文献类型：期刊文献

英文题名：Copolymer micelles function as pH-responsive nanocarriers to enhance the cytotoxicity of a HER2 aptamer in HER2-positive breast cancer cells

作者：Shen, Yinxing[1,2];Zhang, Junqi[2];Hao, Weiju[1];Wang, Tong[1];Liu, Jing[2];Xie, Youhua[2];Xu, Shouhong[1];Liu, Honglai[1]

机构：[1]East China Univ Sci & Technol, Sch Chem & Mol Engn, State Key Lab Adv Mat, 130 Meilong Rd, Shanghai 200237, Peoples R China;[2]Fudan Univ, Sch Basic Med Sci, Key Lab Med Mol Virol MOE MOH, Dept Med Microbiol & Parasitol, 138 Yixueyuan Rd, Shanghai 200032, Peoples R China

年份：2018

卷号：13

起止页码：537

外文期刊名：INTERNATIONAL JOURNAL OF NANOMEDICINE

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000423519100003)】；

基金：Financial support for this work was provided by the National Natural Science Foundation of China (nos 31400123 and 21276074) and Research Funds from Shanghai Municipal Commission of Health and Family Planning (no 201440567).

语种：英文

外文关键词：pH-responsive micelle-like nanoparticles; nucleic acid delivery; HER2-targeted therapy

摘要：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 antihuman 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.