Controlled assemblies of stimuli-responsive mesoporous silica drug delivery systems for controlled release of drugs

Abstract

There has been an ever increasing interest in developing stimuli-responsive mesoporous silica drug delivery systems to improve therapeutic efficacy and minimize the adverse effects of drugs. This paper reports the works of our research group on valved and gated mesoporous silica drug delivery systems. Biocompatible mesoporous silica nanoparticles (MSNs), as drug carriers, were modified with active group-terminated silanes via self-assembly followed by diverse functionalization, a variety of macrocyclic hosts, proteins, DNA, and quantum dots were bound to the MSN surfaces to develop nanovalves and nanogates, through multiple noncovalent interactions, dynamic covalent bonds, and even strong covalent bonds, for the encapsulation of drugs within MSN pores, thus smart valved and gated MSN drug delivery systems were constructed. Under the stimuli of pH, redox, competitive binding, enzymes, and near infrared lights, controlled release of the encapsulated drugs was realized, because of the destruction of multiple noncovalent interactions, the cleavage of dynamic covalent bonds, and the disassociation of gatekeeping scaffolds. The carboxylate-substituted pillar [6] arene (CPA [6] )-valved dimethylbenzimidazolium or bipyridinium-functionalized MSN drug delivery systems were constructed for acidic pH, competitive binding, and metal chelating-responsive controlled release. The γ -CD-gated MSN delivery system functionalized with disulfide-linked carbamoylphenylboronic acid moieties and amines via dual dynamic covalent bonds with dual drug loading was constructed for simultaneous and cascade release of two drugs. It is a smart strategy to take advantage of the specific structures and properties of cyclodextrins (CDs) for use in the MSN drug delivery systems not only as gatekeepers but also as drug carriers. The γ -CD-gated MSN delivery system provided a smart platform for combination drug therapy, in addition to resistance to serum and normal blood glucose levels. The concanavalin A (Con A)-gated mannose-functionalized MSN drug delivery system via multivalent carbohydrate - protein interactions was constructed for the controlled release of drugs either by acidic pH or by competitive binding of glucose at high concentrations. The long and flexible spacers linked with the mannose ligands played an important role in adjusting the local spatial arrangement of the ligands to favor multivalent protein binding, as did the surface density of the ligands. The MSN drug delivery systems functionalized with N -(3-trimethoxysilylpropyl)ethylenediamine triacetate ligands, in the presence of metal ions with and without myoglobin containing surface-accessible histidine residues, were constructed for pH-responsive controlled release. Both the metal-latching ligands and the metal-chelating proteins played a synergetic role in gating MSNs for high-loading drug delivery and stimuli-responsive controlled release. The DNA-gated MSN drug delivery system functionalized with disulfide-linked acridinamine intercalators was constructed for multi-responsive controlled release under different stimuli, including disulfide reducing agents, elevated temperature, and deoxyribonuclease I. The DNA-gated MSN drug delivery system integrated multiple responses and AND logic gate operations into a single smart nanodevice not only for codelivery of drugs and DNA/genes but also for cascade release of two drugs in combination of dual stimuli. The DNA-gated gold nanorod-embedded MSN delivery system functionalized with titanium(IV)-chelating phosphonates with dual drug loading was constructed for simultaneous and cascade release of two drugs. Coordination chemistry is the first strategy for DNA cappings through multivalent chelating interactions in drug delivery systems not only as gatekeepers but also as drug carriers. The two drugs were simultaneously released upon triggering of endonuclease degradation or photothermal dehybridization and were successively released upon first triggering of basic pH and subsequent triggering of photothermal heating. The combination of NIR light-based thermotherapy and triggered chemotherapy (thermo-chemotherapy) could maximize therapeutic efficacy. In addition, the ZnO quantum dot (QD)-gated hollow mesoporous silica drug delivery system was constructed for pH and redox- responsive controlled release, and the ZnO QD-gated mesoporous carbon nanoparticle (MCN) drug delivery system was for pH-responsive controlled release. These constructed stimuli-responsive MSN drug delivery systems have promising applications in targeted tumor therapy.