Mesoporous nanocarriers with a stimulus-responsive cyclodextrin gatekeeper for targeting tumor hypoxia.

Tissue hypoxia developed in most malignant tumors makes a significant difference to normal tissues in the reduction potential and the activity of various bioreductive enzymes. Given the superior enzymatic activity of NAD(P)H:quinone oxidoreductase 1 (NQO1, a cytosolic reductase up-regulated in many human cancers) in hypoxia relative to that in normoxia, NQO1 has great potential for targeting hypoxic tumor cells. In the present report, the core concept of hypoxic NQO1-responsive mesoporous silica nanoparticles (MSNs) is based on the reasoning that the superior enzymatic activity of NQO1 within hypoxic cancer cells can be utilized as a key stimulus for the selective cleavage of an azobenzene stalk triggering the on-off gatekeeping for controlled release of guest drugs. We corroborate that the NQO1 specifically triggers to release the entrapped drug in the nanochannel of MSNs by reductive cleavage of the azobenzene linker only under hypoxic conditions in a controlled manner not only in vitro but also in vivo. Therefore, our results indicate that Si-Azo-CD-PEG could be utilized as a hypoxic cancer-targeting drug delivery carrier, and further suggest that the azobenzene linker could generally be useful for the construction of hypoxic NQO1-responsive nanomaterials.

A mesoporous nanocontainer gated by a stimuli-responsive peptide for selective triggering of intracellular drug release.

Mesoporous silica nanocontainers (MSNs) with biologically responsive gatekeepers have great potential for effective delivery of cargo molecules to the desired sites. For that purpose, peptides could be effective candidates as gatekeepers because of their bioresponsiveness and targeting capability. Taking advantage of the zinc finger domain peptide (CXXC), we designed a biocompatible all-peptide gatekeeper (WCGKC) with on-off gatekeeping capability through stimulus-responsive conformational conversion and the steric bulkiness of the tryptophan unit. The turn structure induced by an intramolecular disulfide bond of the peptide gatekeeper (WCGKC-SS) completely inhibited the release of the entrapped doxorubicin (DOX). However, upon reduction of the disulfide bond by glutathione (GSH), the peptide conformation was converted to a random structure, which opened the orifice of the mesopore leading to the release of DOX. The amine moiety of the lysine of the peptide gatekeeper was PEGylated to enhance dispersion stability and biocompatibility of the nanocontainer. Furthermore, the MSNs with the peptide gatekeeper (PEG-WCGKC-SS-Si) selectively released the entrapped DOX in A549 human lung cancer cells in a controlled manner triggered by intracellular GSH, but not in CCD normal lung cells containing a low intracellular GSH level. In A549 cells, DOX-loaded PEG-WCGKC-SS-Si exhibited about 10-times higher cytotoxicity induced by apoptosis than that in CCD cells.

Self-Assembled Dendron-Cyclodextrin Nanotubes with a Polyethylenimine Surface and Their Gene Delivery Capability.

Self-assembled dendron-cyclodextrin nanotubes (Den-CD-NTs) with selected surface functionalities can serve as templates for the formation of complexes with polymers, and the resulting nanotube-polymer complexes can be utilized as gene carriers. The negatively charged surfaces of Den-CD-NTs were covered with a positively charged polyethylenimine (PEI) layer using electrostatic interactions, and the resulting nanotube-PEI complex, having a positively charged surface exhibited intracellular uptake. Furthermore, the nanotube-PEI complex exhibited the capability for DNA complexation with reduced enzymatic degradation, and also showed higher transfection efficiency and lower cytotoxicity than PEI. Therefore, Den-CD-NTs, in simple complexation with a surface PEI layer, are potentially useful gene delivery vectors.