Copolymer micelles function as pH-responsive nanocarriers to enhance the cytotoxicity of a HER2 aptamer in HER2-positive breast cancer cells
Yinxing Shen,1,2,* Junqi Zhang,2,* Weiju Hao,1 Tong Wang,1 Jing Liu,2 Youhua Xie,2 Shouhong Xu,1 Honglai Liu1 1State Key Laboratory for Advanced Materials, School of Chemistry and Molecular Engineering, East China University of Science and Technology, 2Department of Medical Microbiology and Parasit...
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| Autores principales: | , , , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
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Dove Medical Press
2018
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/7df50c2931ce4e6193859e25586a52bc |
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| Sumario: | Yinxing Shen,1,2,* Junqi Zhang,2,* Weiju Hao,1 Tong Wang,1 Jing Liu,2 Youhua Xie,2 Shouhong Xu,1 Honglai Liu1 1State Key Laboratory for Advanced Materials, School of Chemistry and Molecular Engineering, East China University of Science and Technology, 2Department of Medical Microbiology and Parasitology, Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Efficient delivery of nucleic acids into target cells is crucial for nucleic acid-based therapies. Various nucleic acid delivery systems have been developed, each with its own advantages and limitations. We previously developed a nanoparticle-based delivery system for small chemical drugs using pH-responsive PEG8-PDPA100-PEG8 polymer micelles as carriers. In this study, we extend the application of these pH-responsive micelle-like nanoparticles (MNPs) to deliver oligonucleotides. We demonstrate that the MNPs efficiently encapsulate and deliver oligonucleotides of different lengths (20–100 nt) into cells. The cargo oligonucleotides are rapidly released at pH 5.0. We prepared MNPs carrying a Texas red-fluorescently labeled anti-human epidermal growth factor receptor 2 (HER2) aptamer (HApt). Compared to free HApt, the HApt-MNPs resulted in significantly better cellular uptake, reduced cell viability, and increased apoptosis in SKBR3 breast cancer cells, which overexpress HER2. Moreover, HApt-MNPs were significantly less cytotoxic to MCF7 breast cancer cells, which express low levels of HER2. After cellular uptake, HApt-MNPs mainly accumulated in lysosomes; inhibition of lysosomal activity using bafilomycin A1 and LysoTracker Red staining confirmed that lysosomal activity and low pH were required for HApt-MNP accumulation and release. Furthermore, HER2 protein expression declined significantly following treatment with HApt-MNPs in SKBR3 cells, indicating that HApt-induced translocation of HER2 to lysosomes exerted a potent cytotoxic effect by altering signaling downstream of HER2. In conclusion, this pH-responsive and lysosome-targeting nanoparticle system can efficiently deliver oligonucleotides to specific target cells and has significant potential for nucleic acid-based cancer therapies. Keywords: pH-responsive micelle-like nanoparticles, nucleic acid delivery, HER2-targeted therapy |
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