Ultra-small MoS_2 nanodots-incorporated mesoporous silica nanospheres for pH-sensitive drug delivery and CT imaging

Functionalization of mesoporous silica spheres with well-dispersed and ultra-small nanodots to exert their synergistic effects for biomedical applications has been considered to be an urgent challenge.Herein,homogeneously incorporation of ultra-small and monodispersed MoS₂ nanodots in the mesoporous silica nanospheres(MSN)was achieved by a facile one-step solvothermal reaction.The as-synthesized UsMSND@MSN possessed uniform size(~115 nm)and favorable biocompatibility inherited from MSN.The dispersed UsMSND within MSN could act as anchoring sites for aromatic anti-cancer drug DOX loading,and consequently achieved pH-responsive release based on the specialπ-π/electrostatic interactions with the DOX molecules.More importantly,the well-dispersed UsMSND in MSN could function as the non-toxic contrast agent for the sensitive in vivo CT imaging in various tumors including breast cancer and glioma with different sections.This work promises a good strategy for dispersed incorporation of UsMSND into MSN as an excellent pH-responsive platform for simultaneous cancer imaging and therapy.     

Biopebble Containers: DNA‐Directed Surface Assembly of Mesoporous Silica Nanoparticles for Cell Studies

The development of methods for colloidal self‐assembly on solid surfaces is important for many applications in biomedical sciences. Toward this goal, described is a versatile class of mesoporous silica nanoparticles (MSN) that contain on their surface various types of DNA molecules to enable their self‐assembly into micropatterned surface architectures useful for cell studies. Monodisperse dye‐doped MSN are synthesized by biphase stratification and functionalized with an aptamer oligonucleotide that serves as gatekeeper for the triggered release of encapsulated molecular cargo, such as fluorescent dye rhodamine B or the anticancer drug doxorubicin. One or two additional types of oligonucleotides are installed on the MSN surface to enable DNA‐directed immobilization on solid substrates bearing patterns of complementary capture oligonucleotides. It is demonstrated that this strategy can be used for efficient self‐assembly of microstructured surface architectures, which not only promote the adhesion and guidance of cells but also are capable of affecting the fate of adhered cells through triggered release of their cargo. It is believed that this approach is useful for diverse applications in tissue engineering and nanobio sciences.     

Reduction-responsive drug delivery based on mesoporous silica nanoparticle core with crosslinked poly(acrylic acid) shell

A novel reduction-responsive drug delivery system was successfully constructed with mesoporous silica nanoparticle (MSN) core as a drug carrier and poly(acrylic acid) (PAA) shell crosslinked by disulfide linkages as a drug release switcher. To keep the pore structure of MSN intact, PAA was covalently attached to the exterior surface of MSN before removing structure-template via radical polymerization. After removing structure-template and loading doxorubicin (DOX), the PAA shell was crosslinked by cystamine dihydrochloride through amidation reaction. The loading content and the entrapment efficiency of DOX could reach up to 40.2% and 80.4%, respectively. Because that the dissociation of disulfide linkage is reduction-responsive, the release behavior of DOX could be controlled by varying the concentration of reductant, and the release rate was 49.4% after 24 h with the existence of 2 mM glutathione (simulated environment of cancer cells), about three times higher than that of without glutathione (corresponding to normal human cells), which was only 16.9%. The in vitro cell assays demonstrated that the disulfide linkages crosslinked MSN–PAA (MSN–PAA-crosslinked) was highly biocompatible and suitable to use as drug carrier, and the DOX loaded MSN–PAA-crosslinked showed remarkable cytotoxicity to HeLa cells (human cancer cells), and relatively lower cytotoxicity to 293 cells (human normal cells). These results imply that the MSN–PAA-crosslinked is a promising platform to construct reduction-responsive controlled drug delivery system for cancer therapy.     

Targeted anticancer prodrug with mesoporous silica nanoparticles as vehicles

A targeted anticancer prodrug system was fabricated with 180?nm mesoporous silica nanoparticles (MSNs) as carriers. The anticancer drug doxorubicin (DOX) was conjugated to the particles through an acid-sensitive carboxylic hydrazone linker which is cleavable under acidic conditions. Moreover, folic acid (FA) was covalently conjugated to the particle surface as the targeting ligand for folate receptors (FRs) overexpressed in some cancer cells. The in vitro release profiles of DOX from the MSN-based prodrug systems showed a strong dependence on the environmental pH values. The fluorescent dye FITC was incorporated in the MSNs so as to trace the cellular uptake on a fluorescence microscope. Cellular uptakes by HeLa, A549 and L929 cell lines were tested for FA-conjugated MSNs and plain MSNs respectively, and a much more efficient uptake by FR-positive cancer cells (HeLa) can be achieved by conjugation of folic acid onto the particles because of the folate-receptor-mediated endocytosis. The cytotoxicities for the FA-conjugated MSN prodrug, the plain MSN prodrug and free DOX against three cell lines were determined, and the result indicates that the FA-conjugated MSN prodrug exhibits higher cytotoxicity to FR-positive cells, and reduced cytotoxicity to FR-negative cells. Thus, with 180?nm MSNs as the carriers for the prodrug system, good drug loading, selective targeting and sustained release of drug molecules within targeted cancer cells can be realized. This study may provide useful insights for designing and improving the applicability of MSNs in targeted anticancer prodrug systems.     

Multi‐Responsive and Logic Controlled Release of DNA‐Gated Mesoporous Silica Vehicles Functionalized with Intercalators for Multiple Delivery

Novel DNA‐gated mesoporous silica nanoparticle (MSN) vehicles functionalized with disulfide‐linked acridinamine intercalators are constructed for multi‐responsive controlled release. The DNA‐gated MSN vehicles release cargo encapsulated in the MSN pores under different stimuli, including disulfide reducing agents, elevated temperature, and deoxyribonuclease I (DNase I), for codelivery of drugs and DNA/genes in different forms. Furthermore, the cascade release of encapsulated and intercalative drugs is controlled by AND logic gates in combination of dual stimuli. The ingeniously designed DNA‐gated MSN vehicles integrates 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 and has promising biological applications to meet diverse requirements of controlled release.     

Mesoporous silica nanoparticle-functionalized poly(methyl methacrylate)-based bone cement for effective antibiotics delivery

Poly(methyl methacrylate)-based bone cements are functionalized with mesoporous silica nanoparticles (MSN) to enable a highly efficient and sustained release of antibiotics to reduce the risk of post-operative joint infection. To overcome the limited drug release of 5% for only 1 day with the current commercial-grade bone cements, a 8 wt% MSN-formulated bone cement is able to increase the drug release efficiency by 14-fold and sustain the release for up to 80 days. The loaded MSN is suggested to build up an effective network of rod-shaped silica particles with uniformly arranged nanoporous channels, which is responsible for the effective drug diffusion and extend time-release to the external surfaces. MSN has no detrimental effect on the critical weight-bearing bending modulus and compression strength of bone cement. In vitro assay test results show a much sustained antibacterial effect and low cytotoxicity of MSN demonstrating the potential applicability of MSN-formulated bone cement.     

Multifunctional Mesoporous Silica Nanoparticles with Thermal‐Responsive Gatekeeper for NIR Light‐Triggered Chemo/Photothermal‐Therapy

In this work, a matrix metalloproteinase (MMP)‐triggered tumor targeted mesoporous silica nanoparticle (MSN) is designed to realize near‐infrared (NIR) photothermal‐responsive drug release and combined chemo/photothermal tumor therapy. Indocyanine green (ICG) and doxorubicin (DOX) are both loaded in the MSN modified with thermal‐cleavable gatekeeper (Azo‐CD), which can be decapped by ICG‐generated hyperthermia under NIR illumination. A peptidic sequence containing a short PEG chain, matrix metalloproteinase (MMP) substrate (PLGVR) and tumor cell targeting motif (RGD) are further decorated on the MSN via a host–guest interaction. The PEG chain can protect the MSN during the circulation and be cleaved off in the tumor tissues with overexpressed MMP, and then the RGD motif is switched on to target tumor cells. After the tumor‐triggered targeting process, the NIR irradiation guided by ICG fluorescence can trigger cytosol drug release and realize combined chemo/photothermal therapy.     

Mesoporous silica nanoparticles deliver DNA and chemicals into plants

Surface-functionalized silica nanoparticles can deliver DNA and drugs into animal cells and tissues. However, their use in plants is limited by the cell wall present in plant cells. Here we show a honeycomb mesoporous silica nanoparticle (MSN) system with 3-nm pores that can transport DNA and chemicals into isolated plant cells and intact leaves. We loaded the MSN with the gene and its chemical inducer and capped the ends with gold nanoparticles to keep the molecules from leaching out. Uncapping the gold nanoparticles released the chemicals and triggered gene expression in the plants under controlled-release conditions. Further developments such as pore enlargement and multifunctionalization of these MSNs may offer new possibilities in target-specific delivery of proteins, nucleotides and chemicals in plant biotechnology.     

Mesoporous silica nanoparticle core-shell matrix (MSN CSM) engineered by green approach for pH triggered release of anticancer drugs

The present work exhibits an alternative route to design a nano-carrier using simple electrostatic interactions of biopolymeric layers on Mesoporous Silica Nanoparticle surface using Layer by Layer (LbL) technique. The doxorubicin (DOX) loaded MSN nano-carrier is coated with positively charged chitosan followed by a coating of negatively charged sodium carboxymethyl cellulose (Na-CMC) to form a DOX-loaded MSN Core-Shell Matrix (DOX-MSN CSM). The prepared MSN nano-carrier exhibits a high encapsulation efficiency of DOX (～93 %) due to its porous nature (～832 m²/gm) and negative surface charge (-21.5 mV). It exhibits a controlled release of DOX (～21 %) at physiological pH (7.4 pH) and improved drug release (～67 %) at cancer cells pH (5.4 pH) after 48 h. Further, the in-vitro cell line study using MDA-MB 231 cells reconfirms the slower and controlled release of DOX from the engineered DOX-MSN CSM. The confocal microscopy result shows that the DOX is internalized via endocytosis into the nucleus of the cells. The cell viability assay confirms more cells viable (～76 %) for DOX-MSN CSM than free DOX (～49 %) at the end of 24 h. The present study shows an alternate route to the conventional complex multi-step processes such as coupling reactions or chemical crosslinkers involving solvents. The proposed MSN core–shell matrix can be a potential nano-carrier for cancer drug delivery.     

Preparation of chitosan/mesoporous silica nanoparticle composite hydrogels for sustained co-delivery of biomacromolecules and small chemical drugs

Abstract

We have developed composite hydrogels of chitosan (CS) and mesoporous silica nanoparticles (MSNs) in this study. The gelation rate, gel strength, drug delivery behavior and chondrocyte proliferation properties were investigated. The introduction of MSNs into CS accelerated the gelation process at body temperature and also increased the elastic modulus G′ from 1000 to 1800 Pa. When we used gentamicin (GS) and bovine serum albumin (BSA) as model small chemical drugs and biomacromolecules, respectively, the CS/MSN hydrogels released GS and BSA in a sustained manner simultaneously, but the CS hydrogels only showed sustained BSA release. Furthermore, in vitro chondrocyte culture showed that the CS/MSN composite hydrogels indeed performed much better in supporting chondrocyte growth and maintaining chondrocytic phenotype compared to the CS hydrogels. Therefore, the results suggest that the CS/MSN composite hydrogels can be potentially very useful for cartilage regeneration.     

Simultaneous Imaging of Endogenous Survivin mRNA and On‐Demand Drug Release in Live Cells by Using a Mesoporous Silica Nanoquencher

The design of multifunctional drug delivery systems capable of simultaneous target detection, imaging, and therapeutics in live mammalian cells is critical for biomedical research. In this study, by using mesoporous silica nanoparticles (MSNs) chemically modified with a small‐molecule dark quencher, followed by sequential drug encapsulation, MSN capping with a dye‐labeled antisense oligonucleotide, and bioorthogonal surface modification with cell‐penetrating poly(disulfide)s, the authors have successfully developed the first mesoporous silica nanoquencher (qMSN), characterized by high drug‐loading and endocytosis‐independent cell uptake, which is able to quantitatively image endogenous survivin mRNA and release the loaded drug in a manner that depends on the survivin expression level in tumor cells. The authors further show that this novel drug delivery system may be used to minimize potential cytotoxicity encountered by many existing small‐molecule drugs in cancer therapy.     

模板剂去除方法对介孔氧化硅纳米球的影响

以十六烷基三甲基溴化铵(CTAB)为模板剂,正硅酸四乙酯(TEOS)为硅源,在碱性条件下反应,分别采用煅烧法和酸化乙醇回流萃取法去除氧化硅中的模板剂,获得了直径为100nm分布均匀的六方有序的介孔氧化硅纳米球(MSN)。通过热失重分析(TGA)、透射电子显微镜(TEM)、小角度X射线衍射(SAXRD)和氮气吸附-脱附对MSN中CTAB的残余量和介孔结构进行了表征。结果表明:煅烧法能够彻底去除模板剂,萃取法只能去除80%左右的模板剂;随着萃取时间的延长和萃取次数的增加,MSN的孔径和孔容有所增加,其中6h回流萃取4次去除模板剂后得到的MSN的比表面积、孔容、孔径最大,分别为944.31m2.g-1、1.89cm3.g-1和2.56nm。     

Ultrasensitive aptamer-based multiplexed electrochemical detection by coupling distinguishable signal tags with catalytic recycling of DNase I

This work reports an aptamer-based, disposable, and multiplexed sensing platform for simultaneous electrochemical determination of small molecules, employing adenosine triphosphate (ATP) and cocaine as the model target analytes. The multiplexed sensing strategy is based on target-induced release of distinguishable redox tag-conjugated aptamers from a magnetic graphene platform. The electronic signal of the aptasensors could be further amplified by coupling DNase I with catalytic recycling of self-produced reactants. The assay was based on the change in the current at the various peak potentials in the presence of the corresponding signal tags. Experimental results revealed that the multiplexed electrochemical aptasensor enabled the simultaneous monitoring of ATP and cocaine in a single run with wide working ranges and low detection limits (LODs: 0.1 pM for ATP and 1.5 pM for cocaine). This concept offers promise for rapid, simple, and cost-effective analysis of biological samples.     

Functional Nanovalves on Protein‐Coated Nanoparticles for In vitro and In vivo Controlled Drug Delivery

A multifunctional mesoporous drug delivery system that contains fluorescent imaging molecules, targeting proteins, and pH‐sensitive nanovalves is developed and tested. Three nanovalve‐mesoporous silica nanoparticle (NV‐MSN) systems with varied quantities of nanovalves on the surface are synthesized. These systems are characterized and tested to optimize the trade‐off between the coverage of nanovalves on the MSNs to effectively trap and deliver cargo, and the remaining underivatized silanol groups that can be used for protein attachments. The NV‐MSN system that has satisfactory coverage for high loading and spare silanols is chosen, and transferrin (Tf) is integrated into the system. Abiotic studies are performed to test the operation of the nanovalve in the presence of the protein. In vitro studies are carried out to demonstrate the autonomous activation and function of the nanovalves in the system under biological conditions. Enhanced cellular uptake of the Tf‐modified MSNs is seen using fluorescence microscopy and flow cytometry in MiaPaCa‐2 cells. The MSNs are then tested using SCID mice, which show that both targeted and untargeted NV‐MSN systems are fully functional to effectively deliver cargo. These new multifunctional nanoparticles serve proof of concept of nanovalve functionality in the presence of large proteins and demonstrate another dimension of MSN‐based theranostic platforms.     

Direct observation of calcium-independent intercellular ATP signaling in astrocytes

Adenosine triphosphate (ATP) is assumed to be involved in the regulation of many extracellular signaling systems including calcium wave propagation. So far all supportive evidence is indirect, such as monitoring changes in intracellular calcium on application of extracellular ATP or off-site measurement of ATP from superfusates. Furthermore, the causal relationships among the various signaling agents are still unclear. A novel chemiluminescence dynamic imaging method was developed to monitor ATP release from living biological cells. The assay has linear response over 3 orders of magnitude for fixed concentrations of enzyme and cofactors, with a correlation coefficient of 0.999. The detectability of ATP is down to 10(-8) M at millisecond exposure times with an intensified charge-coupled device camera. The direct imaging of ATP waves in astrocyte cultures was performed together with Fluo-3-Ca imaging at millisecond temporal resolution and micrometer-scale spatial resolution. We discovered that extracellular ATP mediates intercellular calcium wave propagation, but surprisingly, release and propagation of ATP are not calcium dependent. Therefore, ATP rather than Ca or IP3 is the primary intercellular signaling messenger.     

Core‐Cone Structured Monodispersed Mesoporous Silica Nanoparticles with Ultra‐large Cavity for Protein Delivery

A new type of monodispersed mesoporous silica nanoparticles with a core–cone structure (MSN‐CC) has been synthesized. The large cone‐shaped pores are formed by silica lamellae closely packed encircling a spherical core, showing a structure similar to the flower dahlia. MSN‐CC has a large pore size of 45 nm and a high pore volume of 2.59 cm³ g⁻¹. MSN‐CC demonstrates a high loading capacity of large proteins and successfully delivers active β‐galactosidase into cells, showing their potential as efficient nanocarriers for the cellular delivery of proteins with large molecular weights.     

Dual-pH-sensitive mesoporous silica nanoparticle-based drug delivery system for tumor-triggered intracellular drug release

Reducing the side effects and improving the drug utilization are important work in anti-cancer drug delivery. In this paper, a novel dual-pH-sensitive drug delivery system was reported. Mesoporous silica nanoparticle (MSN) was applied to load anti-cancer drug doxorubicin hydrochloride (DOX) and was covered by mono-6-deoxy-6-EDA-β-cyclodextrine (β-CD-NH₂) to block the pores through pH-sensitive boronate ester bond. And the carriers were then coated with methoxy poly(ethylene glycol) (mPEG) through another pH-sensitive benzoic imine bond. mPEG leaving studies, in vitro cellular uptake studies and the flow cytometry analysis, proved that carriers was “stealthy” at pH 7.4, but could be “activated” for cytophagy by cancer cells in weakly acidic tumor tissues (pH 6.5) due to the departure of mPEG. β-CD-NH₂ leaving studies, the in vitro drug release studies and the in vitro cytotoxicity studies proved that boronate ester bond linking MSN and β-CD-NH₂ was stable at both pH 7.4 and 6.5, but could be hydrolyzed intracellular to release DOX for cellular apoptosis due to the lower pH (5.0). In summary, the novel dual-pH-sensitive drug delivery system fabricated with a dynamic protection strategy should have great application potential in anti-cancer drug delivery fields.     

Microelectrode biosensor for real-time measurement of ATP in biological tissue

The purines ATP, ADP, and adenosine are important extracellular signaling agents. Analysis of purinergic signaling has been slowed by lack of direct methods for measurement of purine release in real-time during physiological activity. We have previously reported microelectrode biosensors for adenosine, but similar sensors for ATP have remained elusive. We now describe an ATP biosensor formed by coating a Pt microelectrode with an ultrathin biolayer containing glycerol kinase and glycerol-3-phosphate oxidase. It responds rapidly (10-90% rise time <10 s) and exhibits a linear response to ATP over the physiologically relevant concentrations of 200 nM-50 microM and is very sensitive approximately 250 mA.M(-1).cm(-2). By including phosphocreatine kinase in the biolayer, we can optionally amplify the ATP signal and also make the sensor sensitive to external ADP. We have used our sensors to make the first demonstration that ATP is released from spinal networks in vivo during locomotor activity.     

Enhancing sensitivity and selectivity of long-period grating sensors using structure-switching aptamers bound to gold-doped macroporous silica coatings

High surface area, sol-gel derived macroporous silica films doped with gold nanoparticles (AuNP) are used as a platform for high-density affinity-based immobilization of functional structure-switching DNA aptamer molecules onto Michelson interferometer long-period grating (LPG) fiber sensors, allowing for label-free detection of small molecular weight analytes such as adenosine triphosphate (ATP). The high surface area afforded by the sol-gel derived material allowed high loading of DNA aptamers, while the inclusion of gold nanoparticles within the silica film provided a high refractive index (RI) overlay, which is required to enhance the sensitivity of the LPG sensor according to our numerical simulations. By using a structure-switching aptamer construct that could release an oligonucleotide upon binding of ATP, the effective change in RI was both enhanced and inverted (i.e., binding of ATP caused a net reduction in molecular weight and refractive index), resulting in a system that prevented signals originating from nonspecific binding. This is the first report on the coupling of aptamers to LPG fiber sensors and the first use of high RI AuNP/silica films as supports to immobilize biomolecules onto the LPG sensor surface. The dual functionality of such films to both improve binding density and LPG sensor cladding refractive index results in a substantial enhancement in the sensitivity of such sensors for small molecule detection.