pH-responsive mesoporous silica nanoparticles employed in controlled drug delivery systems for cancer treatment

In the fight against cancer, controlled drug delivery systems have emerged to enhance the therapeutic efficacy and safety of anti-cancer drugs. Among these systems, mesoporous silica nanoparticles （MSNs） with a functional surface possess obvious advantages and were thus rapidly developed for cancer treatment. Many stimuli-responsive materials, such as nanopartides, polymers, and inorganic materials, have been applied as caps and gatekeepers to control drug release from MSNs. This review presents an overview of the recent progress in the production of pH-responsive MSNs based on the pH gradient between normal tissues and the tumor microenvironment. Four main categories of gatekeepers can respond to acidic conditions. These categories will be described in detail.

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.

Light and temperature dual responsive pesticide release system based on mesoporous silica nanoparticles modified by dopamine

A light and temperature dual responsive copolymer,poly(7-(4-vinylbenzy-loxyl)-4-methylcoumarin-co-N vinyl caprolactam-co-tri(ethylene glycol)methyl ether methacrylate)(PVNM),was grafted on the surface of dopamine based mesoporous silica nanoparticles(MSNs).The resulting polymer brush,MSNs-g-PVNM,was characterized by FT-IR,TEM,TGA and XPS.The dual responsive behaviors of MSNs-g-PVNM were systematically studied.With imidacloprid as the model guest pesticide,the loading percentage and loading efficiency of the polymer brush were determined as 9.2%and 40.6%,respectively.The release efficiency of imidacloprid in MSNs-g-PVNM was the lowest value of 5.4%at 20℃ and 365 nm,and it reached the highest value of 52.4%at 50℃ and 254 nm.The loss percentage of imidacloprid on the leaves contained imidacloprid-loaded MSNs-g-PVNM(8.4%)was much less than that contained only imidacloprid(25.2%)after three rinses.It was confirmed that the release process of imidacloprid was well regulated through changing external conditions such as light and temperature.

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 thrce-dimensional （3D） scaffold can provide not only physical properties such as high strength and porosity hut also an optimal environment to enhance tissue regeneration. Sphingosine 1-phosphate （SIP）, an angiogenlc factor, was loaded into mesoporous silica nanoparticles （MSNs） and then incorporated into poly （ L-lactic add ） （ PLLA ） nanofibrons 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 （FTTC） was used as model molecule to investigate the release behavior of SIP from MSNs- incorporated PLLA （MSNs/PLLA） nanofibrons 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 SIP-loaded composite uanofibrons scaffold has potential applications for bone tissue engneering.

Synthesis and Characterization of Carboxyl-terminated Polyethylene Glycol Functionalized Mesoporous Silica Nanoparticles

Colloidal mesoporous silica nanoparticles functionalized with carboxy-terminated polyethylene glycol(CMS-PEG-COOH) were successfully synthesized by covalently grafting dicarboxy-terminated polyethylene glycol(HOOC-PEG-COOH) on the surface of the amino functionalized CMS nanoparticles with amide bond as a cross linker. Moreover, the structural and particle properties of CMS-PEG-COOH were characterized by nuclear magnetic resonance spectroscopy(1 H-NMR), transmission electron microscopy(TEM), dynamic light scattering(DLS), nitrogen adsorption-desorption measurements, X-ray diffraction(XRD), and Fourier transform infrared spectroscopy(FT-IR). The nanomaterials presented a relatively uniform spherical shape morphology with diameters of about 120 nm,and favorable dispersibility in weak acid solution. The CMSPEG-COOH exhibited no changes in the state of amorphous, while the mesopores sizes of 5.25 nm might provide the nanomaterials with large capacity for the loading and releasing of drugs. So the results indicated that CMSPEG-COOH might be a critical nanomaterial for drug delivery system in the future.

Amphipathicity mediated endocytosis of mesoporous silica nanoparticles with tunable frameworks

Due to the amphiphilic nature of phospholipids in the cell membrane,the amphipathicity of the nanomedicine plays a crucial role in the endocytosis.However,limited biological characterization methods restrict the study of the state of nanoparticles with different amphiphilicities on cell membranes.The understanding of interaction of amphiphilic particle with cell membrane is still lacking.Herein,by combining the dissipative particle dynamics(DPD)with the framework construction of mesoporous silica nanoparticles(MSNs),we demonstrate the enhanced endocytosis induced by the hydrophobicity.DPD results confirm that the presence of hydrophobic groups on the surface of nanoparticles can disturb the integrity of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine(POPC)membrane and induce activation of phospholipids to a higher energy level,thereby facilitating the wrapping of nanoparticles.To validate the simulation findings,uniform MSNs with hydrophilic pure silica framework and two types of amphiphilic MSNs with varying hydrophilic organic groups in the framework are rationally synthesized by using different silane precursors.The obtained three kinds of MSNs show similar diameter(~100 nm)and mesopores(~2 nm),but distinct hydrophobicity/hydrophilicity ratio.The phenyl-bridged MSN with a carbon content of 27.1%exhibits enhanced cellular uptake,consistent with the theoretical simulation results.This work sheds light on how the surface amphipathicity influences endocytosis through the interaction with cell membrane.

Bioinspired Hollow Mesoporous Silica Nanoparticles Coating on Titanium Alloy with Hierarchical Structure for Modulating Cellular Functions

3D-printed Porous Titanium Alloy Implants(pTi),owing to their biologically inertness and relatively smooth surface morphology,adversely affect the biological functions of surrounding cells.To address the challenges,constructing a bioinspired interface that mimics the hierarchical structure of bone tissue can enhance the cellular functions of cells.In this context,Hollow Mesoporous Silica Nanoparticles(HMSNs),renowned for their unique physicochemical properties and superior biocompatibility,offer a promising direction for this research.In this research,the initially synthesized HMSNs were used to construct a“hollow-mesoporous-macroporous”hierarchical bioinspired coating on the pTi surface through the Layer-by-Layer technique.Simultaneously,diverse morphologies of coatings were established by adjusting the deposition strategy of PDDA/HMSNs on the pTi surface(pTi-HMSN-2,pTi-HMSN-4,pTi-HMSN-6).A range of techniques were employed to investigate the physicochemical properties and regulation of cellular biological functions of the diverse HMSN coating strategies.Notably,the pTi-HMSN-4 and pTi-HMSN-6 groups exhibited the uniform coatings,leading to a substantial enhancement in surface roughness and hydrophilicity.Meantime,the coating constructed strategy of pTi-HMSN-4 possessed commendable stability.Based on the aforementioned findings,both pTi-HMSN-4 and pTi-HMSN-6 facilitated the adhesion,spreading,and pseudopodia extension of BMSCs,which led to a notable upsurge in the expression levels of vinculin protein in BMSCs.Comprehensive analysis indicates that the coating,when PDDA/HMSNs are deposited four times,possesses favorable overall performance.The research will provide a solid theoretical basis for the translation of HMSN bioinspired coatings for orthopedic implants.

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.

The Capture and Catalytic Conversion of CO_(2) by Dendritic Mesoporous Silica-Based Nanoparticles

Dendritic mesoporous silica nanoparticles own three-dimensional center-radial channels and hierarchical pores,which endows themselves with super-high specific surface area,extremely large pore volumes,especially accessible internal spaces,and so forth.Dissimilar guest species(such as organic groups or metal nanoparticles)could be readily decorated onto the interfaces of the channels and pores,realizing the functionalization of dendritic mesoporous silica nanoparticles for targeted applications.As adsorbents and catalysts,dendritic mesoporous silica nanoparticles-based materials have experienced nonignorable development in CO_(2)capture and catalytic conversion.This comprehensive review provides a critical survey on this pregnant subject,summarizing the designed construction of novel dendritic mesoporous silica nanoparticles-based materials,the involved chemical reactions(such as CO_(2)methanation,dry reforming of CH_(4)),the value-added chemicals from CO_(2)(such as cyclic carbonates,2-oxazolidinones,quinazoline-2,4(1H,3H)-diones),and so on.The adsorptive and catalytic performances have been compared with traditional silica mesoporous materials(such as SBA-15 or MCM-41),and the corresponding reaction mechanisms have been thoroughly revealed.It is sincerely expected that the in-depth discussion could give materials scientists certain inspiration to design brand-new dendritic mesoporous silica nanoparticles-based materials with superior capabilities towards CO_(2)capture,utilization,and storage.

Silica nanoparticle design for colorectal cancer treatment:Recent progress and clinical potential

Colorectal cancer(CRC)is the third most common cancer worldwide and the second most common cause of cancer death.Nanotherapies are able to selectively target the delivery of cancer therapeutics,thus improving overall antitumor eff-iciency and reducing conventional chemotherapy side effects.Mesoporous silica nanoparticles(MSNs)have attracted the attention of many researchers due to their remarkable advantages and biosafety.We offer insights into the recent advances of MSNs in CRC treatment and their potential clinical application value.

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.

Preparation and characterization of mesoporous silica nanoparticles with enlarged pores capped with crosslinked PEI

The epidemiological statistics reveals the striking patterns of cancer in women and highlights the need for novel therapeutic strategies. In this work, mesoporous silica nanoparticles（MSNs） as representative of inorganic nanoparticles were prepared for loading si RNA that plays a role of gene silencing to treat breast carcinoma（MCF-7） cells. The critical processes of synthesis were optimized for the nanoparticles with desired quality attributes that have the enlarged pores for elevated loading capacity. After si RNA loading into mesoporous, crosslinked-polyethylenimine was employed as the cap to coat the enlarged MSN pores and protect the cargo from leakage. The elevated quantity of si RNA（35 μg si RNA/mg MSNs） were loaded in the MSNs. The as-synthesized MSNs were further evaluated on MCF-7 cells in vitro and shown negligible cytotoxicity. As expected, the si RNA loaded in the as-synthesized MSNs was readily internalized into MCF-7 cells and displayed 420 times higher intake than that of naked si RNA. The MSNs may be exploited to become an effective si RNA cell delivery strategy and further studied for the anti-tumor efficacy.

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.

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.

Dual pH and glucose sensitive gel gated mesoporous silica nanoparticles for drug delivery

A low molecular weight gelator with dual pH and glucose sensitive moieties was synthesized. The gelator penetrated in the mesopores of silica nanoparticles(MSNs) and formed low molecular weight gel(LMWG) as gate to fabricate dual pH and glucose responsive nano drug delivery system. Antidiabetic drug was loaded in the gel caped MSNs, the drug release was responsive to the pH and glucose levels and the drug release could be controlled via the stimuli sensitivity of gel.

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.

Facile one-pot synthesis of PEGylated monodisperse mesoporous silica nanoparticles with controllable particle sizes

In this work, we describe the one-pot synthesis of PEGylated mesoporous silica nanoparticles （MSNs） with uniform shape, tunable sizes, and narrow size distributions. The size of these nanoparticles can be controlled from 49 nm to 98 nm by simply varying the concentration oftriethanolamine during the base- catalyzed sol-gel reaction. Particles were characterized by transmission electron microscopy, dynamic light scattering, Fourier transform infrared spectrometry, thermogravimetric analysis, and nitrogen adsorption-desorption measurements. These PEGylated MSNs exhibited excellent long-term stability in biological media, which ensures their potential applications in drug delivery.

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.