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J Drug Target. 2018 Feb;26(2):172-181. doi: 10.1080/1061186X.2017.1354001. Epub 2017 Jul 17.

Ultrasound-mediated drug delivery by gas bubbles generated from a chemical reaction.

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a Department of Biomedical Engineering , Khalifa University of Science Technology and Research , Abu Dhabi , United Arab Emirates.
b Khalifa University Center of Excellence in Biotechnology , Abu Dhabi , United Arab Emirates.
c Centre for Research in Complex Systems, Charles Sturt University , Albury , Australia.
d Department of Bio and Brain Engineering , Korea Advanced Institute of Science and Technology , Daejeon , South Korea.
e Department of Chemical and Biomolecular Engineering , Korea Advanced Institute of Science and Technology , Daejeon , South Korea.


Highly echogenic and ultrasound-responsive microbubbles such as nitrogen and perfluorocarbons have been exploited as ultrasound-mediated drug carriers. Here, we propose an innovative method for drug delivery using microbubbles generated from a chemical reaction. In a novel drug delivery system, luminol encapsulated in folate-conjugated bovine serum albumin nanoparticles (Fol-BSAN) can generate nitrogen gas (N2) by chemical reaction when it reacts with hydrogen peroxide (H2O2), one of reactive oxygen species (ROS). ROS plays an important role in the initiation and progression of cancer and elevated ROS have been observed in cancer cells both in vitro and in vivo. High-intensity focussed ultrasound (HIFU) is used to burst the N2 microbubbles, causing site-specific delivery of anticancer drugs such as methotrexate. In this research, the drug delivery system was optimised by using water-soluble luminol and Mobil Composition of Matter-41 (MCM-41), a mesoporous material, so that the delivery system was sensitive to micromolar concentrations of H2O2. HIFU increased the drug release from Fol-BSAN by 52.9 ± 2.9% in 10 minutes. The cytotoxicity of methotrexate was enhanced when methotrexate is delivered to MDA-MB-231, a metastatic human breast cancer cell line, using Fol-BSAN with HIFU. We anticipate numerous applications of chemically generated microbubbles for ultrasound-mediated drug delivery.


High-intensity focussed ultrasound; cancer; luminol; microbubble generation; reactive oxygen species

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