Characterization of modified mesoporous silica nanoparticles as vectors for siRNA delivery

Gene therapy using siRNA molecules is nowadays considered as a promising approach. For successful therapy, development of a stable and reliable vector for siRNA is crucial. Non-viral and non-organic vectors like mesoporous silica nanoparticles(MSN) are associated with lack of most viral vector drawbacks, such as toxicity, immunogenicity, but also generally a low nucleic acid carrying capacity. To overcome this hurdle, we here modified the pore walls of MSNs with surface-hyperbranching polymerized poly(ethyleneimine)(hbPEI), which provides an abundance of amino-groups for loading of a larger amount of siRNA molecules via electrostatic adsorption. After loading, the particles were covered with a second layer of pre-polymerized PEI to provide better protection of siRNA inside the pores, more effective cellular uptake and endosomal escape. To test the transfection efficiency of PEI covered si RNA/MSNs, MDA-MB 231 breast cancer cells stably expressing GFP were used. We demonstrate that PEI-coated si RNA/MSN complexes provide more effective delivery of si RNAs compared to unmodified MSNs. Thus, it can be concluded that appropriately surface-modified MSNs can be considered as prospective vectors for therapeutic siRNA delivery.

Dual responsive block copolymer coated hollow mesoporous silica nanoparticles for glucose-mediated transcutaneous drug delivery

A self-regulated anti-diabetic drug release device mimicking pancreatic cells is highly desirable for the therapy of diabetes. Herein, a glucose-mediated dual-responsive drug delivery system, which combines pH-and H_(2)O_(2)-responsive block copolymer grafted hollow mesoporous silica nanoparticles(HMSNs)with microneedle(MN) array patch, has been developed to achieve self-regulated administration.The poly[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acrylate]-b-poly[2-(dimethylamino)ethyl methacrylate](PPBEM-b-PDM) polymer serves as gate keeper to prevent drug release from the cavity of HMSNs at normoglycemic level. In contrast, the drug release rate is significantly enhanced upon H_(2)O_(2)and pH stimuli due to the chemical change of H_(2)O_(2)sensitive PPBEM block and acid responsive PDM block. Therefore, incorporation of anti-diabetic drug and glucose oxidase(GOx, which can oxidize glucose to gluconic acid and in-situ produce H_(2)O_(2)) into stimulus polymer coated HMSNs results in a glucose-mediated MN device after depositing the drug-loaded nanoparticles into MN array patch. Both in vitro and in vivo results show this MN device presents a glucose mediated self-regulated drug release characteristic, which possesses a rapid drug release at hyperglycemic level but retarded drug release at normoglycemic level. The result indicates that the fabricated smart drug delivery system is a good candidate for the therapy of diabetes.

Incorporation of Sphingosine 1-Phosphate Loaded Mesoporous Silica Nanoparticles into Poly ( L-lactic acid ) Nanofibrous Scaffolds for Bone Tissue Engineering

Controlled release of the functional factors is the key to improve clinical therapeutic efficacy during the tissue repair and regeneration.The three-dimensional(3D)scaffold can provide not only physical properties such as high strength and porosity but also an optimal environment to enhance tissue regeneration.Sphingosine1-phosphate(S1P),an angiogenic factor,was loaded into mesoporous silica nanoparticles(MSNs)and then incorporated into poly(L-lactic acid)(PLLA)nanofibrous scaffold,which was fabricated by thermally induced phase separation(TIPS)method.The prepared scaffolds were examined by attenuated total reflection Fourier transform infrared spectroscopy(ATR-FTIR),scanning electron microscopy(SEM),and transmission electron microscopy(TEM)and compressive mechanical test.The ATR-FTIR result demonstrated the existence of MSNs in the PLLA nanofibrous scaffold.The SEM images showed that PLLA scaffold had regular pore channel,interconnected pores and nanofibrous structure.The addition of MSNs at appropriate content had no visible effect on the structure of scaffold.The compressive modulus of scaffold containing MSNs was higher than that of the scaffold without MSNs.Furthermore,fluorescein isothiocyanate(FITC)was used as model molecule to investigate the release behavior of S1P from MSNsincorporated PLLA(MSNs/PLLA)nanofibrous scaffold.The result showed that the composite scaffold largely reduced the initial burst release and exhibited prolonged release of FITC than MSNs.Thus,these results indicated that S1P-loaded composite nanofibrous scaffold has potential applications for bone tissue engineering.

Bioinspired surface functionalization of biodegradable mesoporous silica nanoparticles for enhanced lubrication and drug release

Osteoarthritis is associated with the significantly increased friction of the joint,which results in progressive and irreversible damage to the articular cartilage.A synergistic therapy integrating lubrication enhancement and drug delivery is recently proposed for the treatment of early-stage osteoarthritis.In the present study,bioinspired by the self-adhesion performance of mussels and super-lubrication property of articular cartilages,a biomimetic self-adhesive dopamine methacrylamide-poly(2-methacryloyloxyethyl phosphorylcholine)(DMA-MPC)copolymer was designed and synthesized via free radical polymerization.The copolymer was successfully modified onto the surface of biodegradable mesoporous silica nanoparticles(bMSNs)by the dip-coating method to prepare the dual-functional nanoparticles(bMSNs@DMA-MPC),which were evaluated using a series of surface characterizations including the transmission electron microscope(TEM),Fourier transform infrared(FTIR)spectrum,thermogravimetric analysis(TGA),X-ray photoelectron spectroscopy(XPS),etc.The tribological test and in vitro drug release test demonstrated that the developed nanoparticles were endowed with improved lubrication performance and achieved the sustained release of an anti-inflammatory drug,i.e.,diclofenac sodium(DS).In addition,the in vitro biodegradation test showed that the nanoparticles were almost completely biodegraded within 10 d.Furthermore,the dual-functional nanoparticles were biocompatible and effectively reduced the expression levels of two inflammation factors such as interleukin-1β(IL-1β)and interleukin-6(IL-6).In summary,the surface functionalized nanoparticles with improved lubrication and local drug release can be applied as a potential intra-articularly injected biolubricant for synergistic treatment of early-stage osteoarthritis.

Mesoporous silica nanoparticles for drug and gene delivery

Mesoporous silica nanoparticles(MSNs) are attracting increasing interest for potential biomedical applications. With tailored mesoporous structure, huge surface area and pore volume,selective surface functionality, as well as morphology control, MSNs exhibit high loading capacity for therapeutic agents and controlled release properties if modified with stimuli-responsive groups, polymers or proteins. In this review article, the applications of MSNs in pharmaceutics to improve drug bioavailability, reduce drug toxicity, and deliver with cellular targetability are summarized. Particularly,the exciting progress in the development of MSNs-based effective delivery systems for poorly soluble drugs, anticancer agents, and therapeutic genes are highlighted.

Reactive mesoporous silica nanoparticles loaded with limonene for improving physical and mental health of mice at simulated microgravity condition

Astronauts are under high stress for a long time because of the microgravity condition,which leads to anxiety,affects their learning and memory abilities,and seriously impairs the health of astronauts.Aromatherapy can improve the physical and mental health of astronauts in a way that moisturizes them softly and silently.However,the strong volatility of fragrances and inconvenience of aroma treatment greatly limit their application in the field of spaceflight.In this study,reactive mesoporous silica nanoparticles were prepared to encapsulate and slowly release limonene.The limonene loaded nanoparticles were named limonene@mesoporous silica nanoparticles-cyanuric chloride(LE@MSNs-CYC).LE@MSNs-CYC were then applied to wallpaper to improve the convenience of aromatherapy.LE@MSNs-CYC could chemically react with the wallpaper,thus firmly adsorbed on the wallpaper.In the following,the mice were treated with hindlimb unloading(HU)to simulate a microgravity environment.The results showed that 28-day HU led to an increase in the level of anxiety and declines in learning,memory,and physical health in mice.LE@MSNs-CYC showed significant relief effects on anxiety,learning,memory,and physical health of HU treated mice.Subsequently,the molecular mechanisms were explored by hypothalamic-pituitary-adrenal axis related hormones,immune-related cytokines,learning,and memory-related neurotransmitters and proteins.

Hollow mesoporous silica nanoparticles as nanocarriers employed in cancer therapy: A review

Hollow mesoporous silica nanoparticles(HMSNs)have become an attractive drug carrier because of their unique characteristics including stable physicochemical properties,large specific surface area and facile functionalization,especially made into intelligent drug delivery systems(DDSs)for cancer therapy.HMSNS are employed to transport traditional anti-tumor drugs,which can solve the problems of drugs with instability,poor solubility and lack of recognition,etc.,while significantly improving the anti-tumor effect.And an unexpected good result will be obtained by combining functional molecules and metal species with HMSNs for cancer diagnosis and treatment.Actually,HMSNs-based DDSS have developed relatively mature in recent years.This review briefly describes how to successfully prepare an ordinary HMSNs-based DDS,as well as its degradation,different stimuli-responses,targets and combination therapy.These versatile intelligent nanoparticles show great potential in clinical aspects.

Polymer-grafted hollow mesoporous silica nanoparticles integrated with microneedle patches for glucose-responsive drug delivery

A glucose-mediated drug delivery system would be highly satisfactory fordiabetes diagnosis since it can intelligently release drug based on blood glucose levels.Herein,a glucose-responsive drug delivery system by integrating glucose-responsivepoly(3-acrylamidophenylboronic acid)(PAPBA)functionalized hollow mesoporous silicananoparticles(HMSNs)with transcutaneous microneedles(MNs)has been designed.Thegrafted PAPBA serves as gatekeeper to prevent drug release from HMSNs atnormoglycemic levels.In contrast,faster drug release is detected at a typicalhyperglycemic level,which is due to the change of hydrophilicity of PAPBA at highglucose concentration.After transdermal administration to diabetic rats,an effectivehypoglycemic effect is achieved compared with that of subcutaneous injection.Theseobservations indicate that the designed glucose-responsive drug delivery system has apotential application in diabetes treatment.

A pH-responsive mesoporous silica nanoparticles-based drug delivery system with controlled release of andrographolide for OA treatment

Andrographolide(AG)has favorable anti-inflammatory and antioxidative capacity.However,it has low bioavailability due to high lipophilicity and can be easily cleared by the synovial fluid after intra-articular injection,leading to low therapeutic efficiency in osteoarthritis(OA).Herein,we designed a nano-sized pH-responsive drug delivery system(DDS)for OA treatment by using modified mesoporous silica nanoparticles(MSNs)with pH-responsive polyacrylic acid(PAA)for loading of AG to form AG@MSNs-PAA nanoplatform.The nanoparticles have uniform size(120 nm),high drug loading efficiency(22.3860.71%)and pH-responsive properties,beneficial to sustained release in OA environment.Compared with AG,AG@MSNs-PAA showed enhanced antiarthritic efficacy and chondro-protective capacity based on IL-1b-stimulated chondrocytes and anterior cruciate ligament transection-induced rat OA model,as demonstrated by lower expression of inflammatory factors and better prevention of proteoglycan loss.Therefore,the AG@MSNs-PAA nanoplatform may be developed as a promising OA-specific and on-demand DDS.

Rod-like mesoporous silica nanoparticles facilitate oral drug delivery via enhanced permeation and retention effect in mucus

The physiochemical characteristics of nanoparticles affect their in vitro and in vivo performance significantly,such as diameter,surface chemistry,and shape.This paper disclosed the effect of enhanced permeation and retention(EPR)in mucus caused by nanoparticle shape on improving oral absorption.The spherical and rod-like mesoporous silica nanoparticles(MSNs)were used to evaluate shape effect of EPR in mucus.Fenofibrate was loaded in MSNs as model drug.The in vitro release of fenofibrate from MSNs was dependent on nanoparticle shapes,but faster than that of raw drug.The drug release slowed down with the increase of aspect ratio due to longer channels in rod-like MSNs with higher aspect ratio.However,in vivo study showed that the oral bioavailability of fenofibrate was the highest after loading in rod-like MSNs with aspect ratio of 5.The in vitro study of mechanisms revealed that superior mucus diffusion ability of rod-like MSNs with aspect ratio of 5 was conductive to higher bioavailability.Meanwhile,more rod-like MSNs with higher aspect ratio were able to diffuse into mucus and reside there compared to spherical and short counterparts,which demonstrated higher aspect ratio was beneficial to EPR effect of nanoparticles in mucus.This study provides significant implication in rational oral drug carrier design.

Hierarchical dual-porous hydroxyapatite doped dendritic mesoporous silica nanoparticles based scaffolds promote osteogenesis in vitro and in vivo

Biomaterial based scaffolds for treating large bone defects require excellent biocompatibility and osteoconductivity.Here we report on the fabrication of hydroxyapatite-dendritic mesoporous silica nanoparticles(HA-DMSN)based scaffolds with hierarchical micro-pores(5µm)and nano-pores(6.4 nm),and their application for bone regeneration.The in vitro studies demonstrated good biocompatibility of dissolution extracts,as well as enhanced osteogenic potential indicated by dose-dependent upregulation of bone marker gene expression(osteocalcin gene(OCN),osteopontin gene(OPN),collagen type I alpha 1 gene(CoL1A1),runt-related transcription factor 2 gene(RUNX2),and integrin-binding sialoprotein gene(IBSP)),alkaline phosphatise(ALP)activity,and alizarin red staining.The in vivo studies showed that HA-DMSN scaffolds significantly increased bone formation in a rat cranial bone defect model after 4 weeks healing.Our study provides a simple method to fabricate promising inorganic scaffolds with hierarchical pores for bone tissue engineering.

Facile assembly of mesoporous silica nanoparticles with hierarchical pore structure for CO2 capture

In the work,we propose an efficient one-pot approach for synthesis of a new type of mesoporous silica nanoparticles(MSNs).That can be successfully realized by using tetraethylorthosilicate(TEOS) and N-[3-(trimethoxysilyl)propyl]ethylenediamine(TSD) as the silica precursors and cetyltrimethylammonium bromide(CTAB) as the structure-directing agent through a facile assembly process.The as-synthesized MSNs possess a spherical morphology with about 230 nm,a relatively high surface area of133 m^2/g,and a hierarchical pore size distribution.When applied as the sorbents,the amine-functioned MSNs demonstrate the enhanced adsorption capacity for CO2 capture(at 1 bar,15 vol% CO2,up to80.5 mg/g at 75℃),high selectivity,and good cycling durability,benefiting from the suitable modification of polyethyleneimine.

Cell Membrane-camouflaged Multi-functional Dendritic Large Pore Mesoporous Silica Nanoparticles for Combined Photothermal Therapy and Radiotherapy of Cancer

Combining photothermal therapy and radiotherapy(PTT-RT) with reducing tumor hypoxia acts as an important antitumor modality. However, it is a great challenge to realize photothermal therapy, radiotherapy and exogenous oxygen supply in one nanosystem. To realize a combination of the three functions, we fabricated a red blood cell membrane(RBCm)-camouflaged, red blood cell content(RBCc) and the copper sulfide(CuS) co-loaded dendritic large pore mesoporous silica nanoparticle(DLMSN/CuS/RBCc/ RBCm). The cell membrane coating endowed the nanoparticles with good stability in the physiological environment, and CuS allowed the nanoparticle exhibiting good photothermal and radiosensitization properties. RBCc loaded nanoparticle DLMSN/CuS/RBCc enhanced superior anti-tumor effect than DLMSN/CuS during combined PTT-RT therapy because the introduction of RBCc increased the exogenous oxygen supply. The in vitro study further demonstrated that the combination of photothermal therapy and radiotherapy induced superior antitumor efficacy than single therapy. Our work thus presents a unique multifunctional nanoscale platform favorable for combined PTT and RT.

pH-responsive delivery of H_(2) through ammonia borane-loaded mesoporous silica nanoparticles improves recovery after spinal cord injury by moderating oxidative stress and regulating microglial polarization

Imbalance of oxidative and inflammatory regulation is themain contributor to neurofunctional deterioration and failure of rebuilding spared neural networks after spinal cord injury(SCI).As an emerging biosafe strategy for protecting against oxidative and inflammatory damage,hydrogen(H_(2))therapy is a promising approach for improving the microenvironment to allow neural regeneration.However,achieving release of H_(2) at sufficient concentrations specifically into the injured area is critical for the therapeutic effect of H_(2).Thus,we assembled SiO_(2)@mSiO_(2) mesoporous silica nanoparticles and loaded them with ammonia borane(AB),which has abundant capacity and allows controllable release of H_(2) in an acid-dependent manner.The release of H_(2) from AB/SiO_(2)@mSiO_(2) was satisfactory at pH 6.6,which is approximately equal to the microenvironmental acidity after SCI.After AB/SiO_(2)@mSiO_(2) were intrathecally administered to ratmodels of SCI,continuous release of H_(2) fromthese nanoparticles synergistically enhanced neurofunctional recovery,reduced fibrotic scar formation and promoted neural regeneration by suppressing oxidative stress reaction.Furthermore,in the subacute phase of SCI,microglia were markedly polarized toward the M2 phenotype by H_(2) via inhibition of TLR9 expression in astrocytes.In conclusion,H_(2) delivery through AB/SiO_(2)@mSiO_(2) has the potential to efficiently treat SCI through comprehensivemodulation of the oxidative and inflammatory imbalance in themicroenvironment.

Mesoporous SiO_2 Nanoparticles:A Unique Platform Enabling Sensitive Detection of Rare Earth Ions with Smartphone Camera

Fast and sensitive detection of dilute rare earth species still represents a challenge for an on-site survey of new resources and evaluation of the economic value. In this work, a robust and low-cost protocol has been developed to analyze the concentration of rare earth ions using a smartphone camera. The success of this protocol relies on mesoporous silica nanoparticles(MSNs) with large-area negatively charged surfaces, on which the rare earth cations(e.g., Eu^(3+)) are efficiently adsorbed through electrostatic attraction to enable a ‘‘concentrating effect''. The initial adsorption rate is as fast as 4025 mg(g min)^(-1), and the adsorption capacity of Eu^(3+)ions in the MSNs is as high as 4730 mg g^(-1)(equivalent to ～41.2 M) at 70 °C. The concentrated Eu^(3+)ions in the MSNs can form a complex with a light sensitizer of 1,10-phenanthroline to significantly enhance the characteristic red emission of Eu^(3+)ions due to an ‘‘antenna effect'' that relies on the efficient energy transfer from the light sensitizer to the Eu^(3+)ions.The positive synergy of ‘‘concentrating effect'' and ‘‘antenna effect'' in the MSNs enables the analysis of rare earth ions in a wide dynamic range and with a detection limit down to ～80 nM even using a smartphone camera. Our results highlight the promise of the protocol in fieldwork for exploring valuable rare earth resources.

Preparation of Sulfhydryl Functionalized Mesoporous Silica Particles and Application in Adsorption of Cd²⁺

An improved soft template method to prepare sulfhydryl functionalized mesoporous silica nanoparticles is proposed. It is shown that the prepared nanoparticles maintain a relatively uniform spherical structure with a particle size range of 20 - 30 nm and a large specific surface area of about 926 m2/g. The sample is used to absorb heavy metal Cadmium ions (Cd2+) in water. The experimental results show that the sulfhydryl functionalized mesoporous silica is sensitive to Cadmium ions and has good selectivity. The detection limit can be estimated to be as low as 1.35 μg/L.

Dendritic mesoporous silica nanoparticles for enzyme immobilization

Dendritic mesoporous silica nanoparticles(DMSNs)are a new class of solid porous materials used for enzyme immobilization support due to their intrinsic characteristics,including their unique open central-radial structures with large pore channels and their excellent biocompatibility.In this review,we review the recent progress in research on enzyme immobilization using DMSNs with different structures,namely,flower-like DMSNs and tree-branch-like DMSNs.Three DMSN synthesis methods are briefly compared,and the distinct characteristics of the two DMSN types and their effects on the catalytic performance of immobilized enzymes are comprehensively discussed.Possible directions for future research on enzyme immobilization using DMSNs are also proposed.

In Vivo Tumor-Targeted Dual-Modality PET/Optical Imaging with a Yolk/Shell-Structured Silica Nanosystem

Silica nanoparticles have been one of the most promising nanosystems for biomedical applications due to their facile surface chemistry and non-toxic nature. However, it is still challenging to effectively deliver them into tumor sites and noninvasively visualize their in vivo biodistribution with excellent sensitivity and accuracy for effective cancer diagnosis. In this study, we design a yolk/shell-structured silica nanosystem ^(64) Cu-NOTAQD@HMSN-PEG-TRC105, which can be employed for tumor vasculature targeting and dual-modality PET/optical imaging, leading to superior targeting specificity, excellentimaging capability and more reliable diagnostic outcomes.By combining vasculature targeting, pH-sensitive drug delivery, and dual-modality imaging into a single platform,as-designed yolk/shell-structured silica nanosystems may be employed for the future image-guided tumor-targeted drug delivery, to further enable cancer theranostics.

Preparation and application of mesoporous core-shell nanosilica using leucine derivative as template in effective drug delivery

Core-shell structured mesoporous silica nanoparticles have been firstly synthesized with the new template from L-leucine methyl ester hydrochloride(H-Leu-OMe·HCl).LMSNs were characterized by transmission electron microscopy(TEM),nitrogen adsorption/desorption,and small-angle X-ray diffraction(SAXRD),demonstrating a well-ordered mesostructure.After loading doxorubicin hydrochloride(Dox) into pores,considerable loading capacity of 30.5% and favorable cumulative release amount were obtained.MTT assay suggested that Dox-loaded LMSNs demonstrated great promise to anti-tumor.The use of MSNs with the synthesized template,as a drug delivery carrier,will exte nd the pharmaceutical applications of silica materials.

Dual-stimuli responsive near-infrared emissive carbon dots/hollow mesoporous silica-based integrated theranostics platform for real-time visualized drug delivery

Due to better penetrating abilities of near-infrared (NIR) light and lower autofluorescence of biological tissue at NIR region, the combination of NIR fluorescent imaging with therapeutic abilities has gradually emerged as a promising strategy for cancer therapy. Herein, tumor microenvironment (TME) sensitive nanocarriers based on doxorubicin hydrochloride (DOX), NIR emitting carbon dots (C-dots), hollow mesoporous silica nanoparticles (HMSN) and anionic polymer citraconic anhydride-modified polylysine (PLL(cit)) are fabricated for imaging guided drug delivery. The NIR emitting C-dots were conjugated onto the surface of HMSN via disulfide bonds which can be reduced by intracellular glutathione (GSH) and result in the release of DOX into cells. And then the PLL(cit) was grafted on the surface of the nanocarriers to endow the nanocarriers with charge convertible property in mildly acidic TME (pH = 6.50) which results in prolonged blood circulation time and enhanced cellular internalization. The in vitro and in vivo experiments confirmed that the dual pH/GSH responsive features of nanocarriers can eliminate the tumor tissues effectively and elicit much slighter side effects. Moreover, since the fluorescence of C-dots can be recovered after the reduction of disulfide bonds and selectively accumulation of nanocarriers around tumor tissue, the DOX@HMSN-SS-C-dots-PLL(cit) can be served as a promising NIR fluorescence probe for targeted imaging of tumor tissue. As a kind of multifunctional nanocarrier with NIR fluorescent imaging and therapeutic functions, the theranostic nanocarriers hold great potential for tumor therapy and in vivo imaging of tumor tissue.