Enzyme‐Responsive Silica Mesoporous Supports Capped with Azopyridinium Salts for Controlled Delivery Applications

The preparation of a new capped silica mesoporous material, Rh‐Azo‐S , for on‐command delivery applications in the presence of target enzymes is described. The material consists of nanometric mesoporous MCM‐41‐like supports loaded with Rhodamine B and capped with an azopyridine derivative. The material was designed to show “zero delivery” and to display a cargo release in the presence of reductases and esterases, which are usually present in the colon, mainly due to intestinal microflora. The opening and cargo release of Rh‐Azo‐S in vitro studies were assessed and seen to occur in the presence of these enzymes, whereas no delivery was noted in the presence of pepsine. Moreover, Rh‐Azo‐S nanoparticles were used to study controlled Rhodamine B dye delivery in intracellular media. HeLa cells were employed for testing the “non”‐toxicity of nanoparticles. Moreover, delivery of the dye in these cells, through internalization and enzyme‐mediated gate opening, was confirmed by confocal microscopy. Furthermore, the nanoparticles capped with the Azo group and loaded with a cytotoxic camptothecin ( CPT ) were also prepared (solid CPT‐Azo‐S ) and used as delivery nanodevices in HeLa cells. When this solid was employed, the cell viability decreased significantly due to internalization of the nanoparticles and delivery of the cytotoxic agent.     

金粒子包封介孔二氧化硅杂化载药控释体系

靶向给药控释体系既可以增强药物在病灶部位的疗效, 又可以降低药物对正常部位的毒副作用. 基于介孔二氧化硅为"容器"-金纳米粒子为"开关"(MSN-AuNPs)的杂化纳米阀门体系同时具备两种纳米粒子的优良特性, 在化学、生物材料以及临床医药等多学科受到广泛关注. 本文根据刺激手段和应用功能分类, 介绍了单一功能和多重功能的MSN-AuNPs杂化纳米阀门体系的重要研究进展, 以及目前面临的挑战和今后的发展方向.     

New Oleic Acid-Capped Mesoporous Silica Particles as Surfactant-Responsive Delivery Systems

A new delivery microdevice, based on hydrophobic oleic acid-capped mesoporous silica particles and able to payload release in the presence of surfactants, has been developed. The oleic acid functionalization confers to the system a high hydrophobic character, which avoids cargo release unless surfactant molecules are present. The performance of this oleic-acid capped microdevice in the presence of different surfactants is presented and its zero-release operation in the absence of surfactants is demonstrated.     

Cathepsin‐B Induced Controlled Release from Peptide‐Capped Mesoporous Silica Nanoparticles

New capped silica mesoporous nanoparticles for intracellular controlled cargo release within cathepsin B expressing cells are described. Nanometric mesoporous MCM‐41 supports loaded with safranin O ( S1‐P ) or doxorubicin ( S2‐P ) containing a molecular gate based on a cathepsin B target peptidic sequence were synthesized. Solids were designed to show “zero delivery” and to display cargo release in the presence of cathepsin B enzyme, which selectively hydrolyzed in vitro the capping peptide sequence. Controlled delivery in HeLa, MEFs WT, and MEFs lacking cathepsin B cell lines were also tested. Release of safranin O and doxorubicin in these cells took place when cathepsin B was active or present. Cells treated with S2‐P showed a fall in cell viability due to nanoparticles internalization, cathepsin B hydrolysis of the capping peptide, and cytotoxic agent delivery, proving the possible use of these nanodevices as new therapeutic tools for cancer treatment.     

Enzyme‐Controlled Sensing–Actuating Nanomachine Based on Janus Au–Mesoporous Silica Nanoparticles

Novel Janus nanoparticles with Au and mesoporous silica faces on opposite sides were prepared using a Pickering emulsion template with paraffin wax as the oil phase. These anisotropic colloids were employed as integrated sensing–actuating nanomachines for enzyme‐controlled stimuli‐responsive cargo delivery. As a proof of concept, we demonstrated the successful use of the Janus colloids for controlled delivery of tris(2,2’‐bipyridyl) ruthenium(II) chloride from the mesoporous silica face, which was grafted with pH‐sensitive gatelike scaffoldings. The release was mediated by the on‐demand catalytic decomposition of urea by urease, which was covalently immobilized on the Au face.     

Borate‐Driven Gatelike Scaffolding Using Mesoporous Materials Functionalised with Saccharides

We report the development of an MCM‐41 mesoporous support that is functionalised with saccharides at the pore outlets and contains the dye [Ru(bipy)₃]²⁺ in the pores (solid S1 ; bipy=2,2′‐bipyridyl). For this hybrid system, the inhibition of mass transport of the dye from the pore voids to the bulk solution in the presence of borate is demonstrated in water at neutral pH. The formation of the corresponding boroester derivative is related to the selective reaction of borate with the appended saccharides. This control is selective and only anion borate, among several anions and cations, can act as a molecular tap and inhibit the delivery of the entrapped guest. Additionally, the S1 –borate system behaves as pH‐controlled gatelike scaffolding. This pH‐responsive release can be achieved in an acidic pH (due to hydrolysis of the boroester), whereas the system remains closed at neutral pH. Molecular dynamic simulations using force‐field methods have been made to theoretically study the open/close borate‐driven mechanism. A mesoporous silica structure was constructed for this purpose, taking the plane (1?11) of the β‐cristobalite structure as a base on which hexagonal nanopores and anchored saccharide derivatives were included. The final model shows a highly flexible nanopore diameter of approximately 12.5 Å of similar size to the [Ru(bipy)₃]²⁺ complex (ca. 12 Å). However, the anchoring of borate to the appended saccharides results in a remarkable reduction of the pore size (down to ca. 6.4 Å) and a significant constraint in the flexibility and mobility of the saccharides. The theoretical calculations are in agreement with the experimental results and enable visualisation of the functional borate‐driven dye‐delivery‐inhibition outcome.     

A Free‐Blockage Controlled Release System Based on the Hydrophobic/Hydrophilic Conversion of Mesoporous Silica Nanopores

A pH‐responsive free‐blockage release system was achieved through controlling the hydrophobic/hydrophilic conversion of mesoporous silica nanopores. This system further presented pulsatile release with changing pH values between 4.0 and 7.0 for several cycles. This free‐blockage release system could also release antitumor agents to induce cell death after infecting tumor cells and could have the ability of continuous infection to tumor cells with high drug‐delivery efficiency and few side effects.     

Self‐Immolative Linkers as Caps for the Design of Gated Silica Mesoporous Supports

A new hybrid material based on sulforhodamine B dye‐loaded silica mesoporous nanoparticles capped with a self‐immolative gate has been synthesized and characterized. The gated material's controlled release behavior is monitored under different pH conditions. Under acidic and neutral conditions, a low level of dye release is detected. However, at slightly basic pH, significant dye release occurs owing to deprotonation of the phenol moiety in the capping molecule, which results in its disassembly.     

DNA‐Hybrid‐Gated Multifunctional Mesoporous Silica Nanocarriers for Dual‐Targeted and MicroRNA‐Responsive Controlled Drug Delivery

The design of an ideal drug delivery system with targeted recognition and zero premature release, especially controlled and specific release that is triggered by an exclusive endogenous stimulus, is a great challenge. A traceable and aptamer‐targeted drug nanocarrier has now been developed; the nanocarrier was obtained by capping mesoporous silica‐coated quantum dots with a programmable DNA hybrid, and the drug release was controlled by microRNA. Once the nanocarriers had been delivered into HeLa cells by aptamer‐mediated recognition and endocytosis, the overexpressed endogenous miR‐21 served as an exclusive key to unlock the nanocarriers by competitive hybridization with the DNA hybrid, which led to a sustained lethality of the HeLa cells. If microRNA that is exclusively expressed in specific pathological cell was screened, a combination of chemotherapy and gene therapy should pave the way for a targeted and personalized treatment of human diseases.     

Caspase 3 Targeted Cargo Delivery in Apoptotic Cells Using Capped Mesoporous Silica Nanoparticles

Excessive apoptotic cell death is at the origin of several pathologies, such as degenerative disorders, stroke or ischemia‐reperfusion damage. In this context, strategies to improve inhibition of apoptosis and other types of cell death are of interest and may represent a pharmacological opportunity for the treatment of cell‐death‐related disorders. In this scenario new peptide‐containing delivery systems (solids S₁ ‐ P₁ and S₁ ‐ P₂ ) are described based on mesoporous silica nanoparticles (MSNs) loaded with a dye and capped with the KKGDEVDKKARDEVDK ( P₁ ) peptide that contains two repeats of the DEVD target sequence that are selectively hydrolyzed by caspase 3 ( C3 ). This enzyme plays a central role in the execution‐phase of apoptosis. HeLa cells electroporated with S₁ – P₁ are able to deliver the cargo in the presence of staurosporin (STS), which induces apoptosis with the consequent activation of the cytoplasmic C3 enzyme. Moreover, the nanoparticles S₁ ‐ P₂ , containing both a cell‐penetrating TAT peptide and P₁ also entered in HeLa cells and delivered the cargo preferentially in cells treated with the apoptosis inducer cisplatin.     

Redox‐ and Temperature‐Controlled Drug Release from Hollow Mesoporous Silica Nanoparticles

A controlled drug‐delivery system has been developed based on mesoporous silica nanoparticles that deliver anticancer drugs into cancer cells with minimized side effects. The copolymer of two oligo(ethylene glycol) macromonomers cross‐linked by the disulfide linker N,N′‐bis(acryloyl)cystamine is used to cap hollow mesoporous silica nanoparticles (HMSNs) to form a core/shell structure. The HMSN core is applied as a drug storage unit for its high drug loading capability, whereas the polymer shell is employed as a switch owing to its redox/temperature dual responses. The release behavior in vitro of doxorubicin demonstrated that the loaded drugs could be released rapidly at higher temperature or in the presence of glutathione (GSH). Thus, the dual‐stimulus polymer shell exhibiting a volume phase transition temperature higher than 37 °C can effectively avoid drug leakage in the bloodstream owing to the swollen state of the shell. Once internalized into cells, the carriers shed the polymer shell because of cleavage of the disulfide bonds by GSH, which results in the release of the loaded drugs in cytosol. This work may prove to be a significant development in on‐demand drug release systems for cancer therapy.     

pH-Responsive Drug Delivery and Imaging Study of Hybrid Mesoporous Silica Nanoparticles

A system of pH-responsive and imaging nanocarriers was developed using mesoporous silica nanoparticles (MSNs), in which gadolinium (Gd) was doped through in situ doping (Gd₂O₃@MSN). Sodium alginate (SA) was attached to the surfaces of the amino groups of MSNs (NH₂-Gd₂O₃@MSN) through the electrostatic adsorption between the amino groups and the carboxyl groups with the formation of hybrid SA-Gd₂O₃@MSN nanoparticles (NPs). The SA-coated NPs were spherical or near-spherical in shape with an average size of nearly 83.2 ± 8.7 nm. The in vitro drug release experiments of a model rhodamine B (RhB) cargo were performed at different pH values. The result confirmed the pH-responsiveness of the nanocarriers. The results of the cytotoxicity studies indicated that the SA-Gd₂O₃@MSN NPs were not cytotoxic by themselves. The results of the in vivo safety evaluation and the hemolysis assay confirmed that the system is highly biocompatible. It is noteworthy that the T1 contrast of the system was significantly enhanced by the Gd, as indicated by the result of the MR imaging. This study confirms that the synthesized hybrid nanosystem is promising for pH-responsive drug delivery and MR imaging for cancer diagnosis and treatment.     

Bioresponsive Hyaluronic Acid‐Capped Mesoporous Silica Nanoparticles for Targeted Drug Delivery

In this paper, we present a facile strategy to synthesize hyaluronic acid (HA) conjugated mesoporous silica nanoparticles (MSP) for targeted enzyme responsive drug delivery, in which the anchored HA polysaccharides not only act as capping agents but also as targeting ligands without the need of additional modification. The nanoconjugates possess many attractive features including chemical simplicity, high colloidal stability, good biocompatibility, cell‐targeting ability, and precise cargo release, making them promising agents for biomedical applications. As a proof‐of‐concept demonstration, the nanoconjugates are shown to release cargoes from the interior pores of MSPs upon HA degradation in response to hyaluronidase‐1 (Hyal‐1). Moreover, after receptor‐mediated endocytosis into cancer cells, the anchored HA was degraded into small fragments, facilitating the release of drugs to kill the cancer cells. Overall, we envision that this system might open the door to a new generation of carrier system for site‐selective, controlled‐release delivery of anticancer drugs.