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.     

Enzyme‐Responsive Multifunctional Magnetic Nanoparticles for Tumor Intracellular Drug Delivery and Imaging

Enzyme‐responsive, hybrid, magnetic silica nanoparticles have been employed for multifunctional applications in selective drug delivery and intracellular tumor imaging. In this study, doxorubicin (Dox)‐conjugated, enzyme‐cleavable peptide precursors were covalently tethered onto the surface of uniform silica‐coated magnetic nanoparticles through click chemistry. This enzyme‐responsive nanoparticle conjugate demonstrated highly efficient Dox release upon specific enzyme interactions in vitro. It also exhibits multiple functions in selective tumor intracellular drug delivery and imaging in the tumor cells with high cathepsin B expression, whereas it exhibited lower cytotoxicity towards other cells without enzyme expression.     

Azobenzene Polyesters Used as Gate‐Like Scaffolds in Nanoscopic Hybrid Systems

The synthesis and characterisation of new capped silica mesoporous nanoparticles for on‐command delivery applications is reported. Functional capped hybrid systems consist of MCM‐41 nanoparticles functionalised on the external surface with polyesters bearing azobenzene derivatives and rhodamine B inside the mesopores. Two solid materials, Rh‐PAzo8‐S and Rh‐PAzo6‐S, containing two closely related polymers, PAzo8 and PAzo6, in the pore outlets have been prepared. Materials Rh‐PAzo8‐S and Rh‐PAzo6‐S showed an almost zero release in water due to steric hindrance imposed by the presence of anchored bulky polyesters, whereas a large delivery of the cargo was observed in the presence of an esterase enzyme due to the progressive hydrolysis of polyester chains. Moreover, nanoparticles Rh‐PAzo8‐S and Rh‐PAzo6‐S were used to study the controlled release of the dye in intracellular media. Nanoparticles were not toxic for HeLa cells and endocytosis‐mediated cell internalisation was confirmed by confocal microscopy. Furthermore, the possible use of capped materials as a drug‐delivery system was demonstrated by the preparation of a new mesoporous silica nanoparticle functionalised with PAzo6 and loaded with the cytotoxic drug camptothecin (CPT‐PAzo6‐S). Following cell internalisation and lysosome resident enzyme‐dependent gate opening, CPT‐PAzo6‐S induced CPT‐dependent cell death in HeLa cells.     

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.     

Enzyme‐Responsive Intracellular‐Controlled Release Using Silica Mesoporous Nanoparticles Capped with ε‐Poly‐L‐lysine

The synthesis and characterization of two new capped silica mesoporous nanoparticles for controlled delivery purposes are described. Capped hybrid systems consist of MCM‐41 nanoparticles functionalized on the outer surface with polymer ε‐poly‐L ‐lysine by two different anchoring strategies. In both cases, nanoparticles were loaded with model dye molecule [Ru(bipy)₃]²⁺. An anchoring strategy involved the random formation of urea bonds by the treatment of propyl isocyanate‐functionalized MCM‐41 nanoparticles with the lysine amino groups located on the ε‐poly‐L ‐lysine backbone (solid Ru‐rLys‐S1 ). The second strategy involved a specific attachment through the carboxyl terminus of the polypeptide with azidopropyl‐functionalized MCM‐41 nanoparticles (solid Ru‐tLys‐S1 ). Once synthesized, both nanoparticles showed a nearly zero cargo release in water due to the coverage of the nanoparticle surface by polymer ε‐poly‐L ‐lysine. In contrast, a remarkable payload delivery was observed in the presence of proteases due to the hydrolysis of the polymer’s amide bonds. Once chemically characterized, studies of the viability and the lysosomal enzyme‐controlled release of the dye in intracellular media were carried out. Finally, the possibility of using these materials as drug‐delivery systems was tested by preparing the corresponding ε‐poly‐L ‐lysine capped mesoporous silica nanoparticles loaded with cytotoxic drug camptothecin (CPT), CPT‐rLys‐S1 and CPT‐tLys‐S1 . Cellular uptake and cell‐death induction were studied. The efficiency of both nanoparticles as new potential platforms for cancer treatment was demonstrated.     

Bis‐clickable Mesoporous Silica Nanoparticles: Straightforward Preparation of Light‐Actuated Nanomachines for Controlled Drug Delivery with Active Targeting

Bis(clickable) mesoporous silica nanospheres (ca. 100 nm) were obtained by the co‐condensation of TEOS with variable amounts (2–5 % each) of two clickable organosilanes in the presence of CTAB. Such nanoparticles could be easily functionalized with two independent functions using the copper‐catalyzed alkyne‐azide cycloaddition (CuAAC) reaction to transform them into nanomachines bearing cancer cell targeting ligands with the ability to deliver drugs on‐demand. The active targeting was made possible after anchoring folic acid by CuAAC click reaction, whereas the controlled delivery was performed by clicked azobenzene fragments. Indeed, the azobenzene groups are able to obstruct the pores of the nanoparticles in the dark whereas upon irradiation in the UV or in the blue range, their trans‐to‐cis photoisomerization provokes disorder in the pores, enabling the delivery of the cargo molecules. The on‐command delivery was proven in solution by dye release experiments, and in vitro by doxorubicin delivery. The added value of the folic acid ligand was clearly evidenced by the difference of cell killing induced by doxorubicin‐loaded nanoparticles under blue irradiation, depending on whether the particles featured the clicked folic acid ligand or not.     

Targeting Innate Immunity with dsRNA‐Conjugated Mesoporous Silica Nanoparticles Promotes Antitumor Effects on Breast Cancer Cells

We describe herein a Toll‐like receptor 3 (TLR3) targeting delivery system based on mesoporous silica nanoparticles capped with the synthetic double stranded RNA polyinosinic–polycytidylic acid (poly(I:C)) for controlled cargo delivery in SK‐BR‐3 breast carcinoma cells. Our results show that poly(I:C)‐conjugated nanoparticles efficiently targeted breast cancer cells due to dsRNA–TLR3 interaction. Such interaction also triggered apoptotic pathways in SK‐BR‐3, significantly decreasing cells viability. Poly(I:C) cytotoxic effect in breast carcinoma cells was enhanced by loading nanoparticles′ mesopores with the anthracyclinic antibiotic doxorubicin, a commonly used chemotherapeutic agent.     

Dual‐Cargo Selectively Controlled Release Based on a pH‐Responsive Mesoporous Silica System

A pH‐controlled delivery system based on mesoporous silica nanoparticles (MSNs) was constructed for dual‐cargo selective release. To achieve a better controlled‐release effect, a modified sol–gel method was employed to obtain MSNs with tunable particle and pore sizes. The systems selectively released different kinds of cargo when stimulated by different pH values. At the lower pH value (pH 2.0) only one kind of cargo was released from the MSNs, whereas at a higher pH value (pH 7.0) only the other kind of cargo was released from the MSNs. The multi‐cargo delivery system has brought the concept of selective release to new advances in the field of functional nanodevices and allows more accurate and controllable delivery of specific cargoes, which is expected to have promising applications in nanomedicine.     

Biodegradable Oxamide‐Phenylene‐Based Mesoporous Organosilica Nanoparticles with Unprecedented Drug Payloads for Delivery in Cells

We describe biodegradable mesoporous hybrid nanoparticles (NPs) in the presence of proteins and their applications for drug delivery. We synthesized oxamide phenylene‐based mesoporous organosilica nanoparticles (MON) in the absence of a silica source which had remarkably high organic content and high surface areas. Oxamide functions provided biodegradability in the presence of trypsin model proteins. MON displayed exceptionally high payloads of hydrophilic and hydrophobic drugs (up to 84 wt %), and a unique zero premature leakage without the pore capping, unlike mesoporous silica. MON were biocompatible and internalized into cancer cells for drug delivery.     

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.     

Integrated Hollow Mesoporous Silica Nanoparticles for Target Drug/siRNA Co‐Delivery

A hollow mesoporous silica nanoparticle (HMSNP) based drug/siRNA co‐delivery system was designed and fabricated, aiming at overcoming multidrug resistance (MDR) in cancer cells for targeted cancer therapy. The as‐prepared HMSNPs have perpendicular nanochannels connecting to the internal hollow cores, thereby facilitating drug loading and release. The extra volume of the hollow core enhances the drug loading capacity by two folds as compared with conventional mesoporous silica nanoparticles (MSNPs). Folic acid conjugated polyethyleneimine (PEI‐FA) was coated on the HMSNP surfaces under neutral conditions through electrostatic interactions between the partially charged amino groups of PEI‐FA and the phosphate groups on the HMSNP surfaces, blocking the mesopores and preventing the loaded drugs from leakage. Folic acid acts as the targeting ligand that enables the co‐delivery system to selectively bind with and enter into the target cancer cells. PEI‐FA‐coated HMSNPs show enhanced siRNA binding capability on account of electrostatic interactions between the amino groups of PEI‐FA and siRNA, as compared with that of MSNPs. The electrostatic interactions provide the feasibility of pH‐controlled release. In vitro pH‐responsive drug/siRNA co‐delivery experiments were conducted on HeLa cell lines with high folic acid receptor expression and MCF‐7 cell lines with low folic acid receptor expression for comparison, showing effective target delivery to the HeLa cells through folic acid receptor meditated cellular endocytosis. The pH‐responsive intracellular drug/siRNA release greatly minimizes the prerelease and possible side effects of the delivery system. By simultaneously delivering both doxorubicin (Dox) and siRNA against the Bcl‐2 protein into the HeLa cells, the expression of the anti‐apoptotic protein Bcl‐2 was successfully suppressed, leading to an enhanced therapeutic efficacy. Thus, the present multifunctional nanoparticles show promising potentials for controlled and targeted drug and gene co‐delivery in cancer treatment.     

Cell‐Penetrating Poly(disulfide) Assisted Intracellular Delivery of Mesoporous Silica Nanoparticles for Inhibition of miR‐21 Function and Detection of Subsequent Therapeutic Effects

The design of drug delivery systems capable of minimal endolysosomal trapping, controlled drug release, and real‐time monitoring of drug effect is highly desirable for personalized medicine. Herein, by using mesoporous silica nanoparticles (MSNs) coated with cell‐penetrating poly(disulfide)s and a fluorogenic apoptosis‐detecting peptide (DEVD‐AAN), we have developed a platform that could be uptaken rapidly by mammalian cells via endocytosis‐independent pathways. Subsequent loading of these MSNs with small molecule inhibitors and antisense oligonucleotides resulted in intracellular release of these drugs, leading to combination inhibition of endogenous miR‐21 activities which was immediately detectable by the MSN surface‐coated peptide using two‐photon fluorescence microscopy.     

Stimulus‐Induced Conformational Transformation of a Cyclic Peptide for Selective Cell‐Targeting On–Off Gatekeeper for Mesoporous Nanocarriers

α_vβ₃ Integrin is upregulated on many cancer cells. We designed a dual functional cyclic peptide gatekeeper with a capability of stimuli‐responsive conformational transformation which could serve as a selective cell‐targeting on–off gatekeeper for mesoporous nanocarriers. The advantage of employing the motif of stimuli‐induced conformational transformation of cyclic peptides is that they could be utilized not only as an on–off gatekeeper for the triggered release of cargo drugs but also as a targeting ligand of the carriers to desired cells with their respective binding receptors. The peptide gatekeepers on the surface of nanocarriers exhibited on–off gatekeeping via conformational transformation triggered by intracellular glutathione levels of the cancer cells. The cyclic RGD sequence of the peptide gatekeepers enhanced the intracellular uptake into tumor cells (A549) and the therapeutic efficacy of the nanocarrier.     

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.     

Cathepsin B‐Specific Metabolic Precursor for In Vivo Tumor‐Specific Fluorescence Imaging

Recently, metabolic glycoengineering with bioorthogonal click reactions has focused on improving the tumor targeting efficiency of nanoparticles as delivery vehicles for anticancer drugs or imaging agents. It is the key technique for developing tumor‐specific metabolic precursors that can generate unnatural glycans on the tumor‐cell surface. A cathepsin B‐specific cleavable substrate (KGRR) conjugated with triacetylated N‐azidoacetyl‐d ‐mannosamine (RR‐S‐Ac₃ManNAz) was developed to enable tumor cells to generate unnatural glycans that contain azide groups. The generation of azide groups on the tumor cell surface was exogenously and specifically controlled by the amount of RR‐S‐Ac₃ManNAz that was fed to target tumor cells. Moreover, unnatural glycans on the tumor cell surface were conjugated with near infrared fluorescence (NIRF) dye‐labeled molecules by a bioorthogonal click reaction in cell cultures and in tumor‐bearing mice. Therefore, our RR‐S‐Ac₃ManNAz is promising for research in tumor‐specific imaging or drug delivery.     

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.     

Hollow Carbon Nanobubbles: Synthesis,Chemical Functionalization,and Container‐Type Behavior in Water

Thin‐walled, hollow carbon nanospheres with a hydrophobic interior and good water dispersability can be synthesized in two steps: First, metal nanoparticles, coated with a few layers of graphene‐like carbon, are selectively modified on the outside with a covalently attached hydrophilic polymer. Second, the metal core is removed at elevated temperature treatment with acid, leaving a well‐defined carbon‐based hydrophobic cavity. Loading experiments with the dye rhodamine B and doxorubicin confirmed the filling and release of a cargo and adjustment of a dynamic equilibrium (cargo‐loaded versus release). Rhodamine B preferably accumulates in the interior of the bubbles. Filled nanobubbles allowed constant dye release into pure water. Studies of the concentration‐dependent loading and release show an unusual hysteresis.     

Polymer Nanoassembly as Delivery Systems and Anti‐Bacterial Toolbox: From PGMAs to MSN@PGMAs

Researches on cargo delivery systems have received burgeoning attention and advanced rapidly. For synthetic nanodevices, polymer nanoassemblies and their inorganic‐organic hybrid materials, especially smart mesoporous silica nanoparticle (MSN)‐polymer hybrids (e. g., MSN@PGMAs), have attracted increasing attention in recent years. Their superior characteristics and unique features such as dynamic transition of morphology endow them the ability to efficiently entrap cargo molecules and undergo smart cargo delivery and release in response to various external stimuli. In this Personal Account, we present our recent research progress in the construction of cargo delivery systems based on polymers, poly(glycidyl methacrylate) (PGMA) and its derivatives in particular, ranging from polymer nanoparticles, reverse micelles, to vesicles and reverse vesicles, and their performance in the delivery and controlled release of model molecules and therapeutic agents. Significantly, MSN‐PGMA hybrid nanoassemblies (MSN@PGMAs), constructed with the aid of atom transfer radical polymerization, host‐guest interactions, or layer‐by‐layer self‐assembly techniques, and their potential bio‐related applications and anti‐bacterial applications as new nanocarriers are reviewed. Finally, the prospects and challenges of such nanoplatforms are also discussed.     

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.     

Acetylcholinesterase‐capped Mesoporous Silica Nanoparticles Controlled by the Presence of Inhibitors

Two different acetylcholinesterase (AChE)‐capped mesoporous silica nanoparticles (MSNs), S1‐AChE and S2‐AChE , were prepared and characterized. MSNs were loaded with rhodamine B and the external surface was functionalized with either pyridostigmine derivative P1 (to yield solid S1 ) or neostigmine derivative P2 (to obtain S2 ). The final capped materials were obtained by coordinating grafted P1 or P2 with AChE′s active sites (to give S1‐AChE and S2‐AChE , respectively). Both materials were able to release rhodamine B in the presence of diisopropylfluorophosphate (DFP) or neostigmine in a concentration‐dependent manner via the competitive displacement of AChE through DFP and neostigmine coordination with the AChE‘s active sites. The responses of S1‐AChE and S2‐AChE were also tested with other enzyme inhibitors and substrates. These studies suggest that S1‐AChE nanoparticles can be used for the selective detection of nerve agent simulant DFP and paraoxon.