Increase of intracellular cisplatin levels and radiosensitization by ultrasound in combination with microbubbles.

Authors:
Clemens Bos
Clemens Bos
University Medical Center Utrecht
Netherlands
Gert Storm
Gert Storm
MIRA Institute for Biomedical Technology and Technical Medicine
Netherlands
Chrit T Moonen
Chrit T Moonen
University Medical Center Utrecht
Netherlands
Roel Deckers
Roel Deckers
University Medical Center Utrecht
Netherlands

J Control Release 2016 09 29;238:157-165. Epub 2016 Jul 29.

Imaging Division, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address:

The possibility to enhance drug delivery by using ultrasound in combination with microbubbles (USMB) is extensively studied. So far, these studies have focused on the delivery and efficacy of a single drug, e.g. in chemotherapy. In this study, we investigated the intracellular delivery of cisplatin by USMB and the subsequent increased efficacy in combination with radiotherapy in a head and neck cancer cell line in vitro. After USMB-mediated intracellular delivery was verified using the model-drug SYTOX® Green, we investigated the efficacy of cisplatin when combined with USMB and radiotherapy and measured whether intracellular cisplatin concentration was enhanced after applying USMB. In addition, the effect of USMB on cisplatin and radiotherapy-induced DNA damage was studied. Flow cytometry showed that USMB treatment increased the average percentage SYTOX® Green positive cells from 2.2% to 34.5%. Clonogenic assays demonstrated that exposure to USMB significantly increased the efficacy of cisplatin combined with radiotherapy. The enhanced efficacy was associated with increased intracellular cisplatin levels, which were 2.7-fold higher when cisplatin was combined with USMB. As a result, an 82% increase in levels of DNA double strand breaks was found when cisplatin was combined with USMB, compared to cisplatin only (p<0.05). In conclusion, cisplatin uptake was significantly increased by USMB, which resulted in enhanced levels of DNA damage and increased efficacy of cisplatin in combination with radiotherapy in vitro.

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http://dx.doi.org/10.1016/j.jconrel.2016.07.049DOI Listing
September 2016
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