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Ultrasound- and Microbubble-Assisted Gemcitabine Delivery to Pancreatic Cancer Cells

1
Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen 5021, Norway
2
Department of Clinical Science, Faculty of Medicine, University of Bergen, Bergen 5021, Norway
3
Phoenix Solutions AS, Ullernchausseen 64, 0379 Oslo, Norway
4
National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen 5021, Norway
5
Department of Clinical Medicine, University of Bergen, Bergen 5021, Norway
6
KinN Therapeutics AS, Bergen 5021, Norway
7
Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen 5021, Norway
8
Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen 5021, Norway
*
Authors to whom correspondence should be addressed.
Joint first authorship.
Joint senior authorship.
Pharmaceutics 2020, 12(2), 141; https://doi.org/10.3390/pharmaceutics12020141
Received: 3 January 2020 / Revised: 28 January 2020 / Accepted: 4 February 2020 / Published: 7 February 2020
Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer death worldwide. Poor drug delivery to tumours is thought to limit chemotherapeutic treatment efficacy. Sonoporation combines ultrasound (US) and microbubbles to increase the permeability of cell membranes. We assessed gemcitabine uptake combined with sonoporation in vitro in three PDAC cell lines (BxPC-3, MIA PaCa-2 and PANC-1). Cells were cultured in hypoxic bioreactors, while gemcitabine incubation ± sonoporation was conducted in cells with operational or inhibited nucleoside membrane transporters. Intracellular active metabolite (dFdCTP), extracellular gemcitabine, and inactive metabolite (dFdU) concentrations were measured with liquid chromatography tandem mass spectrometry. Sonoporation with increasing US intensities resulted in decreasing extracellular gemcitabine concentrations in all three cell lines with inhibited membrane transporters. In cells with inhibited membrane transporters, without sonoporation, dFdCTP concentrations were reduced down to 10% of baseline. Sonoporation partially restored gemcitabine uptake in these cells, as indicated by a moderate increase in dFdCTP concentrations (up to 37% of baseline) in MIA PaCa-2 and PANC-1. In BxPC-3, gemcitabine was effectively inactivated to dFdU, which might represent a protective mechanism against dFdCTP accumulation in these cells. Intracellular dFdCTP concentrations did not change significantly following sonoporation in any of the cell lines with operational membrane transporters, indicating that the gemcitabine activation pathway may have been saturated with the drug. Sonoporation allowed a moderate increase in gemcitabine transmembrane uptake in all three cell lines, but pre-existing nucleoside transporters were the major determinants of gemcitabine uptake and retention. View Full-Text
Keywords: gemcitabine; sonoporation; pancreatic cancer; PDAC; hENT; nucleoside transporters; in vitro gemcitabine; sonoporation; pancreatic cancer; PDAC; hENT; nucleoside transporters; in vitro
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MDPI and ACS Style

Bjånes, T.; Kotopoulis, S.; Murvold, E.T.; Kamčeva, T.; Gjertsen, B.T.; Gilja, O.H.; Schjøtt, J.; Riedel, B.; McCormack, E. Ultrasound- and Microbubble-Assisted Gemcitabine Delivery to Pancreatic Cancer Cells. Pharmaceutics 2020, 12, 141. https://doi.org/10.3390/pharmaceutics12020141

AMA Style

Bjånes T, Kotopoulis S, Murvold ET, Kamčeva T, Gjertsen BT, Gilja OH, Schjøtt J, Riedel B, McCormack E. Ultrasound- and Microbubble-Assisted Gemcitabine Delivery to Pancreatic Cancer Cells. Pharmaceutics. 2020; 12(2):141. https://doi.org/10.3390/pharmaceutics12020141

Chicago/Turabian Style

Bjånes, Tormod; Kotopoulis, Spiros; Murvold, Elisa T.; Kamčeva, Tina; Gjertsen, Bjørn T.; Gilja, Odd H.; Schjøtt, Jan; Riedel, Bettina; McCormack, Emmet. 2020. "Ultrasound- and Microbubble-Assisted Gemcitabine Delivery to Pancreatic Cancer Cells" Pharmaceutics 12, no. 2: 141. https://doi.org/10.3390/pharmaceutics12020141

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