Enzyme-Induced and Tumor-Targeted Drug Delivery System Based on Multifunctional Mesoporous Silica Nanoparticles
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Abstract
Functional mesoporous silica particles have attracted growing research interest for controlled drug delivery in targeted cancer therapy. For the purpose of efficient targeting tumor cells and reducing the adverse effect of antitumor drug doxorubicin (DOX), biocompatible and enzyme-responsive mesoporous silica nanoparticles (MSNs) with tumor specificity were desired. To construct these functional MSNs, the classic rotaxane structure formed between alkoxysilane tether and α-cyclodextrin (α-CD) was employed to anchor onto the orifices of MSNs as gatekeeper in this work. After subsequent modification by multifunctional peptide (azido-GFLGR7RGDS with tumor-targeting, membrane-penetrating, and cathepsin B-responsive functions) to stabilize the gatekeeper, the resulting functional MSNs showed a strong ability to load and seal DOX in their nanopores. When incubating these DOX-loaded MSNs with tumor and normal cells, the nanoparticles could efficiently employ their surface-encoded RGDS and continuous seven arginine (R7) sequences to target tumor cells, penetrate the cell membrane, and enter tumor cells. Because cathepsin B overexpressed in late endosomes and lysosomes of tumor cells could specifically hydrolyze GFLG sequences of the nanovalves, the DOX-loaded MSNs showed an "off-on" drug release behavior that ∼80% loaded DOX could be released within 24 h and thus showed a high rate of apoptosis. Furthermore, in vitro cellular experiments indicated that DOX-loaded MSNs (DOX@MSN-GFLGR7RGDS/α-CD) had high growth inhibition toward αvβ3-positive HeLa cancerous cells. The research might offer a practical way for designing the tumor-targeted and enzyme-induced drug delivery system for cancer therapy.
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