Synergistic ultrasonic biophysical effect-responsive nanoparticles for enhanced gene delivery to ovarian cancer stem cells
Chun Liufu,
Yue Li,
Yan Lin,
Jinsui Yu,
Meng Du,
Yuhao Chen,
Yaozhang Yang,
Xiaojing Gong,
Zhiyi Chen
Affiliations
Chun Liufu
Department of Ultrasound Medicine, Laboratory of Ultrasound Molecular Imaging, The Third Affiliated Hospital of Guangzhou Medical University, The Liwan Hospital of the Third Affiliated Hospital of Guangzhou Medical University
Yue Li
Department of Ultrasound Medicine, Laboratory of Ultrasound Molecular Imaging, The Third Affiliated Hospital of Guangzhou Medical University, The Liwan Hospital of the Third Affiliated Hospital of Guangzhou Medical University
Yan Lin
Department of Ultrasound Medicine, Laboratory of Ultrasound Molecular Imaging, The Third Affiliated Hospital of Guangzhou Medical University, The Liwan Hospital of the Third Affiliated Hospital of Guangzhou Medical University
Jinsui Yu
Department of Ultrasound Medicine, Laboratory of Ultrasound Molecular Imaging, The Third Affiliated Hospital of Guangzhou Medical University, The Liwan Hospital of the Third Affiliated Hospital of Guangzhou Medical University
Meng Du
Department of Ultrasound Medicine, Laboratory of Ultrasound Molecular Imaging, The Third Affiliated Hospital of Guangzhou Medical University, The Liwan Hospital of the Third Affiliated Hospital of Guangzhou Medical University
Yuhao Chen
Department of Ultrasound Medicine, Laboratory of Ultrasound Molecular Imaging, The Third Affiliated Hospital of Guangzhou Medical University, The Liwan Hospital of the Third Affiliated Hospital of Guangzhou Medical University
Yaozhang Yang
Department of Ultrasound Medicine, Laboratory of Ultrasound Molecular Imaging, The Third Affiliated Hospital of Guangzhou Medical University, The Liwan Hospital of the Third Affiliated Hospital of Guangzhou Medical University
Xiaojing Gong
Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen University Town
Zhiyi Chen
Department of Ultrasound Medicine, Laboratory of Ultrasound Molecular Imaging, The Third Affiliated Hospital of Guangzhou Medical University, The Liwan Hospital of the Third Affiliated Hospital of Guangzhou Medical University
Ovarian cancer stem cells (OCSCs) that are a subpopulation within bulk tumor survive chemotherapy and conduce to chemo-resistance and tumor relapse. However, conventional gene delivery is unsuitable for the on-demand content release, which limits OCSCs therapeutic utility. Here, we reported ultrasound-targeted microbubble destruction (UTMD)-triggerable poly(ethylene glycol)-disulfide bond-polyethylenimine loaded microbubble (PSP@MB). Taking advantage of glutathione (GSH) responsiveness, ultrasound triggering and spatiotemporally controlled release manner, PSP@MB is expected to realize local gene delivery for OCSCs treatment. But the biophysical mechanisms of gene delivery via PSP@MB and ultrasound remain unknown. The aim of this study is to determine the potential of gene delivery to OCSCs via ultrasonic synergistic biophysical effects and GSH-sensitive PSP@MB. The GSH-sensitive disulfide bond cleavable properties of PSP@MB were confirmed by 1H NMR spectra and infrared spectroscopy. The biophysical mechanisms between PSP@MB and cells were confirmed by scanning electron microscopy (SEM) and confocal laser scanning microscope (CLSM) to optimize the ultrasonic gene delivery system. The gene transfection via ultrasound and PSP@MB was closely related to the biophysical mechanisms (sonoporation, enhanced-endocytosis, sonoprinting, and endosomal escape). Ultrasound combined with PSP@MB successfully delivered aldehyde dehydrogenase 1 (ALDH1) short hairpin RNA (shRNA) plasmid to OCSCs and promoted apoptosis of OCSCs. The gene transfection rate and apoptosis rate were (18.41 ± 2.41)% and (32.62 ± 2.36)% analyzed by flow cytometry separately. This study showed that ultrasound triggering and GSH responsive PSP@MB might provide a novel strategy for OCSCs treatment via sonoporation and enhanced-endocytosis.
