Enhanced Cellular Uptake and Gene Silencing Activity of Survivin-siRNA via Ultrasound-Mediated Nanobubbles in Lung Cance
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RESEARCH PAPER
Enhanced Cellular Uptake and Gene Silencing Activity of Survivin-siRNA via Ultrasound-Mediated Nanobubbles in Lung Cancer Cells Hasan Akbaba 1
&
Gülşah Erel-Akbaba 1,2 & Mustafa Kotmakçı 1 & Yücel Başpınar 1
Received: 3 February 2020 / Accepted: 20 July 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
ABSTRACT Purpose Paclitaxel is a first-line drug for the therapy of lung cancer, however, drug resistance is a serious limiting factor, related to overexpression of anti-apoptotic proteins like survivin. To overcome this phenomenon, developing novel ultrasound responsive nanobubbles - nanosized drug delivery system- for the delivery of paclitaxel and siRNA in order to silence survivin expression in the presence of ultrasound was aimed. Methods Paclitaxel-carrying nanobubble formulation was obtained by modifying the multistep method. Then, the complex formation of the nanobubbles - paclitaxel formulation with survivin-siRNA, was examined in terms of particle size, polydispersity index, zeta potential, and morphology. Furthermore, siRNA binding and protecting ability, cytotoxicity, cellular uptake, gene silencing, and induction of apoptosis studies were investigated in terms of lung cancer cells. Results Developed nanobubbles have particle sizes of 218.9– 369.6 nm, zeta potentials of 27–34 mV, were able to protect siRNA from degradation and delivered siRNA into the lung cancer cells. Survivin expression was significantly lower compared with the control groups and enhanced apoptosis was induced by the co-delivery of survivin-siRNA and paclitaxel. Furthermore, significantly higher effects were obtained in the presence of ultrasound induction. Conclusion The ultrasound responsive nanobubble system carrying paclitaxel and survivin-siRNA is a promising and effective approach against lung cancer cells.
KEY WORDS lung cancer cell . nanobubble . paclitaxel .
* Hasan Akbaba [email protected]
ZP
1
Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Ege University, 35100 İzmir, Turkey
INTRODUCTION
2
Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Izmir Katip Çelebi University, İzmir, Turkey
Lung Cancer is the major reason of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) as the
survivin-siRNA . ultrasound
ABBREVIATIONS DDAB DMEM ELISA FBS FITC NB NB-PTX NBPTX:siRNA NSCLC OD PDI SCLC SDS SEM siRNA PBS PFP PTX TBS TEM US XTT
Dimethyldiocta-decylammonium bromide Dulbecco’s Modified Eagle’s Medium Enzyme-linked immunosorbent assay Fetal bovine serum Fluorescein isothiocyanate Nanobubbles Paclitaxel loaded nanobubbles siRNA carrying paclitaxel loaded nanobubbles Non-small cell lung cancer Optical density Polydispersity index Small cell lung cancer Sodium dodecyl sulfate Scanning electron microscopy Small interfering RNA Phosphate buffered saline Perfluoropentane Paclitaxel Tris-buffered saline Transmission electron microscopy Ultrasound 2,3-bis-(2-methoxy-4-nitro-5sulfophenyl)-2H-tetrazolium-5carboxanilide Zeta potenti
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