Lipid/PAA-coated mesoporous silica nanoparticles for dual-pH-responsive codelivery of arsenic trioxide/paclitaxel against breast cancer cells

Bing-bing Zhang1, Xiao-jie Chen1, Xu-dong Fan1, Jing-jing Zhu1, Ying-hui Wei1, Hang-sheng Zheng1, Hong-yue Zheng2, Bin-hui Wang3, Ji-gang Piao1, Fan-zhu Li1
1 College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
2 Libraries of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou 310053, China
3 The Affiliated Municipal Hospital of Taizhou University, Taizhou 318000, China
Correspondence to: Bin-hui Wang:, Ji-gang Piao:, Fan-zhu Li:,
DOI: 10.1038/s41401-021-00648-x
Received: 14 November 2020
Accepted: 12 March 2021
Advance online: 6 April 2021


Nanomedicine has attracted increasing attention and emerged as a safer and more effective modality in cancer treatment than conventional chemotherapy. In particular, the distinction of tumor microenvironment and normal tissues is often used in stimulus- responsive drug delivery systems for controlled release of therapeutic agents at target sites. In this study, we developed mesoporous silica nanoparticles (MSNs) coated with polyacrylic acid (PAA), and pH-sensitive lipid (PSL) for synergistic delivery and dual-pH-responsive sequential release of arsenic trioxide (ATO) and paclitaxel (PTX) (PL-PMSN-PTX/ATO). Tumor-targeting peptide F56 was used to modify MSNs, which conferred a target-specific delivery to cancer and endothelial cells under neoangiogenesis. PAA- and PSL-coated nanoparticles were characterized by TGA, TEM, FT-IR, and DLS. The drug-loaded nanoparticles displayed a dual-pH-responsive (pHe = 6.5, pHendo = 5.0) and sequential drug release profile. PTX within PSL was preferentially released at pH = 6.5, whereas ATO was mainly released at pH = 5.0. Drug-free carriers showed low cytotoxicity toward MCF-7 cells, but ATO and PTX co-delivered nanoparticles displayed a significant synergistic effect against MCF-7 cells, showing greater cell-cycle arrest in treated cells and more activation of apoptosis-related proteins than free drugs. Furthermore, the extracellular release of PTX caused an expansion of the interstitial space, allowing deeper penetration of the nanoparticles into the tumor mass through a tumor priming effect. As a result, FPL-PMSN-PTX/ATO exhibited improved in vivo circulation time, tumor-targeted delivery, and overall therapeutic efficacy.
Keywords: mesoporous silica nanoparticles; arsenic trioxide; paclitaxel; breast cancer; polyacrylic acid; pH-responsive

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