多功能介孔二氧化硅纳米粒在肿瘤治疗中的研究进展

介孔二氧化硅纳米粒由于较高的物理化学稳定性、易于官能化、低毒性以及对许多不同类型治疗剂的巨大负载能力,涉及了化学药物治疗、光热治疗、光动力治疗以及联合治疗,在肿瘤治疗方面受到极大的关注和广泛的研究探索。本文介绍了近年来基于介孔二氧化硅纳米粒作为载体在肿瘤治疗方面的一些研究报道,这些智能化的多功能性已经促使介孔二氧化硅纳米粒成为将来用于临床的非常有前途的药物纳米载体。     

A comparison of mesoporous silica nanoparticles and mesoporous organosilica nanoparticles as drug vehicles for cancer therapy

Mesoporous silica nanoparticles (MSNs) are promising drug carriers for use in cancer treatment owing to their excellent biocompatibility and drug‐loading capacity. However, MSN's incomplete drug release and toxic bioaccumulation phenomena limit their clinical application. Recently, researchers have presented redox responsive mesoporous organosilica nanoparticles containing disulfide (S–S) bridges (ss‐MONs). These nanoparticles retained their ability to undergo structural degradation and increased their local release activity when exposed to reducing agents. Disulfide‐based mesoporous organosilica nanoparticles offer researchers a better option for loading chemotherapeutic drugs due to their effective biodegradability through the reduction of glutathione. Although the potential of ss‐MONs in cancer theranostics has been studied, few researchers have systematically compared ss‐MONs with MSNs with regard to endocytosis, drug release, cytotoxicity, and therapeutic effect. In this work, ss‐MONs and MSNs with equal morphology and size were designed and used to payload doxorubicin hydrochloride (DOX) for liver cancer chemotherapy. The ss‐MONs showed considerable degradability in the presence of glutathione and performed comparably to MSNs on biocompatibility measures, including cytotoxicity and endocytosis, as well as in drug‐loading capacity. Notably, DOX‐loaded ss‐MONs exhibited higher intracellular drug release in cancer cells and better anticancer effects in comparison with DOX‐loaded MSNs. Hence, the ss‐MONs may be more desirable carriers for a highly efficient and safe treatment of cancer.     

Polydopamine and peptide decorated doxorubicin-loaded mesoporous silica nanoparticles as a targeted drug delivery system for bladder cancer therapy

We reported a simple polydopamine (PDA)-based surface modification method to prepare novel targeted doxorubicin-loaded mesoporous silica nanoparticles and peptide CSNRDARRC conjugation (DOX-loaded MSNs@PDA-PEP) for enhancing the therapeutic effects on bladder cancer. Drug-loaded NPs were characterized in terms of size, size distribution, zeta potential, transmission electron microscopy (TEM), Brunauer–Emmett–Teller (BET) surface area and drug loading content. In vitro drug release indicated that DOX-loaded MSNs@PDA and MSNs@PDA-PEP had similar release kinetic profiles of DOX. The PDA coating well controlled DOX release and was highly sensitive to pH value. Confocal laser scanning microscopy (CLSM) showed that drug-loaded MSNs could be internalized by human bladder cancer cell line HT-1376, and DOX-loaded MSNs@PDA-PEP had the highest cellular uptake efficiency due to ligand–receptor recognition. The antitumor effects of DOX-loaded nanoparticles were evaluated by the MTT assay in vitro and by a xenograft tumor model in vivo, demonstrating that targeted nanocarriers DOX-loaded MSNs@PDA-PEP were significantly superior to free DOX and DOX-loaded MSNs@PDA. The novel DOX-loaded MSNs@PDA-PEP, which specifically recognized HT-1376 cells, can be used as a potential targeted drug delivery system for bladder cancer therapy.     

Rod-shaped mesoporous silica nanoparticles for nanomedicine: recent progress and perspectives

Introduction: Interest in mesoporous silica nanoparticles for drug delivery has resulted in a good understanding of the impact of size and surface chemistry of these nanoparticles on their performance as drug carriers. Shape has emerged as an additional factor that can have a significant effect on delivery efficacy. Rod-shaped mesoporous silica nanoparticles show improvements in drug delivery relative to spherical mesoporous silica nanoparticles.

Areas covered: This review summarises the synthesis methods for producing rod-shaped mesoporous silica nanoparticles for use in nanomedicine. The second part covers recent progress of mesoporous silica nanorods by comparing the impact of sphere and rod-shape on drug delivery efficiency.

Expert opinion: As hollow mesoporous silica nanorods are capable of higher drug loads than most other drug delivery vehicles, such particles will reduce the amount of mesoporous silica in the body for efficient therapy. However, the importance of nanoparticle shape on drug delivery efficiency is not well understood for mesoporous silica. Studies that visualize and quantify the uptake pathway of mesoporous silica nanorods in specific cell types and compare the cellular uptake to the well-studied nanospheres should be the focus of research to better understand the role of shape in uptake.     

Development of novel delivery system for warfarin based on mesoporous silica: adsorption characteristics of silica materials for the anticoagulant

The adsorption of the anticoagulant warfarin onto unmodified (UMS) and modified (phenyl (PhMS), methyl (MMS), mercaptopropyl (MPMS)) mesoporous silica materials was studied at pH 1.6 and 7.4 and in the temperature range of 293–325?K. The silica materials were prepared by sol-gel method for further characterization by FTIR spectroscopy, N₂ adsorption/desorption method, transmission electron microscopy and zeta potential measurements. The effects of medium pH, temperature and surface modification of mesoporous silica material on their adsorption characteristics (adsorption capacity, thermodynamic parameters of adsorption) relative to anticoagulant warfarin were investigated. It was found that medium acid–base properties strongly affect the adsorption of warfarin due to the pH-dependent structural diversity of the drug and ionization state of the silica surfaces. The adsorption capacity of the silica materials at pH 1.6 decreases in the order: MMS?>?MPMS?>?UMS?>?PhMS. The influence of various non-covalent interactions on the adsorption capacity of the silica materials and energy of the drug-silica interactions is discussed. These results may be useful for the development of a novel delivery system of warfarin.     

Facile synthesis of PEI-based crystalline templated mesoporous silica with molecular chirality for improved oral delivery of the poorly water-soluble drug

The aim of this study was to build up a novel chiral mesoporous silica called PEIs@TA-CMS through a facile biomimetic strategy and to explore its potential to serve as a drug carrier for improving the delivery efficiency of poorly water-soluble drug. PEIs@TA-CMS was synthesized by using a chiral crystalline complex associated of tartaric acid and polyethyleneimine (PEIs) as templates, scaffolds and catalysts. The structural features including morphology, size, pore structure and texture properties were systematacially studied. The results showed that PEIs@TA-CMS was monodispersed spherical nanoparticles in a uniformed diameter of 120–130 nm with well-developed pore structure (S_BET: 1009.94 m²/g, pore size <2.21 nm). Then PEIs@TA-CMS was employed as nimodipine (NMP) carrier and compared with the drug carry ability of MCM41. After drug loading, NMP was effectively transformed from the crystalline state to an amorphous state due to the space confinement in mesopores. As expected, PEIs@TA-CMS had superiority in both drug loading and drug release compared to MCM41. It could incorporate NMP with high efficiency, and the dissolution-promoting effect of PEIs@TA-CMS was more obvious because of the unique interconnected curved pore channels. Meanwhile, PEIs@TA-CMS could significantly improve the oral adsorption of NMP to a satisfactory level, which showed approximately 3.26-fold higher in bioavailability, and could effectively prolong the survival time of mice on cerebral anoxia from 10.98 to 17.33 min.     

单分散性介孔二氧化硅的制备及靶向性评价

目的：为了制备可稳定分散的介孔二氧化硅纳米材料，并将其用于尾静脉注射的纳米制剂。方法：本文采用Stober法，以十六烷基三甲基溴化铵（CTAB）为模板剂，正硅酸乙酯（TEOS）为硅源，通过酸液萃取法去除模板，制备出分散性良好的MSN纳米粒。通过FTIR、扫描电子显微镜及透射电镜等仪器，进行结构和形貌的表征。结果：单因素实验结果可知MSN的最佳制备工艺为：CTAB/TEOS质量比为1：5，pH 10，反应温度70~80℃，搅拌速率为500 r·min^-1。MSN负载DOX，表现出高负载率；体外释放实验表明DOX在中性条件下释放缓慢，弱酸性条件下释放迅速；体内实验表明MSN具有良好的靶向性。结论：通过优化后的制备工艺，MSN可稳定分散，该制剂制备方法简单，具有pH敏感性，良好的靶向性，有利于达到肿瘤靶向给药的要求，介孔二氧化硅在靶向传递系统的应用具有广阔前景。     

以介孔硅为基质的固体分散体片剂的制备与性质考察

目的将替米沙坦与介孔硅制备成片剂,并考察片剂的稳定性。方法在处方筛选的基础上,采用粉末直接压片法压制替米沙坦-介孔硅片剂;采用高效液相色谱法测定药物含量;采用示差扫描量热、X-射线衍射和溶出法考察制剂的晶型稳定性。结果替米沙坦-介孔硅分散体66 g、交联聚乙烯吡咯烷酮30 g、微晶纤维素50 g、甘露醇50 g、硬脂酸镁4 g,混合均匀,压制成1 000片,含量均匀度和溶出度符合要求,在12个月内替米沙坦稳定性良好,且一直以无定型状态存在。结论利用自制介孔硅制备固体分散体,介孔硅的孔道使难溶性药物长期以无定型状态存在,故制剂稳定性良好。     

有序介孔硅胶提高难溶性药物白藜芦醇的溶出速率

本研究的目的是制备有序介孔硅胶并考察其作为难溶性药物载体的体外药物释放特点。以十六烷基三甲基溴化铵为模板合成了有序介孔硅胶, 以白藜芦醇为模型药物, 采用扫描电镜、透射电镜、N₂吸附-脱附、X-射线衍射和红外光谱对载药前后的有序介孔硅胶进行表征, 并考察药物体外释放行为。结果表明, 合成的有序介孔硅胶比表面积大、粒度均匀, 具有有序六方孔道结构, 载药后药物以无定形态或分子态存在, 释放速率明显提高。有序介孔硅胶有望成为新型的难溶性药物载体。     

Gold-capped mesoporous silica nanoparticles as an excellent enzyme-responsive nanocarrier for controlled doxorubicin delivery

Abstract

Mesoporous silica nanoparticles (MSNs) have ideal characteristics as next generation of controlled drug delivery systems. In this study, a MSN-based nanocarrier was fabricated and gold nanoparticle (GNP)-biotin conjugates were successfully grafted onto the pore outlets of the prepared MSN. This bioconjugate served as a capping agent with a peptide-cleavable linker sensitive to matrix metalloproteinases (MMPs), which are overexpressed extracellular proteolytic enzymes in cancerous tissue. The prepared nanocarriers were fully characterised by scanning electron microscopy (SEM), transmission electron microscopy (TEM), nitrogen adsorption/desorption, Fourier transform infra-red spectroscopy (FTIR), dynamic light scattering (DLS) and thermo gravimetric analysis (TGA). In vitro release studies showed efficient capping of MSNs with gold gate and controlled release of Doxorubicin (DOX) in the presence of matrix metalloproteinase-2 (MMP-2) and acidic pH values. High DOX-loading capacity (21%) and encapsulation efficiency (95.5%) were achieved using fluorescence technique. DOX-loaded nanocarriers showed high cytocompatibility and could efficiently induce cell death and apoptosis in the MMP-2 overexpressed cell lines. Moreover, Haemolysis, platelet activation and inflammatory responses assessment approved excellent hemocompatibility and minimal side effects by encapsulation of DOX in MSNs carrier.     

Development of phosphonate-terminated magnetic mesoporous silica nanoparticles for pH-controlled release of doxorubicin and improved tumor accumulation

In this study, phosphonate-terminated magnetic mesoporous nanoparticles (pMMSNs) was designed by incorporation of MNPs in the center of mesoporous silica nanoparticles (MSNs) and followed by grafting phosphonate group on to the surface of MMSNs. The carrier exhibited a typical superparamagnetic feature and the saturation magnetization was 4.89 emu/g measured by vibrating sample magnetometer (VSM). pMMSNs had a spherical morphology and a pore size of 2.2 nm. From N₂ adsorption-desorption analysis, pMMSNs had a surface area of 613.4 m²/g and a pore volume of 0.78 cm³/g. Phosphonate modification improved the colloidal stability of MMSNs, and the hydrodynamic diameter of pMMSNs was around 175 nm. The hydrophilic phosphonate group significantly enhanced the negative surface charge of MMSNs from −19.3 mV to −28.8 mV pMMSNs with more negative surface charge had a 2.3-fold higher drug loading capacity than that of MMSNs. In addition, the rate and amount of release of doxorubicin (DOX) from DOX/pMMSNs was pH-dependent and increased with the decrease of pH. At pH 7.4, the release amount was quite low and only approximately 17 wt% of DOX was released in 48 h. At pH 5.0 and 3.0, the release rate increased significantly and the release amount achieved 31 wt% and 60 wt% in 48 h, respectively. To evaluate the magnetic targeting performance of pMMSNs, FITC labeled pMMSNs was injected into mice bearing S180 solid tumor. FITC labeled pMMSNs controlled by an external magnetic field showed higher tumor accumulation and lower normal tissue distribution.     

Lipid/PAA-coated mesoporous silica nanoparticles for dual-pH-responsive codelivery of arsenic trioxide/paclitaxel against breast cancer cells

Nanomedicine has attracted increasing attention and emerged as a safer and more effective modality in cancer treatment than conventional chemotherapy. In particular, the distinction of tumor microenvironment and normal tissues is often used in stimulus-responsive drug delivery systems for controlled release of therapeutic agents at target sites. In this study, we developed mesoporous silica nanoparticles (MSNs) coated with polyacrylic acid (PAA), and pH-sensitive lipid (PSL) for synergistic delivery and dual-pH-responsive sequential release of arsenic trioxide (ATO) and paclitaxel (PTX) (PL-PMSN-PTX/ATO). Tumor-targeting peptide F56 was used to modify MSNs, which conferred a target-specific delivery to cancer and endothelial cells under neoangiogenesis. PAA- and PSL-coated nanoparticles were characterized by TGA, TEM, FT-IR, and DLS. The drug-loaded nanoparticles displayed a dual-pH-responsive (pH_e = 6.5, pH_endo = 5.0) and sequential drug release profile. PTX within PSL was preferentially released at pH = 6.5, whereas ATO was mainly released at pH = 5.0. Drug-free carriers showed low cytotoxicity toward MCF-7 cells, but ATO and PTX co-delivered nanoparticles displayed a significant synergistic effect against MCF-7 cells, showing greater cell-cycle arrest in treated cells and more activation of apoptosis-related proteins than free drugs. Furthermore, the extracellular release of PTX caused an expansion of the interstitial space, allowing deeper penetration of the nanoparticles into the tumor mass through a tumor priming effect. As a result, FPL-PMSN-PTX/ATO exhibited improved in vivo circulation time, tumor-targeted delivery, and overall therapeutic efficacy.     

Anti-miRNA21 and resveratrol-loaded polysaccharide-based mesoporous silica nanoparticle for synergistic activity in gastric carcinoma

Abstract

Anti-miR21 and resveratrol (RSV)-loaded mesoporous silica nanoparticles (MSNs) conjugated with hyaluronic acid (HA) were developed to enhance therapeutic efficacy in gastric carcinoma. The surface conjugation of HA, which acts as a targeting ligand to the overexpressed CD44 receptor on gastric cancer cells, was clearly identified by the presence of a greyish shell on the dark MSNs. Confocal laser-scanning microscopy and flow cytometry analysis showed higher cellular internalisation of HA/RSVmirNP compared to RSVmirNP. In vitro cytotoxicity and apoptosis assays confirmed the superior anticancer effect of the optimised formulation and synergistic effects of anti-miR21 and RSV in gastric cancer cells. Importantly, HA/RSVmirNP showed significant (p?<?.001) reductions in the tumour burden compared to the other group. Indeed, HA/RSVmirNP showed a threefold higher tumour regression effect compared to that of free RSV and a twofold tumour regression effect compared to that of RSVmirNP, indicating its anticancer efficacy. The percentage of TUNEL-positive cells was significantly higher in HA/RSVmirNP-treated cells compared to any other group, indicating that the mechanism underlying the superior anticancer efficacy of HA/RSVmirNP included apoptosis and cell necrosis. Thus, a combination of anti-miR21 and RSV in a targeted nanocarrier might be a promising drug delivery system for gastric cancer therapy.     

Enhanced dissolution of valsartan-vanillin binary co-amorphous system loaded in mesoporous silica particles

The study was aimed to prepare a co-amorphous system of valsartan (VAL) with vanillin (VAN) for improving its solubility and dissolution followed by its confinement in mesoporous silica particles (MSPs) to stabilise the co-amorphous system and prevent its recrystallization. Amorphous VAL and VAN were obtained through quench-cooling and VAL/VAN binary co-amorphous system (VAL/VAN-CAS) was prepared through solvent evaporation technique. The particle size and morphology of VAL/VAN-CAS-MSPs were studied using scanning electron microscopy (SEM) and solid-state characterisation was performed by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). The in vitro dissolution was investigated by dialysis bag diffusion method. SEM analysis revealed irregular shaped VAL/VAN-CAS-MSPs with a size range of 5–25?μm, while outcomes of DSC and XRPD confirmed the formation of VAL/VAN-CAS. The in vitro dissolution profiles demonstrated a significantly increased dissolution in first 60?minutes from VAL/VAN-CAS (～68%) and VAL/VAN-CAS-MSPs (～76%) compared to powder VAL (～25%).     

Effect of mesoporous silica nanoparticles on cell viability and markers of oxidative stress

Abstract

In the recent years, the use of mesoporous silica nanoparticles (MSNs) has been extended in biomedical fields such as cancer therapy, drug and gene delivery, biosensors, and enzyme immobilization. Although nanomaterials are currently being widely used in modern technology, there is a lack of information regarding to the health and environmental implications of manufactured nanomaterials. In the present study, the effects of MSNs and surface functionalized MSNs on cell viability, markers of oxidative damages (mainly intracellular reactive oxygen species (ROS) formation), and oxidative DNA damage were investigated in vitro in rat pheochromocytoma PC12 cells. Following exposure of these nanoparticles (1.95–1000?µg/mL) to PC12 cells for 12 and 24?h, no significant reduction of cell viability was observed compared with control. Moreover, ROS formation and oxidative DNA damage were not significantly changed by these nanoparticles even at high concentrations or prolong exposures. In conclusion, the results showed that neither MSNs nor functionalized MSNs exhibited any remarkable in vitro toxic properties in PC12 cells even at high concentration.     

Evaluation of mesoporous silica particles as drug carriers in hydrogels

Mesoporous silica particles have recently been used in the preparation of solid oral as well as dermal pharmaceutical formulations. In this work, the use of mesoporous silica of different particle size, pore size and pore volume as carrier for curcumin in hydrogels for dermal use was investigated. Oil absorption capacity of the silica, in vitro release of curcumin from formulations and chemical stability of curcumin during three months storage were evaluated. It was found that the silica particles did not alter in vitro release of curcumin compared to an emulsion. Furthermore, curcumin was found to exhibit similar or inferior stability in hydrogels containing mesoporous silica opposed to emulsions.     

铜掺杂介孔硅载双硫仑抗肠癌活性研究

目的 以铜掺杂介孔硅（Cu/MSNs）为载体包载双硫仑（DSF）制备成纳米粒,研究其对CT.26WT肠癌细胞的体外抑制活性。方法 Stober法制备二氧化硅微粒后对其进行优化,MTT法验证其体外抗肿瘤活性。结果 通过单因素法优化得到在1.5 mL氨水、12.5 mL水和温度85 ℃时具有最佳粒径;MTT法得到DSF、5-Fu和DSF-NPs在48 h下的IC₅₀值分别为7.532、3.359和1.208 μg·mL^-1,72 h的IC50值分别为2.258、1.137和0.985 μg·mL^-1。结论 铜掺杂介孔硅能有效的负载双硫仑并增强其抗肠癌细胞活性,具有优良的抗肠癌潜力。     

mPEG修饰的新藤黄酸介孔硅纳米粒的制备及体外评价

目的：制备甲氧基聚乙二醇（mPEG）修饰的介孔二氧化硅（MSNs）载新藤黄酸（gambogenic acid,GNA）纳米粒（mPEG-GNA-MSNs）,以实现对药物的缓释并增强其抗肿瘤活性。方法：采用改良的Stöber法合成氨基改性的MCM-41型介孔二氧化硅（NH₂-MSNs）,挥干溶剂法载入GNA,以甲氧基聚乙二醇琥珀酰亚胺基活化酯（mPEG-NHS）与NH₂-MSNs形成酰胺键来制备mPEG以封堵载GNA介孔的二氧化硅纳米粒（mPEG-GNA-MSNs）。通过透射电镜、傅里叶红外光谱、氮气吸-脱附、X射线小角粉末衍射、热重分析等方法对纳米粒进行表征,透析袋法考察mPEG-GNA-MSNs的体外释放规律。采用MTT法考察空白载体和载药纳米粒对人源肝癌细胞（HepG2）和肝正常细胞（LO2）的毒性。结果：制备的mPEG-GNA-MSNs在透射电镜下呈球形,粒径均一;mPEG-GNA-MSNs的载药量和包封率分别为（3.59±0.26）%和（14.52±0.18）%;体外释放结果显示,纳米粒具有明显的缓释作用,48 h释放达到平衡;细胞毒性实验结果表明,mPEG的修饰能够降低载体对HepG2和LO2细胞的毒性,并增强纳米粒对肝癌细胞的毒性。结论：mPEG修饰的介孔二氧化硅纳米粒具有良好的生物安全性,对GNA具有显著的缓释作用,并能增强药物的抗肿瘤活性。