title: Increase of intracellular cisplatin levels and radiosensitization by ultrasound in combination with microbubbles.
abstract: 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.
authors.affiliation: Imaging Division, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Bart H A
authors.initials: BHA
authors.lastname: Lammertink
authors.affiliation: Imaging Division, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Clemens
authors.initials: C
authors.lastname: Bos
authors.affiliation: Imaging Division, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Kim M
authors.initials: KM
authors.lastname: van der Wurff-Jacobs
authors.affiliation: Targeted Therapeutics, MIRA Institute, University of Twente, Enschede, The Netherlands; Pharmaceutics Department, Utrecht University, Utrecht, The Netherlands.
authors.forename: Gert
authors.initials: G
authors.lastname: Storm
authors.affiliation: Imaging Division, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Chrit T
authors.initials: CT
authors.lastname: Moonen
authors.affiliation: Imaging Division, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: r.deckers-2@umcutrecht.nl.
authors.forename: Roel
authors.initials: R
authors.lastname: Deckers
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy; D002945:Cisplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D016503:Drug Delivery Systems / Q000379:methods*; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D006801:Humans; D045423:Microbubbles; D014465:Ultrasonics / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin
keywords: Cisplatin; Drug delivery; Microbubbles; Radiosensitizer; Radiotherapy; Sonoporation; Ultrasound