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 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.
Highlights
Chemotherapy is typically used as systemic treatment to destroy metastatic cancer cells that have spread away from the primary tumor
After evaluation of three clinical US probes and a set of parameters, the US probe with the lowest center frequency (i.e., 1.6 MHz for S5-1) showed the highest ultrasound and microbubbles (USMB) efficiency as measured by SYTOXTM Green (SG) uptake. This was consistent with literature showing that a frequency close to the resonance frequency of SonoVue [i.e., 1.6–3.1 MHz depending on the bubble size] was the most efficient (Kooiman et al, 2014; Roovers et al, 2019)
At lower pressures a larger number of cycles per pulse was beneficial. This was seen in previous studies, some conflicting results have been reported and intermediate pulse lengths might be optimal (Rahim et al, 2006; Karshafian et al, 2009; Phillips et al, 2010; Keller et al, 2019; Roovers et al, 2019)
Summary
Chemotherapy is typically used as systemic treatment to destroy metastatic cancer cells that have spread away from the primary tumor. Neoadjuvant chemotherapy can lead to less extensive surgery and reduce the risk of local recurrences (Dietz et al, 2018; van Ramshorst et al, 2018). Chemotherapy can enhance the local effect of Frontiers in Pharmacology | www.frontiersin.org de Maar et al. Ultrasound-Mediated Drug Delivery radiotherapy during chemoradiation (Geoffrois et al, 2018; Versteijne et al, 2020; Zhao et al, 2020). There is substantial heterogeneity in the local response to systemic treatment within and across cancer types. A plausible explanation for suboptimal response is the heterogeneous and/or insufficient delivery of drugs to tumor cells caused by biophysical barriers of the tumor tissue (Tredan et al, 2007; de Maar et al, 2020)
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