Polymer-coated mesoporous silica nanoparticles for the controlled release of macromolecules

With the goal of achieving constant release of large biological molecules over an extended period of time we focused on hybrid inorganic/organic nanoparticles. We synthesized poly(ethylene glycol) (PEG)-coated mesoporous silica nanoparticles (MSNs) with incorporated trypsin inhibitor (TI), a model protein molecule for growth factors. Due to the goal of incorporating large protein molecules the pore size of the as-synthesized MSNs was expanded by a hydrothermal treatment prior to TI incorporation. In vitro release from the MSNs without the thin polymer film shows an initial burst followed by continuous release. In the case of polymer-coated MSNs the initial burst release was completely suppressed and approximate zero order release was achieved for 4 weeks.     

Surfactant-assisted controlled release of hydrophobic drugs using anionic surfactant templated mesoporous silica nanoparticles

A series of mesoporous silica nanoparticles (MSNs) were synthesized using the co-structure directing method. A non-cytotoxic anionic surfactant, undec-1-en-11-yltetra(ethylene glycol) phosphate monoester surfactant (PMES), was used as a structure directing agent (SDA) together with aminopropyltrimethoxysilane that functioned as a co-structure directing agent (CSDA). The morphology and mesoporous structure of these materials were tuned by changing the molar ratio of CSDA and SDA. These mesoporous nanomaterials containing PMES inside the pores showed excellent biocompatibility in vitro. The cellular internalization and endosome escape of PMES-MSNs in cervical cancer cells (HeLa) was demonstrated by flow cytometry and confocal microscopy, respectively. The PMES-MSNs were used as drug delivery carriers for resveratrol, a low water solubility drug, by taking advantage of the hydrophobic environment created by the PMES micelle inside the pores. This surfactant-assisted delivery strategy was tested under physiological conditions showing an increase of the drug loading compared to the material without surfactant and steady release of resveratrol. Finally, the therapeutic properties of resveratrol-loaded PMES-MSNs were evaluated in vitro using HeLa and Chinese hamster ovarian cells. We envision that this surfactant-assisted drug delivery method using MSNs as nanovehicles would lead to a new generation of carrier materials for intracellular delivery of a variety of hydrophobic therapeutic agents.     

Fluorescent mesoporous silica nanotubes incorporating CdS quantum dots for controlled release of ibuprofen

Mesoporous silica nanotubes (MSNTs) and amine-functionalized MSNTs (NH₂-MSNTs) have been successfully synthesized via a sol–gel route using needle-like CaCO₃ nanoparticles as inorganic templates and post-modification with 3-aminopropyltriethoxysilane. Subsequently, the preformed nanotubes were functionalized with blue fluorescent CdS quantum dots, as demonstrated by transmission electron microscopy and confocal laser scanning microscopy. The morphology and microstructure of the produced materials were characterized by scanning electron microscopy and N₂ adsorption–desorption measurements. A comparative study of the capacity of several kinds of nanotube materials to store ibuprofen indicated that the drug-loading amount in CdS-NH₂-MSNTs (CdS-incorporated NH₂-MSNTs) could reach up to 740 mg/g silica, similar to that in as-prepared MSNTs (762 mg/g silica) and NH₂-MSNTs (775 mg/g silica). Drug release studies in simulated body fluid revealed that the loaded ibuprofen released from amine-functionalized systems at a significantly lower release rate as compared to that from amine-free systems, and the incorporation of CdS quantum dots had nearly no effect on the ibuprofen release process. Further study on the ibuprofen release from CdS-NH₂-MSNTs in other media, i.e. borate buffer saline, pure water and normal saline, indicated that CdS-NH₂-MSNTs are pH- and ion-sensitive drug carriers, which should facilitate controlled drug delivery and disease therapy.     

介孔二氧化硅纳米颗粒的生物相容性

背景：介孔二氧化硅纳米颗粒具有很多优异的物理性质,在生物医学领域应用广泛,但目前对其生物相容性研究不足。 目的：综述国内外对介孔二氧化硅纳米颗粒生物相容性的研究进展。 方法：检索PubMed、EMBASE、万方、CNKI、维普、中国生物医学数据库有关介孔二氧化硅纳米颗粒细胞毒性和动物毒性的相关文献。 结果与结论：介孔二氧化硅纳米颗粒可通过内吞作用被细胞摄取,其可能通过在细胞内产生活性氧化物导致细胞毒性;介孔二氧化硅纳米颗粒致细胞毒作用与介孔二氧化硅纳米颗粒浓度、颗粒尺寸、表面活性剂去除方式、细胞种类有关。介孔二氧化硅纳米颗粒在动物体内主要富集在肝脏和脾脏,尿液和粪便是其主要排泄途径;介孔二氧化硅纳米颗粒在体内局部生物相容性良好,而大剂量介孔二氧化硅纳米颗粒经腹腔注射或静脉注射可导致严重全身反应。介孔二氧化硅纳米颗粒在体外和体内均显示出较好的生物相容性,但其安全性仍需进一步研究。     

Biofunctionalized polymer-lipid supported mesoporous silica nanoparticles for release of chemotherapeutics in multidrug resistant cancer cells

Multidrug resistance (MDR) is a major impediment to the success of cancer chemotherapy. A polymer-lipid supported mesoporous silica nanoparticle (PLS-MSNs) is described here to facilitate intracellular delivery of anticancer drug and enhance the antitumor efficacy against MDR breast cancer cells. By coating MSNs with a synthetic dual-functional polymer-lipid material P123-DOPE, the supported membrane acted as an intact barrier against the escape of encapsulated drugs before reaching the target cells, leading to depolymerization and triggered storm release of loaded irinotecan (CPT-11) in acidic endosomal pH of tumor cells. In addition, P123-DOPE can inhibit breast cancer resistance protein (BCPR) mediated CPT-11 efflux in drug resistant MCF-7/BCRP breast cancer cells, thus acting as a “door blocker”. Compared to free CPT-11, PLS-MSNs resulted in a maximum increase in the intracellular CPT-11 concentration (12.9-fold), had 7.1-fold higher cytotoxicity and processed a stronger cell cycle arrest in MCF-7/BCRP cells. Moreover, CPT-11 loaded PLS-MSNs showed high therapeutic performance and low toxicity in BALB/c nude mice bearing drug resistant breast tumors, with an inhibition rate of 81.2% compared to free CPT-11 treatment group. The reported PLS-MSNs provide promising applicability in future preclinical and clinical MDR cancer treatment.     

Bi2S3-embedded mesoporous silica nanoparticles for efficient drug delivery and interstitial radiotherapy sensitization

A novel design of Bi₂S₃ nanoparticles with a coating of mesoporous silica (BMSN) is obtained by a surfactant induced condensation method. It was found that BMSNs exhibited a high doxorubicin (DOX) loading efficiency of 45 wt% and pH-responsive controlled drug release owing to the electrostatic interaction between silanol surface and DOX molecules. The cell viability results demonstrated the encapsulation of DOX into BMSNs could lead to significantly enhanced therapeutic effect against multidrug-resistance cancer cells compared to that of free DOX drug. Furthermore, the comparable study of tumor growth by different treatments demonstrated that the introduction of BMSNs in the X-ray therapy could lead to higher therapeutic effect, with just 2.10-fold increase in tumor volume through 24 days, in comparison to 4.40-fold increase for X-ray beams treatment alone. Meanwhile, the in vitro interstitial radiotherapy experiments demonstrated that the cell inhibiting effect of P-32 interstitial radiotherapy combined with BMSNs (50 μg/mL) was 1.55-fold higher than that of P-32 alone. Significantly, it is notable that the simultaneous chemo- and interstitial radiotherapy based on BMSNs could tremendously increase the therapeutic effect compared to those treatment alone. More importantly, the in vivo P-32 radiotherapy in conjunction with BMSNs was proved to present a significantly eradication of the tumor volumes by an average of 21% reduction to its initial values, in comparison to 2.01-fold increase in case of P-32 treatment alone. Thus, it is expected that the BMSNs could be applied as a highly efficient multifunctional nanosystem to realize the enhanced chemo- and radiotherapy in the further clinical applications.     

纳米控释系统在组织工程领域的应用

纳米控释系统作为药物、基因传递和控释的载体,由于它的超微小体积,使其具有特殊的重要性。对纳米控释系统在组织工程领域的研究进行评述,表明纳米粒子作为生长因子控制释放、信号分子传递和基因转染的载体在组织工程领域具有广阔的应用前景。     

The comparative effects of mesoporous silica nanoparticles and colloidal silica on inflammation and apoptosis

Mesoporous silica (MPS), synthesized via the supramolecular polymer templating method, is one of the most attractive nanomaterials for biomedical applications, such as drug delivery systems, labeling, and tissue engineering. The significant difference between MPS and general silica (colloidal silica) is the pore architectures, such as specific surface area and pore volume. The pore structures of nanomaterials have been considered to be one of the key conditions, causing nanotoxicity due to their different efficiency of cellular uptake and immune response. We first studied the influence of pore structural conditions of silica nanoparticles on both inflammation and apoptosis, in?vitro and in?vivo, by comparing MPS and colloidal silica, and defined underlying mechanisms of action. Both the MPS and colloidal silica nanoparticles are produced by almost similar synthetic conditions, except the use of polymer template for MPS. The specific surface area of colloidal silica and MPS was 40 and 1150?m(2)?g(-1), respectively, while other conditions, including particle size (100?nm) and shape (spherical), were kept constant. In both MTT assay and FACS analysis, MPS nanoparticles showed significantly less cytotoxicity and apoptotic cell death than colloidal silica nanoparticles. MPS nanoparticles induced lower expression of pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, in macrophages. The reduced inflammatory response and apoptosis elicited by MPS nanoparticles were resulting from the reduction of mitogen-activated protein kinases, nuclear factor-κB, and caspase 3. In addition, using the local lymph node assay, a standalone in?vivo method for hazard identification of contact hypersensitivity, we showed that colloidal silica nanoparticles act as an immunogenic sensitizer and induce contact hypersensitivity but not MPS nanoparticles. In conclusion, the pore architecture of silica nanoparticles greatly influences their biocompatibility and should be carefully designed. The MPS nanoparticles exhibit better biocompatibility than colloidal silica and promise excellent potential usage in the field of biomedical and biotechnological applications.     

Luminescent mesoporous nanoreservoirs for the effective loading and intracellular delivery of therapeutic drugs

Development of biocompatible and multifunctional nanocarriers is important for the therapeutic efficacy of drug molecules in the treatment of disease and tissue repair. A novel nanocarrier of luminescent hollowed mesoporous silica (L-hMS) was explored for the loading and controlled delivery of drugs. For the synthesis of L-hMS, self-activated luminescence hydroxyapatite (LHA) was used as a template. Different thicknesses (∼7–62 nm) of mesoporous silica shell were obtained by varying the volume of silica precursor and the subsequent removal of the LHA core, which resulted in hollow-cored (size of ∼40 nm × 10 nm) mesoporous silica nanoreservoirs, L-hMS. While the silica shell provided a highly mesoporous structure, enabling an effective loading of drug molecules, the luminescent property of LHA was also well preserved in both the silica-shelled and the hollow-cored nanocarriers. Doxorubicin (DOX), used as a model drug, was shown to be effectively loaded onto the mesopore structure and within the hollow space of the nanoreservoir. The DOX release was fairly pH-dependent, occurring more rapidly at pH 5.3 than at pH 7.4, and a long-term sustainable delivery over the test period of 2 weeks was observed. The nanoreservoir exhibited favorable cell compatibility with low cytotoxicity and excellent cell uptake efficiency (over 90%). Treatment of HeLa cells with DOX-loaded L-hMS elicited a sufficient degree of biological efficacy of DOX, as confirmed in the DOX-induced apoptotic behaviors, including stimulation in caspase-3 expression, and was even more effective than the direct DOX treatment. Overall, the newly developed L-hMS nanoreservoirs may be potentially useful as a multifunctional (luminescent, mesoporous and biocompatible) carrier system to effectively load and sustainably deliver small molecules, including anticancer drugs.     

Monodisperse mesoporous superparamagnetic single-crystal magnetite nanoparticles for drug delivery

In this contribution, we report a facile, gram-scale, low-cost route to prepare monodisperse superparamagnetic single-crystal magnetite NPs with mesoporous structure (MSSMN) via a very simple solvothermal method. The formation mechanism of MSSMN is also discussed and we think that Ostwald ripening probably plays an important role in this synthesis process. It is also interestingly found that the size and morphology of mesoporous Fe₃O₄ NPs can be easily controlled by changing the amount of NaOH and 1,2-ethylenediamine (ETH). Most importantly, the MSSMN can be used as an effective drug delivery carrier. A typical anticancer drug, doxorubicin (Dox), is used for drug loading, and the release behaviors of Dox in two different pH solutions are studied. The results indicate that the MSSMN has a high drug loading capacity and favorable release property for Dox; thus, it is very promising for the application in drug delivery.     

载万古霉素MSNs复合硫酸钙制备人工骨的缓释与抗菌作用研究

目的检测载万古霉素介孔二氧化硅纳米颗粒(MSNs)复合硫酸钙人工骨,延长万古霉素释放时间及其抑菌作用。方法分别制备相同载万古霉素量的Van-MSNs-CaSO4和Van-CaSO4颗粒,按0.1 g/mL比例浸泡于PBS溶液中,37℃恒温浸提,按不同时间点取浸提液,全量和半量更换新鲜PBS溶液,分别检测两种颗粒浸提液中的万古霉素含量,并取浸提液行抑菌试验,测量抑菌环大小,比较两种载药颗粒的持续释药时间及相同时间点浸提液的抑菌能力。结果全量更换PBS组Van-MSNs-CaSO4的释药时间为4 d,Van-CaSO4的释药时间为2 d;半量更换PBS组释药时间达35 d,Van-CaSO4的释药时间为14 d。抑菌环直径检测释出药物有抑菌作用。结论 Van-MSNs-CaSO4复合材料较Van-CaSO4可以明显延长万古霉素释放时间并具有抑菌活性。     

In vitro characterizations of mesoporous hydroxyapatite as a controlled release delivery device for VEGF in orthopedic applications

Following bone implant surgery, prolonged ischemic conditions at the implant site often result in postsurgical complications like failure of osseointegration at the bone-implant interface which can lead to implant failure. Thus, restoration of the vascular supply is paramount to the proper development of the bone. High surface area mesostructured materials have been shown to be attractive candidates for bone regeneration to enhance cell adhesion and cell proliferation. This study uses hydroxyapatite, a naturally occurring mineral in the bone, fabricated to a range of suitable pore sizes, infused with vascular endothelial growth factor (VEGF), to be progressively released to stimulate revascularization. In this study, several characterizations including nitrogen adsorption analysis, Fourier-transformed infrared spectroscopy, X-ray diffraction, field emission scanning electron microscope, and transmission electron microscope were used to evaluate the synthesized mesoporous hydroxyapatite (MHA). The results showed that MHA can gradually release VEGF for enhancing revascularization, which is beneficial for orthopedic applications. ? 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 100A:3143-3150, 2012.     

Effects of particle size and surface coating on cellular uptake of polymeric nanoparticles for oral delivery of anticancer drugs

This study evaluated cellular uptake of polymeric nanoparticles by using Caco-2 cells, a human colon adenocarcinoma cell line, as an in vitro model with the aim to apply nanoparticles of biodegradable polymers for oral chemotherapy. The feasibility was demonstrated by showing the localization and quantification of the cell uptake of fluorescent polystyrene nanoparticles of standard size and poly(lactic-co-glycolic acid) (PLGA) nanoparticles coated with polyvinyl alcohol (PVA) or vitamin E TPGS. Coumarin-6 loaded PLGA nanoparticles were prepared by a modified solvent extraction/evaporation method and characterized by laser light scattering for size and size distribution, scanning electron microscopy (SEM) for surface morphology, zeta-potential for surface charge, and spectrofluorometry for fluorescent molecule release from the nanoparticles. The effects of particle size and particle surface coating on the cellular uptake of the nanoparticles were quantified by spectrofluorometric measurement. Cellular uptake of vitamin E TPGS-coated PLGA nanoparticles showed 1.4 folds higher than that of PVA-coated PLGA nanoparticles and 4-6 folds higher than that of nude polystyrene nanoparticles. Images of confocal laser scanning microscopy, cryo-SEM and transmission electron microscopy clearly evidenced the internalization of nanoparticles by the Caco-2 cells, showing that surface modification of PLGA nanoparticles with vitamin E TPGS notably improved the cellular uptake. It is highly feasible for nanoparticles of biodegradable polymers to be applied to promote oral chemotherapy.     

Dual drug release from electrospun poly(lactic-co-glycolic acid)/mesoporous silica nanoparticles composite mats with distinct release profiles

The aim of this study was to fabricate dual drug-loaded poly(lactic-co-glycolic acid) (PLGA)/mesoporous silica nanoparticles (MSNs) electrospun composite mat, with the two model drugs (fluorescein (FLU) and rhodamine B (RHB)) releasing in separate and distinct release kinetics. The PLGA-based electrospun mat loading with the same amount of FLU (5%, with respect to the weight of PLGA) and different amounts of RHB-loaded MSNs (5, 15 and 25%, with respect to the weight of PLGA) were prepared and studied for their releasing properties. The morphology of the composite mats was characterized by scanning electron microscopy and transmission electron microscopy. Finally, the release profiles of the dual drug-loaded electrospun mats were measured, and the results indicated that the FLU and RHB released from the PLGA/FLU/RHB-loaded MSNs electrospun mats showed separate and distinct profiles. Most of the FLU was released rapidly during the 324 h of the trial; however, RHB showed a sustained release behavior, and the release rate could be controlled by the content of the RHB-loaded MSNs in the electrospun mat.     

Intracellular delivery of core-shell fluorescent silica nanoparticles

Highly fluorescent core-shell silica nanoparticles made by the modified St?ber process (C dots) are promising as tools for sensing and imaging subcellular agents and structures but will only be useful if they can be easily delivered to the cytoplasm of the subject cells. This work shows that C dots can be electrostatically coated with cationic polymers, changing their surface charge and enabling them to escape from endosomes and enter the cytoplasm and nucleus. As an example of cellular delivery, we demonstrate that these particles can also be complexed with DNA and mediate and trace DNA delivery and gene expression.     

The packaging of siRNA within the mesoporous structure of silica nanoparticles

Mesoporous silica nanoparticle (MSN) is a promising material for biomedical applications, such as delivering drugs or biological molecules (siRNA or DNA), to the target cells or tissues. With positive-charge functionalization on their surface, MSNs have already been used as vectors for siRNA delivery. Nevertheless, such siRNA packaging strategy avoids utilizing the mesopores and consequently hinders further modifications on the delivery vehicle surface. To solve these problems, we have successfully packaged siRNA into the mesopores of magnetic mesoporous silica nanoparticles (M-MSNs) under a strongly dehydrated solution condition. The siRNA-loaded M-MSNs were mixed with polyethyleneimine (PEI) to form a polymer layer on their external surface. The obtained aggregates were further treated by ultrasonication in acidic solution to prepare well dispersed siRNA delivery vehicles (M-MSN_siRNA@PEI). Such delivery vehicles, with effective siRNA protective effect and negligible cytotoxicity, could be internalized into cancer cells and release siRNA in the cytoplasm. In gene silencing experiments, these delivery vehicles mediated, with high efficiency, knockdown of both exogenous enhanced green fluorescent protein (EGFP) gene and endogenous B-cell lymphoma 2 (Bcl-2) gene. In summary, our siRNA packaging strategy extends the application potential of M-MSNs and the resulting siRNA delivery vehicles can be further tested for in?vivo experiments.     

Label-free dendrimer-like silica nanohybrids for traceable and controlled gene delivery

To create advanced functional nanocarriers for achieving excellent gene delivery performance, fluorescence label-free hybridized dendrimer-like silica nanocarriers (HPSNs-AC-PEI) were developed by using the endosomal pH and cytoplasmic glutathione (GSH) responsive autofluorescent acetaldehyde-modified-cystine (AC) to link non-toxic low molecular weight branched polyethyleneimine (PEI) onto amino-functionalized dendrimer-like silica nanoparticles with hierarchical pores (HPSNs-NH₂). The specific microstructure of this hybridized nanocarrier makes it not only show low cytotoxicity and high gene loading capability, but also display high gene transfection efficiency. The cleavage of disulfide bonds caused by GSH facilitates plasmid DNA (pDNA) release. Moreover, the pH and GSH controlled gene delivery profile can be real–time tracked using the autofluorescence of HPSNs-AC-PEI.     

Single-phased luminescent mesoporous nanoparticles for simultaneous cell imaging and anticancer drug delivery

Multifunctional materials for biological use have mostly been designed with composite or hybrid nanostructures in which two or more components are incorporated. The present work reports on a multifunctional biomaterial based on single-phased luminescent mesoporous lanthanide oxide nanoparticles that combine simultaneous drug delivery and cell imaging. A simple strategy based on solid-state-chemistry thermal decomposition process was employed to fabricate the spherical mesoporous Gd(2)O(3):Eu nanoparticles with homogeneous size distribution. The porous nanoparticles developed by this strategy possess well-defined mesopores, large pore size and volume, and high specific surface area. The mesoporous features of nanoparticles impart the material with capabilities of loading and releasing the drug with a relatively high loading efficiency and a sustained release behavior of drugs. The DOX-loaded porous Gd(2)O(3) nanoparticles are able to kill the cancer cells efficiently upon incubation with the human cervical carcinoma (HeLa) cells, indicating the potential for treatment of cancer cells. Meanwhile, the intrinsic luminescence of Gd(2)O(3):Eu nanoparticles gives the function of optical imaging. Therefore, the drug release activity and effect of drugs on the cells can be effectively monitored via luminescence of nanoparticles themselves, realizing multifunctionality of simultaneous cell imaging and anticancer drug delivery in a single-phased nanoparticle.     

A pH-responsive mesoporous silica nanoparticles-based multi-drug delivery system for overcoming multi-drug resistance

A type of pH-responsive nano multi-drug delivery systems (nano-MDDSs) with uniform particle size (100?±?13?nm) and excellent monodispersity was developed by in situ co-self-assembly among water-insoluble anti-cancer drug (doxorubicin, DOX), surfactant micelles (CTAB) as chemosensitiver and silicon species forming drugs/surfactant micelles-co-loaded mesoporous silica nanoparticles (drugs@micelles@MSNs or DOX@CTAB@MSNs) via a micelles-MSNs self-assembly mechanism. The nano-MDDS DOX@CTAB@MSNs had a highly precise pH-responsive drug release behavior both in?vitro and in?vivo, and exhibited high drug efficiencies against drug-resistant MCF-7/ADR cells as well as drug-sensitive MCF-7 cells by the MSNs-mediated transmembrane delivery, the sustained drug release and the high anti-cancer and multi-drug resistance (MDR)-overcoming efficiencies. The MDR-overcoming mechanism was proved to be a synergistic cell cycle arrest/apoptosis-inducing effect resulted from the chemosensitization of the surfactant CTAB. These results demonstrated a very promising nano-MDDS for the pH-responsive controlled drug release and the cancer MDR overcoming.     

In-vitro osteogenesis of synovium stem cells induced by controlled release of bisphosphate additives from microspherical mesoporous silica composite

In this study, in-vitro osteogenesis was successfully induced in the highly chondrogenic synovium mesenchymal stem cells (SMSCs) by controlled release of a nitrogenous bisphosphonate additive – alendronate (AL) from a mesoporous silica (MS)–hydroxyapatite (HA) composite that was mediated in poly(lactic-co-glycolic acid) (PLGA) microspheres. This microspherical based controlled release system is constructed with three levels of degradable structures: (1) the AL drug was first hybridized with HA nanoparticles; (2) the HA–AL complexes were filled into the mesopores of MS particles by self-assembly in situ; and (3) the HA–AL-laden MS constructs (MSH–AL) were built in the bulk of PLGA microspheres. In comparison with any mono-component construct, the superiority of this multi-component system comes from two aspects of functionalities: (1) significantly greater loading capacity of the extremely hydrophilic drug-AL; and (2) better controlled profile of AL release. Based on this newly developed PLGA/MSH–AL releasing system, as recipients the SMSCs, which usually exhibit exclusively high chondrogenesis, demonstrated a strong osteogenic commitment. The results were verified by alkaline phosphatase (ALP) activity assay, calcium secretion assay, real time PCR and immunohistochemistry analysis. Considering the renewable source and high proliferative profile of SMSCs, the achievement of engineered SMSC osteogenesis with this PLGA/MSH–AL controlled release system would open a new door to major bony reparation and regeneration.