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To investigate the crucial role of particle size in the biological effects of nanoparticles, a series of mesoporous silica nanoparticles (MSNs) were prepared with particle size gradients (50, 100, 150, 200 nm) with the traditional Stober method and adjusting the type and ratio of the silica source. The correlation between toxicity and size-caused biological effects were then further examined both in vitro and in vivo. The results indicated that the prepared MSNs had a uniform size, good dispersal, and ordered mesoporous structure. Hemolytic toxicity was found to be independent of particle size. At the cellular level, MSNs with smaller particle sizes were more readily internalized by cells, which initiated to more intense oxidative stress, therefor inducing higher cytotoxicity, and apoptosis rate. In vivo studies demonstrated that MSNs primarily accumulated in the liver and kidneys of mice. Pharmacokinetic analysis revealed that larger MSNs were eliminated more efficiently by the urinary system than smaller MSNs. The mice's body weight monitoring, blood tests, and pathological sections of major organs indicated good biocompatibility for MSNs of different sizes. Animal welfare and the animal experimental protocols were strictly consistent with related ethics regulations of Zhejiang Chinese Medical University. Overall, this study prepared MSNs with a particle size gradient to investigate the correlation between toxicity and particle size using macrophages and endothelial cells. The study also examined the biosafety of MSNs with different particle sizes in vivo and in vitro, which could help to improve the safety design strategy of MSNs for drug delivery systems.
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Background Silica nanoparticles (SiNPs) enter the human body through respiratory tract, digestive tract, and skin, causing body damage. Lung is one of the main damaged organs. Objective To observe the expressions of complement activated fragment C3a and its receptor C3aR in the lungs of mice exposed to SiNPs through respiratory tract, and to explore the involvement of C3a/C3aR in lung injury induced by SiNPs exposure. Methods The ultrastructure of SiNPs (particle size 5-20 nm) was determined under a transmission electron microscope, and the hydrodynamic diameter and surface Zeta potential of SiNPs were determined using a nanoparticle size analyzer. A total of 88 SPF C57BL/6J mice were randomly divided into five groups: a blank control group without any treatment (14 mice), a vehicle control group treated with 50 μL stroke-physiological saline solution by intratracheal instillation (14 mice), and three SiNPs exposure groups (low-dose group, medium-dose group, and high-dose group with 20 mice in each group, who were given 50 μL SiNPs suspension of 7, 21, and 35 mg·kg−1 respectively and exposed once every 3 days for 5 times). The mice were anesthetized on day 1 (1-day model group) and day 15 (15-day model group) after exposure, then sacrificed after extraction of bronchoalveolar lavage fluid (BALF), and lung tissues were retained. The morphological changes of lung tissues were observed by HE staining, the expression level of C3a in BALF was detected by enzyme-linked immunosorbent assay, the deposition of C3a and C3aR in lung tissues were observed by immunohistochemistry, the protein expression level of C3aR was determined by Western blotting, and the localization and semi-quantitative detection of C3a and C3aR in lung tissues was observed by immunofluorescence. Results SiNPs agglomerated in stroke-physiological saline solution. The average hydrodynamic diameter was (185.60±7.39) nm and the absolute value of Zeta potential was (43.33±0.76) mV. The condition of mice in the 1-day model group and the 15-day model group was good, while 2 mice died in the medium-dose group of the 1-day model group due to misoperation. The autopsy results of the two mice showed congestion of the lung tissue, emphysema, and no imperfection of trachea integrity. No death was observed in other dose groups. The HE staining results showed pathological damage to the mouse lung, including alveolar wall thickening and inflammatory cell infiltration after SiNPs exposure. The pathological damage became more serious with the increase of dose. Regarding pathological changes, the 15-day model group was slightly relieved compared with the 1-day model group, but there were still pathological changes. The enzyme-linked immunosorbent assay results showed that there was no difference in the expression level of C3a between the blank control group and the vehicle control group (P＞0.05), the expression levels of C3a in the medium-dose group and the high-dose group were significantly higher than that in the vehicle control group (P<0.05). The immunohistochemistry results showed that C3a deposition was consistent with the enzyme-linked immunosorbent assay results. The Western blotting and the immunohistochemistry results showed that C3aR expression was low in the blank control group and the vehicle control group, while the expression in each dose group tended to increase with the increase of dose. The immunofluorescence results showed that the fluorescence signals of C3a and C3aR were weak in the blank control group and the vehicle control group in the 1-day model group and the 15-day model group, while the fluorescence signals in the lung tissues of mice in the SiNPs exposure groups tended to increase with the increase of dose. Conclusion The increased expressions of C3a and C3aR in complement activation may be related to lung injury induced by intratracheal instillation of SiNPs, suggesting that C3a/C3aR may be involved in lung injury induced by SiNPs exposure.
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Chemoimmunotherapy has attracted much attention as an emerging therapy pattern for the treatment of cancers. Exploring effective drug combination schemes and reasonable delivery methods remained the key issue in current research. Herein, we designed sorafenib (SF) and anti-Tim-3 monoclonal antibody (Tim-3 mAb) co-loaded MMP2-responsive mesoporous silica nanoparticles (ST-MSNs) for combined chemoimmunotherapy of hepatocellular carcinoma (HCC). The shell of ST-MSNs was fabricated by Tim-3 mAb through matrix metalloproteinase 2 (MMP2) sensitive peptides as "gatekeepers" to prevent drug release during the blood circulation. In tumor microenvironment, the high levels of MMP2 caused the responsive shedding of Tim-3 mAb, leading to the triggerred release of SF and Tim-3 mAb. Then, SF could be delivered to tumor cells and Tim-3 mAb could be delivered to T cells, respectively. In vivo tumor inhibition study results demonstrated that ST-MSNs can significantly enhance synergistic antitumor activity compared with sequential administration of free SF solution and Tim-3 mAb solution. Meanwhile, the expression of antitumor cytokines IFN-γ, IL-12 and the percentage of CD3+CD4+ cells, CD3+CD8+ cells in tumors were upregulated after the administration of ST-MSNs, demonstrating good immunomodulatory ability. In addition, within the dosage range, the ST-MSNs had low cytotoxicity and hemolysis, and no obvious tissue toxicity was observed. All animal experiments were performed in line with national regulations and approved by the Animal Experiments Ethical Committee of Shandong University. In conclusion, this study provided a promising drug combination of chemoimmunotherapy with good application prospects for clinical HCC treatment, and exhibited a potential drug carrier for clinical chemoimmunotherapy.
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OBJECTIVE: To prepare mesoporous silica nanoparticles (MSNs) modified by targeted ingredients to improve the tumor cell lethality of antitumor drugs. METHODS: MSNs were prepared by template-hot water method, and modified with amino group and polyethyleneimine. The nano-carriers were characterized by their morphology, particle size and infrared absorption. Meanwhile, the intracellular uptake and in vitro antitumor activity of MSNs were evaluated on human breast carcinoma cell line (MCF-7). RESUTLS Three kinds of nanoparticles, MSNs, MSNs-NH2 and MSNs-PEI were all spherical, with mean diameters of (65±19), (77±17) and (117±21) nm, respectively. Infrared spectrum and differential thermal analysis RESULTS: indicated that the functional groups were linked onto the surface of MSNs, and slower drug release was observed for MSNs-NH2 and MSNs-PEI. Moreover, the cellular uptake of three nanoparticles were 2.05, 2.89, and 2.63 times higher than free doxorubicin, and the cytotoxicity activity against MCF-7 cells were 1.77, 2.21, and 2.19 times, respectively. CONCLUSION: The preparation method can be used to prepare MSNs nano-carriers. MSNs-NH2 and MSNs-PEI have improved carrier property and antitumor activity.
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The mesoporous silica nanoparticles (MSN) in different pore size and sirolimus (SRL) loaded self-microemulsifying drug delivery system (SMEDDS) were prepared. The results in morphology were collected by scanning electron microscope, transmission electron microscope, small-angle X-ray diffraction, and N2 adsorption-desorption. The results showed that the prepared MSN has ordered nanochannels with a pore size of 6.3, 8.1, 10.8 nm, respectively. The particle size of SRL-SMEDDS were measured by particle sizing system, which was 20.6±1.3 nm. The stirring method was developed to prepare SRL-SMEDDS-MSN. It was found that the optimal ratio of SRL-SMEDDS to MSN was 2:1, while the drug loading rate was near 0.83%, and the flow properties of SRL-SMEDDS-MSN were of good condition. The differential scanning calorimetry results proving a molecular or amorphous dispersed state of SRL in MSN while the suspension experiment has shown great reconstitution properties of SRL-SMEDDS-MSN. There is no significant influence on maximum drug release rate of different pore size of SRL-SMEDDS-MSN in 250 mL water within 2 h, while the results of the first 40 min have an obvious difference. Above all, MSN might provide a new strategy for the solidification of SMEDDS.
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Referring to the recent literatures, this review summarized the recent research progress of SR-MSNDDS which were responsive to different stimulus, including pH, reduction, temperature, light, magnetic field or biomolecules, etc. To review the recent research progress of stimuli responsive mesoporous silica nanoparticle (SR-MSNDDS) drug delivery systems and predict their application prospect. SR-MSNDDS could overcome the problem of controlling drug release from MSN and achieve tumor specific drug release, which has become a research hotspot in the field of tumor diagnosis and therapy.
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Objective: Taking mesoporous silica nanoparticle (MSN) as carrier, to prepare curcumin (Cur)-MSN-solid dispersion (SD) for study on its effect on the dissolution rate and solubility of Cur. Methods: MSN was prepared by condensation method and Cur-MSN-SD was obtained using solvent evaporation method. Then, Cur-MSN-SD was characterized with scanning electron microscope, nitrogen adsorption test, infrared spectrum analysis, and differential scanning calorimetry. Then the dissolution rate and solubility between Cur and Cur-MSN-SD were compared. Results: The average pore diameter of prepared MSN was 2.737 nm, with the feature of typical mesoporous structure, and Cur was distributed in the channel. The cumulative dissolution rate and solubility of the drug were the best as the mass ratio of Cur to MSN was 1∶4. Conclusion: The Cur-MSN-SD prepared with the MSN as carrier could improve the cumulative dissolution rate and solubility of Cur, which provides an effective method for solving the water non-solubility of Cur.
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OBJECTIVE: To prepare and evaluate resveratrol-loaded mesoporous silica nanoparticles modified by amino (NH2-MSN-RES) to improve the bioavailability of resveratrol. METHODS: Mesoporous silica nanoparticles modified by amino (NH2-MSN) were synthesized by the modified Stober method. The structure of the nanoparticles were analyzed and characterized by FT-IR, Malvern particle size analyzer, and TEM. By introducing the innovative preparation process of repeated saturated solution adsorbing method, RES was encapsulated into NH2-MSN in larger amount. Dialysis bag method was used to investigate the in vitro drug release characteristics and MTT method was used to investigate the cytotoxicity on Caco-2 cells. The transport ability of the carrier was investigated by the Caco-2 cells monolayer model. Finally, the pharmacokinetics of NH2-MSN-RES was studied in rats. RESULTS: The particle size distribution of NH2-MSN was uniform with an average value of (98.4±2.8) nm, and the Zeta potential was (13.2±1.8) mv. Within the scope of 0-20 μg·mL-1, NH2-MSN had no obvious toxicity on Caco-2 cells. After 8 times of repeated adsorption, the drug loading of NH2-MSN-RES reached up to (19.26±2.51)%. In the drug release experiment, the cumulative release quantity of NH2-MSN-RES was 73.3% within 48 h, indicating sustained-release characteristics. NH2-MSN-RES had good ability of transmembrane transport in the Caco-2 cell monolayer model, and the two-way apparent permeability coefficient (Papp) was much larger than the RES solution. In the pharmacokinetic study, RES solution complied with one-compartment model, whereas NH2-MSN-RES complied with two-compartment model, indicating that the carrier changed the pharmacokinetic characteristics of RES. The AUC0-∞ of NH2-MSN-RES was 2.58-fold of that of RES solution, what's more, the t1/2, tmax, and ρmax of NH2-MSN-RES were significantly greater than those of RES solution. CONCLUSION: NH2-MSN is synthesized by modified Stober method successfully. Repeated saturated solution adsorbing method could effectively improve the drug loading. NH2-MSN-RES improves the bioavailability of RES prominently. NH2-MSN will be a promising nano-material for oral drug delivery carrier.
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Objective To investigate the cytotoxicity of silica nanoparticles on vascular endothelial cells, and to clarify its action mechanism.Methods The 60 nm silica nanoparticle was selected and the invitro cultured human umbilical vein endothelial cells (HUVECs)were used as cell model.The HUVECs were divided into control and silica nanoparticle exposure groups with concentrations of 12.5,25.0,and 100.00 mg·L-1 .MTT assay was used for the determination of cell viability,lactate dehydrogenase (LDH)release assay for membrane integrity,flow cytometry (FCM)for intracellular reactive oxygen species (ROS)content,and real-time PCR assay for intracellular NF-E2-related factor 2 (Nrf2 ), heme oxygenase-1 (HO-1 ), superoxide dismutase 2 (SOD2 ) and glutamate-cysteine ligase catalytic subunit (GCLC)mRNA levels.Results The MTT results showed that the cell viabilities in each silica nnaoparticle exposure group were decreased compared with control group in a dose-dependent manner. Upon the silica nanoparticle exposure for 12 h,the cell viability was declined significantly only in 100 mg·L-1 exposure group compared with control group (P<0.05).When exposured for 24 h,the cell viabilities in 25.0, 50.0,and 100.0 mg·L-1 exposure groups were declined significantly compared with control group (P<0.05). Under the exposure to silica nanoparticle with the same dose, the cell viabilities were decreased along with the elongation of exposure time.LDH assay and FCM showed that except for that in 12.5 mg·L-1 exposure group, both the LDH activities in media and intracellular ROS levels in other exposure groups were increased compared with control group (P<0.05 ). The results of real-time fluorescence PCR showed that the mRNA levels of Nrf2, HO-1,SOD2 and GCLC in 100 mg·L-1 silica nanoparticle exposure group were increased significantly compared with control group (P<0.05).Conclusion Silica nanoparticles have toxicity to vascular endothelial cells,which includes reducing cell viability,membrane integrity destruction,induction of ROS generation,and tranSCriptional regulation of redox-related factors. Oxidative damage is one of the mechanisms of vascular endothelial toxicity mediated by silica nanoparticles.
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Objective To study the ability of silica nanoparticles as gene carriers for adult human epidermal keratinocytes gene transfection.Methods The silica nanoparticles-DNA conjugated with the enhanced green fluorescence protein plasmid DNA(pEGFP-N_1) was transfected into adult human epidermal keratinocytes.The expression of green fluorescence protein was investigated in transfected keratinocytes by eletromicroscope examine and the efficiency of gene transfection was revealed.Results The silica nanoparticles-DNA complexes can be effectively transfected into adult human epidermal keratinocytes and the efficiency of gene transfection was about 20%～30%.Conclusion The silica nanoparticles can be used as DNA carriers for gene transfection,and can efficiency transfect the pEGFP-N_1 into adult human epidermal keratinocytes.