Elsevier B.V. https://doi.org/10.1016/j.colsurfa.2016.01.050
Suzuki, R., Oda, Y., Utoguchi, N., & Maruyama, K. (2011a). Progress in the development of ultrasound-mediated gene delivery systems utilizing nano- and microbubbles.In Journal of Controlled Release (Vol. 149, Issue 1, pp. 36–41).https://doi.org/10.1016/j.jconrel.2010.05.009
Suzuki, R., Oda, Y., Utoguchi, N., & Maruyama, K. (2011b). Progress in the development of ultrasound-mediated gene delivery systems utilizing nano- and microbubbles.In Journal of Controlled Release (Vol. 149, Issue 1, pp. 36–41).https://doi.org/10.1016/j.jconrel.2010.05.009
Takahashi, M., Chiba, K., & Li, P. (2007).Free-radical generation from collapsing microbubbles in the absence of a dynamic stimulus.Journal of Physical Chemistry B, 111(6), 1343–1347. https://doi.org/10.1021/jp0669254
Tan, B. H., An, H., &Ohl, C. D. (2021). Stability of surface and bulk nanobubbles.In Current Opinion in Colloid and Interface Science (Vol. 53). Elsevier Ltd. https://doi.org/10.1016/j.cocis.2021.101428
Thakur, S. S., Ward, M. S., Popat, A., Flemming, N. B., Parat, M. O., Barnett, N. L., & Parekh, H. S. (2017). Stably engineered nanobubblesand ultrasound - An effective platform for enhanced macromolecular delivery to representative cells of the retina.PLoS ONE, 12(5).https://doi.org/10.1371/journal.pone.0178305
Tian, J., Yang, F., Cui, H., Zhou, Y., Ruan, X., & Gu, N. (2015). A novel approach to making the gas-filled liposome real: Based on the interaction of lipid with free nanobubble within the solution. ACS Applied Materials and Interfaces, 7(48), 26579–26584. https://doi.org/10.1021/acsami.5b07778
Tian, Y., Liu, Z., Zhang, L., Zhang, J., Han, X., Wang, Q., & Cheng, W. (2018a).Apatinib-loaded lipid nanobubbles combined with ultrasound-targeted nanobubble destruction for synergistic treatment of HepG2 cells in vitro. OncoTargets and Therapy, 11, 4785–4795. https://doi.org/10.2147/OTT.S170786
Tian, Y., Liu, Z., Zhang, L., Zhang, J., Han, X., Wang, Q., & Cheng, W. (2018b).Apatinib-loaded lipid nanobubbles combined with ultrasound-targeted nanobubble destruction for synergistic treatment of HepG2 cells in vitro. OncoTargets and Therapy, 11, 4785–4795. https://doi.org/10.2147/OTT.S170786
Unger, E. C., Porter, T., Culp, W., Labell, R., Matsunaga, T., & Zutshi, R. (2004).Therapeutic applications of lipid-coated microbubbles. Advanced Drug Delivery Reviews, 56(9), 1291–1314.https://doi.org/10.1016/j.addr.2003.12.006
vanLiew, H. D., Raychaudhuri, S., Liew, V., & RaychaudhuriStabi-, S. (1997). modeling in physiology Stabilized bubbles in the body: pressure-radius relationships and the limits to stabilization. In J. Appl. Physiol (Vol. 82, Issue 6).http://www.jap.org
Vantimitta, S. R., & Jeganath, S. (2022). Novel approaches of gastro retentive drug delivery system: A review. International Journal of Health Sciences,6(S1), 3464–3476. https://doi.org/10.53730/ijhs.v6nS1.554
Wang, S., Dhanaliwala, A. H., Chen, J. L., &Hossack, J. A. (2013).Production rate and diameter analysis of spherical monodispersemicrobubbles from two-dimensional, expanding-nozzle flow-focusing microfluidic devices. Biomicrofluidics, 7(1).https://doi.org/10.1063/1.4774069
Wang, Y., Li, X., Zhou, Y., Huang, P., &Xu, Y. (2010).Preparation of nanobubbles for ultrasound imaging and intracelluar drug delivery. International Journal of Pharmaceutics, 384(1–2), 148–153. https://doi.org/10.1016/j.ijpharm.2009.09.027
Xie, X., Lin, W., Liu, H., Deng, J., Chen, Y., Liu, H., Fu, X., & Yang, Y. (2016). Ultrasound-responsive nanobubbles contained with peptide–camptothecin conjugates for targeted drug delivery. Drug Delivery, 23(8), 2756–2764.https://doi.org/10.3109/10717544.2015.1077289
Xing, Z., Wang, J., Ke, H., Zhao, B., Yue, X., Dai, Z., & Liu, J. (2010). The fabrication of novel nanobubble ultrasound contrast agent for potential tumor imaging. Nanotechnology, 21(14).https://doi.org/10.1088/0957-4484/21/14/145607
Yao, E., Chen, J., Zhao, X., Zheng, Y., Wu, X., Han, F., Huang, H., Liang, P., Liu, J., Wu, F., & Lin, L. (2018).Efficacy of Stereotactic Body Radiotherapy for Recurrent or Residual Hepatocellular Carcinoma after Transcatheter Arterial Chemoembolization.BioMed Research International, 2018. https://doi.org/10.1155/2018/5481909
Yin, T., Wang, P., Zheng, R., Zheng, B., Cheng, D., Zhang, X., &Shuai, X. (2012).Nanobubbles for enhanced ultrasound imaging of tumors.International Journal of Nanomedicine, 7, 895–904. https://doi.org/10.2147/IJN.S28830
Zerbini, A., Pilli, M., Laccabue, D., Pelosi, G., Molinari, A., Negri, E., Cerioni, S., Fagnoni, F., Soliani, P., Ferrari, C., & Missale, G. (2010). Radiofrequency Thermal Ablation for Hepatocellular Carcinoma Stimulates Autologous NK-Cell Response. Gastroenterology, 138(5).https://doi.org/10.1053/j.gastro.2009.12.051
Zhang, X., Zheng, Y., Wang, Z., Huang, S., Chen, Y., Jiang, W., Zhang, H., Ding, M., Li, Q., Xiao, X., Luo, X., Wang, Z., & Qi, H. (2014).Methotrexate-loaded PLGA nanobubbles for ultrasound imaging and Synergistic Targeted therapy of residual tumor during HIFU ablation.Biomaterials, 35(19), 5148–5161. https://doi.org/10.1016/j.biomaterials.2014.02.036
Zhao, Y. Z., Du, L. N., Lu, C. T., Jin, Y. G., &Ge, S. P. (2013a). Potential and problems in ultrasound-responsive drug delivery systems.In International Journal of Nanomedicine (Vol. 8, pp. 1621–1633).https://doi.org/10.2147/IJN.S43589
Zhao, Y. Z., Du, L. N., Lu, C. T., Jin, Y. G., &Ge, S. P. (2013b). Potential and problems in ultrasound-responsive drug delivery systems.In International Journal of Nanomedicine (Vol. 8, pp. 1621–1633).https://doi.org/10.2147/IJN.S43589
Published
How to Cite
Issue
Section
Copyright (c) 2022 International journal of health sciences

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Articles published in the International Journal of Health Sciences (IJHS) are available under Creative Commons Attribution Non-Commercial No Derivatives Licence (CC BY-NC-ND 4.0). Authors retain copyright in their work and grant IJHS right of first publication under CC BY-NC-ND 4.0. Users have the right to read, download, copy, distribute, print, search, or link to the full texts of articles in this journal, and to use them for any other lawful purpose.
Articles published in IJHS can be copied, communicated and shared in their published form for non-commercial purposes provided full attribution is given to the author and the journal. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this journal.
This copyright notice applies to articles published in IJHS volumes 4 onwards. Please read about the copyright notices for previous volumes under Journal History.








