Ultrasound-Mediated Drug Delivery With a Clinical Ultrasound System: In Vitro Evaluation
de Maar, Josanne S; Rousou, Charis; van Elburg, Benjamin; Vos, Hendrik J; Lajoinie, Guillaume P R; Bos, Clemens; Moonen, Chrit T W; Deckers, Roel
(2021) Frontiers in Pharmacology, volume 12
(Article)
Abstract
Chemotherapy efficacy is often reduced by insufficient drug uptake in tumor cells. The combination of ultrasound and microbubbles (USMB) has been shown to improve drug delivery and to enhance the efficacy of several drugs in vitro and in vivo, through effects collectively known as sonopermeation. However, clinical translation of USMB
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therapy is hampered by the large variety of (non-clinical) US set-ups and US parameters that are used in these studies, which are not easily translated to clinical practice. In order to facilitate clinical translation, the aim of this study was to prove that USMB therapy using a clinical ultrasound system (Philips iU22) in combination with clinically approved microbubbles (SonoVue) leads to efficient in vitro sonopermeation. To this end, we measured the efficacy of USMB therapy for different US probes (S5-1, C5-1 and C9-4) and US parameters in FaDu cells. The US probe with the lowest central frequency (i.e. 1.6 MHz for S5-1) showed the highest USMB-induced intracellular uptake of the fluorescent dye SYTOX™ Green (SG). These SG uptake levels were comparable to or even higher than those obtained with a custom-built US system with optimized US parameters. Moreover, USMB therapy with both the clinical and the custom-built US system increased the cytotoxicity of the hydrophilic drug bleomycin. Our results demonstrate that a clinical US system can be used to perform USMB therapy as efficiently as a single-element transducer set-up with optimized US parameters. Therefore, future trials could be based on these clinical US systems, including validated US parameters, in order to accelerate successful translation of USMB therapy.
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Keywords: USMB, chemotherapy, drug delivery, imaging, microbubbles, sonopermeation, sonoporation, ultrasound, Pharmacology, Pharmacology (medical)
ISSN: 1663-9812
Publisher: Frontiers Media S. A.
Note: Funding Information: We will apply for reimbursement of (part of) the publication fee from the Utrecht University Open Access Fund. The contribution of CR to this research was funded by the European Union’s Horizon 2020 research and innovation program under the Marie Sko̢ dowska-Curie Grant Agreement No. 722717. Funding Information: -The researchers and technicians of the department of Pharmaceutics, Utrecht University, for the opportunity to use their laboratory facilities and for their support.-Kim van der Wurff-Jacobs for her assistance with the flow cytometry experiments.-Corlinda ten Brink from Cell Microscopy Core, Department of Cell Biology, Center for Molecular Medicine, UMC Utrecht, for use of the LSM700 and technical support.-Sandra Bruggink for her work on the bleomycin IC50 experiments during her internship. Publisher Copyright: © Copyright © 2021 de Maar, Rousou, van Elburg, Vos, Lajoinie, Bos, Moonen and Deckers.
(Peer reviewed)