文献类型：期刊文献

英文题名：A dual-functional HER2 aptamer-conjugated, pH-activated mesoporous silica nanocarrier-based drug delivery system provides in vitro synergistic cytotoxicity in HER2-positive breast cancer cells

作者：Shen, Yinxing[1,2];Li, Mengya[1];Liu, Tianqi[1];Liu, Jing[2];Xie, Youhua[2];Zhang, Junqi[2];Xu, Shouhong[1];Liu, Honglai[1]

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

年份：2019

卷号：14

起止页码：4029

外文期刊名：INTERNATIONAL JOURNAL OF NANOMEDICINE

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000470675900002)】；

基金：Financial support for this work was provided by the National Natural Science Foundation of China (No. 21776071 and No. 31400123), the National Natural Science Foundation of China for Innovative Research Groups (No. 51621002), and Research Funds from Shanghai Municipal Commission of Health and Family Planning (No. 201440567).

语种：英文

外文关键词：mesoporous silica nanoparticle; pH-sensitive nanovalve; HER2 aptamer; synergistic cytotoxicity

摘要：Purpose: As well as functioning as a ligand that is selectively internalized by cells overexpressing human epidermal growth factor receptor-2 (HER2), HApt can exert cytotoxic effects by inducing cross-linking and subsequent translocation of HER2 to cytoplasmic vesicles, such downregulation of HER2 inhibits cell proliferation and induces apoptosis. We aimed to exploit the potential of HApt as both a targeting agent and antagonist to maximize the efficacy of mesoporous silica nanoparticle (MSN)-based drug release systems for HER2-positive breast cancer. Materials and methods: We fabricated novel HApt aptamer-functionalized pH-sensitive beta-cyclodextrin (beta-CD)-capped doxorubicin (DOX)-loaded mesoporous silica nanoparticles (termed MSN-BM/CD-HApt@DOX) for targeted delivery and selective targeting of HER2-positive cells. MSN-functionalized benzimidazole (MSN-BM) was used to load and achieve pH stimuliresponsive release of the chemotherapeutic agent doxorubicin (DOX). beta-cyclodextrin was introduced as a gatekeeper for encapsulated DOX and HApt as a selective HER2-targeting moiety and biotherapeutic agent. Results: Physical and chemical characterizations (FT-IR, XRD, TEM and BET) confirmed successful construction of MSN-BM/CD-HApt@DOX nanoparticles. In vitro release assays verified pH-sensitive DOX release. MSN-BM/CD-HApt@DOX (relative DOX concentration, 3.6 mu g/mL) underwent HER2-mediated endocytosis and was more cytotoxic to HER2-positive SKBR3 cells than HER2-negative MCF7 cells. MSN-BM/CD-HApt@DOX also exhibited better uptake and stronger growth inhibition in SKBR3 cells than the control MSN-BM/CD-NCApt@DOX functionalized with a scrambled nucleotide sequence on CD. Overall, intracellular delivery of DOX and the biotherapeutic agent HApt resulted in synergistic cytotoxic effects in HER2-positive cancer cells in comparison to either DOX or HApt alone. Conclusion: MSN-BM/CD-HApt@DOX enables HER2-mediated targeting and biotherapeutic effects as well as pH-responsive DOX drug release, resulting in synergistic cytotoxic effects in HER2-overexpressing cells in vitro. This novel nanocarrier could potentially enable specific targeting to improve the efficacy of chemotherapy for HER2-positive cancer.