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.     

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.     

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.     

Chitosan‐Capped Mesoporous Silica Nanoparticles as pH‐Responsive Nanocarriers for Controlled Drug Release

Herein, we present a straightforward synthesis of pH‐responsive chitosan‐capped mesoporous silica nanoparticles (MSNs). These MCM‐41‐type MSNs could be used as nanocapsules to accommodate guest molecules. Subsequently, (3‐glycidyloxypropyl)trimethoxysilane was grafted onto the surface of the MSNs, which served as a bridge to link between MSNs and chitosan, which is ubiquitous in nature and commercially available. Owing to the pH‐responsive and biocompatible features of chitosan, the loading and release of an anti‐cancer drug, doxorubicin hydrochloride, were carried out in vitro, in which the composite chitosan‐capped MSNs (CS‐MSNs) showed excellent environmental response. As the pH value of the media decreased, the degree of drug release correspondingly increased. Moreover, thanks to the perfect biocompatibility of chitosan, the CS‐MSNs exhibited lower cytotoxicity than that of the naked MSNs in an MTT assay. In addition, the in vitro kill potency against MCF‐7 breast‐cancer cells was enhanced over time, as well as with increasing concentration of the drug‐loaded CS‐MSNs. These results indicate that CS‐MSNs are promising candidates for pH‐responsive drug delivery in cancer therapy.     

Chemical Design of Nuclear‐Targeting Mesoporous Silica Nanoparticles for Intra‐nuclear Drug Delivery

Targeted drug delivery has been widely explored for efficient tumor therapy with desired efficacy but minimized side effects. It is widely known that large numbers of DNA‐toxins, such as doxorubicin, genes, reactive oxygen species, serving as therapeutic agents, can result in maximized therapeutic effects via the interaction directly with DNA helix. So after cellular uptake, these agents should be further delivered into cell nuclei to play their essential roles in damaging the DNA helix in cancer cells. Here, we demonstrate the first paradigm established in our laboratory in developing nuclear‐targeted drug delivery systems (DDSs) based on MSNs for enhanced therapeutic efficiency in the hope of speeding their translation into the clinics. Firstly, nuclear‐targeting DDSs based on MSNs, capable of intranuclear accumulation and drug release therein, were designed and constructed for the first time, resulting in much enhanced anticancer effects both in vitro and in vivo. Such an MSNs‐based and nuclear‐targeted drug/agent delivery strategy was further applied to overcome multidrug resistance (MDR) of malignant tumors, intra‐nuclearly deliver therapeutic genes, photosensitizers, radio‐enhancement agents and photothermal agents to realize efficient gene therapy, photodynamic therapy, radiation therapy and photothermal therapy, respectively.     

Mesoporous silica nanoparticles for 19F magnetic resonance imaging,fluorescence imaging,and drug delivery

Multifunctional mesoporous silica nanoparticles (MSNs) are good candidates for multimodal applications in drug delivery, bioimaging, and cell targeting. In particular, controlled release of drugs from MSN pores constitutes one of the superior features of MSNs. In this study, a novel drug delivery carrier based on MSNs, which encapsulated highly sensitive ¹⁹F magnetic resonance imaging (MRI) contrast agents inside MSNs, was developed. The nanoparticles were labeled with fluorescent dyes and functionalized with small molecule-based ligands for active targeting. This drug delivery system facilitated the monitoring of the biodistribution of the drug carrier by dual modal imaging (NIR/¹⁹F MRI). Furthermore, we demonstrated targeted drug delivery and cellular imaging by the conjugation of nanoparticles with folic acid. An anticancer drug (doxorubicin, DOX) was loaded in the pores of folate-functionalized MSNs for intracellular drug delivery. The release rates of DOX from the nanoparticles increased under acidic conditions, and were favorable for controlled drug release to cancer cells. Our results suggested that MSNs may serve as promising ¹⁹F MRI-traceable drug carriers for application in cancer therapy and bio-imaging.     

A Selective Release System Based on Dual‐Drug‐Loaded Mesoporous Silica for Nanoparticle‐Assisted Combination Therapy

A selective release system was demonstrated with a dual‐cargo loaded MSNs. When stimulated by different signals (UV or H⁺), this system could selectively release different kinds of cargoes individually. Furthermore, this system has been used to provide a combination of chemotherapy and biotherapy for cancer treatment. This controlled release system could be an important step in the development of more effective and sophisticated nanomedicine and nanodevices, due to the possibility of selective release of a complex multi‐drug.     

Metallo‐Supramolecular Nanogels for Intracellular pH‐Responsive Drug Release

A simple process is developed to fabricate metallo‐supramolecular nanogels (MSNs) by the metallo‐supramolecular‐coordinated interaction between histidine and iron‐meso‐tetraphenylporphin. MSNs are composed of histidine‐modified dextran (DH) and iron‐meso‐tetraphenylporphin (Fe–Por) and exhibit excellent biocompatibility and stability. MSNs show pH responsiveness in the intracellular mildly acidic environment, which has great potential for acid‐triggered drug release delivery. In vitro drug release profiles demonstrate that the pH‐dependent disassembly of MSNs to histidine and Por results in a quicker release rate of loaded‐DOX at pH 5.3, while at pH 7.4 MSNs could hinder the release of loaded‐DOX due to the enhanced stability of MSNs.

     

Photo‐Degradable,Protein–Polyelectrolyte Complex‐Coated,Mesoporous Silica Nanoparticles for Controlled Co‐Release of Protein and Model Drugs

The fabrication of photo‐degradable, protein–polyelectrolyte complex (PPC)‐coated, mesoporous silica nanoparticles (MSNs) and their controlled co‐release of protein and model drugs is reported. Random copolymers composed of oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA), and a photolabile o‐nitrobenzyl‐containing monomer, 5‐(2′‐(dimethylamino)ethoxy)‐2‐nitrobenzyl methacrylate (DENBMA), are first anchored onto the MSNs and then quaternary aminated, to obtain positively charged P(OEGMA‐co‐TENBMA) which exhibits photo‐induced charge conversion characteristics. PPCs consisting of P(OEGMA‐co‐TENBMA) and the protein bovine serum albumin (BSA) are utilized as capping agents for the nanopores of the MSNs. Upon UV irradiation, charge conversion of P(OEGMA‐co‐TENBMA) can lead to the disruption of PPCs on MSNs and co‐release of BSA and rhodamine B by electrostatic repulsion.     

An Adjustable pH‐Responsive Drug Delivery System Based on Self‐Assembly Polypeptide‐Modified Mesoporous Silica

In this study, an adjustable pH‐responsive drug delivery system using mesoporous silica nanoparticles (MSNs) as the host materials and the modified polypeptides as the nanovalves is reported. Since the polypeptide can self‐assemble via electrostatic interaction at pH 7.4 and be disassembled by pH changes, the modified poly(l ‐lysine) and poly(l ‐glutamate) are utilized for pore blocking and opening in the study. Poly(l ‐lysine)‐MSN (PLL‐MSN) and poly(l ‐glutamate)‐MSN (PLG‐MSN) are synthesized via the ring opening polymerization of N‐carboxyanhydrides onto the surface of mesoporous silica nanoparticles. The successful modification of the polypeptide on MSN is proved by Zeta potential change, X‐ray photoelectron spectroscopy (XPS), solid state NMR, and MALDI‐TOF MS. In vitro simulated dye release studies show that PLL‐MSN and PLG‐MSN can successfully load the dye molecules. The release study shows that the controlled release can be constructed at different pH by adjusting the ratio of PLL‐MSN to PLG‐MSN. Cellular uptake study indicates that the drug is detected in both cytoplasm and nucleus, especially in the nucleus. In vitro cytotoxicity assay indicates that DOX loaded mixture nanoparticles (ratio of PLL‐MSN to PLG‐MSN is 1:1) can be triggered for drug release in HeLa cells, resulting in 88% of cell killing.     

P(VPBA-DMAEA) as a pH-sensitive nanovalve for mesoporous silica nanoparticles based controlled release

A pH-sensitive controlled release system was proposed in this work, which consists of mesoporous silica nanoparticles(MSNs) functionalized on the pore outlets with poly(4-vinylphenybronic acid-co-2-(dimethylamino)ethyl acrylate) [P(VPBA-DMAEA)]. Four kinds of P(VPBA-DMAEA)-gated MSNs were synthesized and applied for the p H-sensitive controlled release. The results showed that P(VPBADMAEA) can work as a p H-sensitive nanovalve. The release behavior of the hybrid nanoparticles could be adjusted by changing the mole ratio of VPBA and DMAEA. With the increasing of the mole ratio of VPBA,the leakage of the entrapped molecules in the pores of MSNs could be decreased at neutral and alkaline conditions. By altering the p H of buffer from 4.0 to 8.0, the valve could be switched ‘‘on' and ‘‘off'reversibly. In addition, cells viability results indicated that these P(VPBA-DMAEA)-gated MSNs had good biocompatibility. We believe that these MSNs based p H-sensitive controlled release system will provide a promising nanodevice for sited release of drug delivery.     

Visible Light and pH Responsive Polymer‐Coated Mesoporous Silica Nanohybrids for Controlled Release

A visible light and pH responsive anticancer drug delivery system based on polymer‐coated mesoporous silica nanoparticles (MSNs) has been developed. Perylene‐functionalized poly(dimethylaminoethyl methacrylates) sensitive to visible light and pH are electrostatically attached on the surface of MSNs to seal the nanopores. Stimulation of visible light and acid can unseal the nanopores to induce controlled drug release from the MSNs. More interestingly, the release can be enhanced under the combined stimulation of the dual‐stimuli. The synergistic effect of visible light and acid stimulation on the efficient release of anticancer drugs from the nanohybrids endows the system with great potential for cancer therapy.

     

Targeting Cancer with PCPA‐Drug Conjugates: LSD1 Inhibition‐Triggered Release of 4‐Hydroxytamoxifen

Targeting cancer with small molecule prodrugs should help overcome problems associated with conventional cancer‐targeting methods. Herein, we focused on lysine‐specific demethylase 1 (LSD1) to trigger the controlled release of anticancer drugs in cancer cells, where LSD1 is highly expressed. Conjugates of the LSD1 inhibitor trans‐2‐phenylcyclopropylamine (PCPA) were used as novel prodrugs to selectively release anticancer drugs by LSD1 inhibition. As PCPA‐drug conjugate (PDC) prototypes, we designed PCPA‐tamoxifen conjugates 1 a and 1 b , which released 4‐hydroxytamoxifen in the presence of LSD1 in vitro. Furthermore, 1 a and 1 b inhibited the growth of breast cancer cells by the simultaneous inhibition of LSD1 and the estrogen receptor without exhibiting cytotoxicity toward normal cells. These results demonstrate that PDCs provide a useful prodrug method that may facilitate the selective release of drugs in cancer cells.     

Lipid,protein and poly(NIPAM) coated mesoporous silica nanoparticles for biomedical applications

In the past decade, mesoporous silica nanoparticles (MSNs) as nanocarriers have showed much potential in advanced nanomaterials due to their large surface area and pore volume. Especially, more and more MSNs based nanodevices have been designed as efficient drug delivery systems (DDSs) or biosensors. In this paper, lipid, protein and poly(NIPAM) coated MSNs are reviewed from the preparation, properties and their potential application. We also introduce the preparative methods including physical adsorption, covalent binding and self-assembly on the MSNs' surfaces. Furthermore, the interaction between the aimed cells and these molecular modified MSNs is discussed. We also demonstrate their typical applications, such as photodynamic therapy, bioimaging, controlled release and selective recognition in biomedical field.     

Hypoxia‐Activated Prodrugs of PERK Inhibitors

Tumour hypoxia plays an important role in tumour progression and resistance to therapy. Under hypoxia unfolded proteins accumulate in the endoplasmic reticulum (ER) and this stress is relieved through the protein kinase R‐like ER kinase (PERK) signalling arm of the unfolded protein response (UPR). Targeting the UPR through PERK kinase inhibitors provides tumour growth inhibition, but also elicits on‐mechanism normal tissue toxicity. Hypoxia presents a target for tumour‐selective drug delivery using hypoxia‐activated prodrugs. We designed and prepared hypoxia‐activated prodrugs of modified PERK inhibitors using a 2‐nitroimidazole bioreductive trigger. The new inhibitors retained PERK kinase inhibitory activity and the corresponding prodrugs were strongly deactivated. The prodrugs were able to undergo fragmentation following radiolytic reduction, or bioreduction in HCT116 cells, to release their effectors, albeit inefficiently. We examined the effects of the prodrugs on PERK signalling in hypoxic HCT116 cells. This study has identified a 2‐substituted nitroimidazole carbamate prodrug with potential to deliver PERK inhibitors in a hypoxia‐selective manner.     

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.     

Thermo‐triggered Release of CRISPR‐Cas9 System by Lipid‐Encapsulated Gold Nanoparticles for Tumor Therapy

CRISPR/Cas9 system is a powerful toolbox for gene editing. However, the low delivery efficiency is still a big hurdle impeding its applications. Herein, we report a strategy to deliver Cas9‐sgPlk‐1 plasmids (CP) by a multifunctional vehicle for tumor therapy. We condensed CPs on TAT peptide‐modified Au nanoparticles (AuNPs/CP, ACP) via electrostatic interactions, and coated lipids (DOTAP, DOPE, cholesterol, PEG2000‐DSPE) on the ACP to form lipid‐encapsulated, AuNPs‐condensed CP (LACP). LACP can enter tumor cells and release CP into the cytosol by laser‐triggered thermo‐effects of the AuNPs; the CP can enter nuclei by TAT guidance, enabling effective knock‐outs of target gene (Plk‐1) of tumor (melanoma) and inhibition of the tumor both in vitro and in vivo. This AuNPs‐condensed, lipid‐encapsulated, and laser‐controlled delivery system provides a versatile method for high efficiency CRISPR/Cas9 delivery and targeted gene editing for treatment of a wide spectrum of diseases.     

New advances in gated materials of mesoporous silica for drug controlled release

Drug delivery systems (DDS) are used to deliver therapeutic drugs to improve selectivity and reduce side effects. With the development of nanotechnology, many nanocarriers have been developed and applied to drug delivery, including mesoporous silica. Mesoporous silica nanoparticles (MSNs) have attracted a lot of attention for simple synthesis, biocompatibility, high surface area and pore volume. Based on the pore system and surface modification, gated mesoporous silica nanoparticles can be designed to realize on-command drug release, which provides a new approach for selective delivery of antitumor drugs. Herein, this review mainly focuses on the “gate keepers” of mesoporous silica for drug controlled release in nearly few years (2017–2020). We summarize the mechanism of drug controlled release in gated MSNs and different gated materials: inorganic gated materials, organic gated materials, self-gated drug molecules, and biological membranes. The facing challenges and future prospects of gated MSNs are discussed rationally in the end.     

An Aptamer Intrinsically Comprising 5‐Fluoro‐2′‐deoxyuridine for Targeted Chemotherapy

An aptamer specifically binding the interleukin‐6 receptor and intrinsically comprising multiple units of the nucleoside analogue 5‐fluoro‐2′‐deoxyuridine can exert a cytostatic effect direcly on certain cells presenting the receptor. Thus the modified aptamer fulfils the requirements for active drug targeting in an unprecedented manner. It can easily be synthesized in a single enzymatic step and it binds to a cell surface receptor that is conveyed into the lysosome. Upon degradation of the aptamer by intracellular nucleases the active drug is released within the targeted cells exclusively. In this way the aptamer acts as a prodrug meeting two major prerequisites of a drug delivery system: specific cell targeting and the controlled release of the drug triggered by an endogenous stimulus.     

Enzyme-inspired controlled release of cucurbit[7]uril nanovalves by using magnetic mesoporous silica

The controlled release of drugs by biostimuli is highly desirable under physiological conditions for their potential use in advanced applications. The enzyme-inspired controlled release of cucurbituril nanovalves by using magnetic mesoporous silica nanoparticles (MSNs) in near-neutral aqueous solutions is reported for the first time. The encirclement of cucurbit[7]uril (CB[7]) onto the protonated 1,4-butanediamine stalks tethered to the external surfaces of superparamagnetic Fe(3) O(4) -embedded mesoporous silica particles leads to tight blocking of the nanopores. The supramolecular nanovalves are activated by the enzymatic decarboxylation products of lysine, cadaverine (in the protonated form), which has a high affinity for CB[7], so that the encapsulated guest molecules, calcein, in the nanopores are released into the bulk solution. The release of calcein can be controlled in small portions on command by alternating changes in enzymatic decarboxylation products and CB[7]. The amino acid derived polyamines have long been associated with cell growth and cancers. The guest molecules released from the delivery system of magnetic MSNs can act not only on sensing probes for levels of decarboxylases and polyamines, but also on efficacious drugs to specific tissues and cells for regulation of polyamine synthesis.