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
Yinxing Shen,1,2 Mengya Li,1 Tianqi Liu,1 Jing Liu,2 Youhua Xie,2 Junqi Zhang,2 Shouhong Xu,1 Honglai Liu11Key Laboratory for Advanced Materials, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237, People’s Republic of China; 2Ke...
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| Formato: | article |
| Lenguaje: | EN |
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Dove Medical Press
2019
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| Acceso en línea: | https://doaj.org/article/a5feb160141744239f3cd45c0e94bdf0 |
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| Sumario: | Yinxing Shen,1,2 Mengya Li,1 Tianqi Liu,1 Jing Liu,2 Youhua Xie,2 Junqi Zhang,2 Shouhong Xu,1 Honglai Liu11Key Laboratory for Advanced Materials, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237, People’s Republic of China; 2Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, People’s Republic of ChinaPurpose: 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 β-cyclodextrin (β-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 stimuli-responsive release of the chemotherapeutic agent doxorubicin (DOX). β-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 μg/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.Keywords: mesoporous silica nanoparticle, pH-sensitive nanovalve, HER2 aptamer, synergistic cytotoxicity |
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