Mesoporous silica nanoparticles improve magnetic labeling efficiency in human stem cells

Tumblerlike magnetic/fluorescein isothiocyanate (FITC)-labeled mesoporous silica nanoparticles, Mag-Dye@MSNs, have been developed, which are composed of silica-coated core-shell superparamagnetic iron oxide (SPIO@SiO(2)) nanoparticles co-condensed with FITC-incorporated mesoporous silica. Mag-Dye@MSNs can label human mesenchymal stem cells (hMSCs) through endocytosis efficiently for magnetic resonance imaging (MRI) in vitro and in vivo, as manifested by using a clinical 1.5-T MRI system with requirements of simultaneous low incubation dosage of iron, low detection cell numbers, and short incubation time. Labeled hMSCs are unaffected in their viability, proliferation, and differentiation capacities into adipocytes and osteocytes, which can still be readily detected by MRI. Moreover, a higher MRI signal intensity decrease is observed in Mag-Dye@MSN-treated cells than in SPIO@SiO(2)-treated cells. This is the first report that MCM-41-type MSNs are advantageous to cellular uptake, as manifested by a higher labeling efficiency of Mag-Dye@MSNs than SPIO@SiO(2).     

Mesoporous silica nanoparticles for efficient rivastigmine hydrogen tartrate delivery into SY5Y cells

Rivastigmine hydrogen tartrate (RT) is a molecule with both hydrophilic and hydrophobic properties used for the treatment of the Alzheimer’s disease. In this work, the larger pore size of mesoporous silica nanoparticles (P1-MSN) was synthesized and then, P1-MSN were functionalized by succinic anhydride (S-P1-MSN) and 3-aminopropyltriethoxysilane (APTES) (AP-CO-P1-MSN) using the grafting and co-condensation methods, respectively. A new method was used for the functionalization of P1-MSN by succinic anhydride at room temperature. Nanoparticles were characterized by special instrumental analysis and loaded by RT. Maximum entrapment efficiency and RT loading percentage into P1-MSN, AP-CO-P1-MSN and S-P1-MSN were respectively obtained as 21.26 and 25.5%, 41.5 and 49.8%, and 11.9 and 14.28% for 24?h. In the simulated gastric and body fluids, the release rate of RT-loaded AP-CO-P1-MSN (AP-CO-P1-MSN-RT) was lower than that of other RT-loaded nanoparticles. In oral pathway, the sustained release of RT was observed in AP-CO-P1-MSN-RT. Moreover, no cytotoxicity effect was observed for P1-MSN, but the cells treated by AP-CO-P1-MSN showed a reduction in SY5Y cell viability due to easy entrance of these nanoparticles and their accumulation in different parts of the cell as observed by TEM.     

Patterning as a signature of human epidermal stem cell regulation

Understanding how stem cells are regulated in adult tissues is a major challenge in cell biology. In the basal layer of human epidermis, clusters of almost quiescent stem cells are interspersed with proliferating and differentiating cells. Previous studies have shown that the proliferating cells follow a pattern of balanced stochastic cell fate. This behaviour enables them to maintain homeostasis, while stem cells remain confined to their quiescent clusters. Intriguingly, these clusters reappear spontaneously in culture, suggesting that they may play a functional role in stem cell auto-regulation. We propose a model of pattern formation that explains how clustering could regulate stem cell activity in homeostatic tissue through contact inhibition and stem cell aggregation.     

Multifunctional Upconversion Mesoporous Silica Nanostructures for Dual Modal Imaging and In Vivo Drug Delivery

Incorporating the agents for magnetic resonance imaging (MRI), optical imaging, and therapy in one nanostructured matrix to construct multifunctional nanomedical platform has attracted great attention for simultaneous diagnostic and therapeutic applications. In this work, a facile methodology is developed to construct a multifunctional anticancer drug nanocarrier by combining the special advantages of upconversion nanoparticles and mesoporous silica. β‐NaYF₄:Yb³⁺, Er³⁺@β‐NaGdF₄:Yb³⁺ is chosen as it can provide the dual modality of upconversion luminescence and MRI. Then mesoporous silica is directly coated onto the upconversion nanoparticles to form discrete, monodisperse, highly uniform, and core–shell structured nanospheres (labeled as UCNPs@mSiO₂), which are subsequently functionalized with hydrophilic polymer poly(ethylene glycol) (PEG) to improve the colloidal stability and biocompatibility. The obtained multifunctional nanocomposites can be used as an anticancer drug delivery carrier and applied for imaging. The anticancer drug doxorubicin (DOX) is absorbed into UCNPs@mSiO₂‐PEG nanospheres and released in a pH‐sensitive pattern. In vitro cell cytotoxicity tests on cancer cells verify that the DOX‐loaded UCNPs@mSiO₂‐PEG has comparable cytotoxicity with free DOX at the same concentration of DOX. In addition, the T₁‐weighted MRI that measures in aqueous solutions reveals that the contrast brightening increases with the concentration of Gd³⁺ component. Upconversion luminescence images of UCNPs@mSiO₂‐PEG uptaken by cells show green emission under 980 nm infrared laser excitation. Finally, the nanocomposites show low systematic toxicity and high in vivo antitumor therapy efficacy. These findings highlight the fascinating features of upconversion‐mesoporous nanocomposites as multimodality imaging contrast agents and nanocarrier for drug molecules.     

Fluorescent silica nanoparticles improve optical imaging of stem cells allowing direct discrimination between live and early-stage apoptotic cells

Highly bright and photostable cyanine dye-doped silica nanoparticles, IRIS Dots, are developed, which can efficiently label human mesenchymal stem cells (hMSCs). The application procedure used to label hMSCs is fast (2 h), the concentration of IRIS Dots for efficient labeling is low (20 μg mL(-1) ), and the labeled cells can be visualized by flow cytometry, confocal microscopy, and transmission electron microscopy. Labeled hMSCs are unaffected in their viability and proliferation, as well as stemness surface marker expression and differentiation capability into osteocytes. Moreover, this is the first report that shows nonfunctionalized IRIS Dots can discriminate between live and early-stage apoptotic stem cells (both mesenchymal and embryonic) through a distinct external cell surface distribution. On the basis of biocompatibility, efficient labeling, and apoptotic discrimination potential, it is suggested that IRIS Dots can serve as a promising stem cell tracking agent.     

Preparation of magnetic mesoporous silica nanoparticles as a multifunctional platform for potential drug delivery and hyperthermia

We report the preparation of magnetic mesoporous silica (MMS) nanoparticles with the potential multifunctionality of drug delivery and magnetic hyperthermia. Carbon-encapsulated magnetic colloidal nanoparticles (MCN@C) were used to coat mesoporous silica shells for the formation of the core-shell structured MMS nanoparticles (MCN@C/mSiO₂), and the rattle-type structured MMS nanoparticles (MCN/mSiO₂) were obtained after the removal of the carbon layers from MCN@C/mSiO₂ nanoparticles. The morphology, structure, magnetic hyperthermia ability, drug release behavior, in vitro cytotoxicity and cellular uptake of MMS nanoparticles were investigated. The results revealed that the MCN@C/mSiO₂ and MCN/mSiO₂ nanoparticles had spherical morphology and average particle sizes of 390 and 320 nm, respectively. The MCN@C/mSiO₂ nanoparticles exhibited higher magnetic hyperthermia ability compared to the MCN/mSiO₂ nanoparticles, but the MCN/mSiO₂ nanoparticles had higher drug loading capacity. Both MCN@C/mSiO₂ and MCN/mSiO₂ nanoparticles had similar drug release behavior with pH-controlled release and temperature-accelerated release. Furthermore, the MCN@C/mSiO₂ and MCN/mSiO₂ nanoparticles showed low cytotoxicity and could be internalized into HeLa cells. Therefore, the MCN@C/mSiO₂ and MCN/mSiO₂ nanoparticles would be promising for the combination of drug delivery and magnetic hyperthermia treatment in cancer therapy.     

Ultrasmall Nanoplatforms as Calcium‐Responsive Contrast Agents for Magnetic Resonance Imaging

The preparation of ultrasmall and rigid platforms (USRPs) that are covalently coupled to macrocycle‐based, calcium‐responsive/smart contrast agents (SCAs), and the initial in vitro and in vivo validation of the resulting nanosized probes (SCA‐USRPs) by means of magnetic resonance imaging (MRI) is reported. The synthetic procedure is robust, allowing preparation of the SCA‐USRPs on a multigram scale. The resulting platforms display the desired MRI activity—i.e., longitudinal relaxivity increases almost twice at 7 T magnetic field strength upon saturation with Ca²⁺. Cell viability is probed with the MTT assay using HEK‐293 cells, which show good tolerance for lower contrast agent concentrations over longer periods of time. On intravenous administration of SCA‐USRPs in living mice, MRI studies indicate their rapid accumulation in the renal pelvis and parenchyma. Importantly, the MRI signal increases in both kidney compartments when CaCl₂ is also administrated. Laser‐induced breakdown spectroscopy experiments confirm accumulation of SCA‐USRPs in the renal cortex. To the best of our knowledge, these are the first studies which demonstrate calcium‐sensitive MRI signal changes in vivo. Continuing contrast agent and MRI protocol optimizations should lead to wider application of these responsive probes and development of superior functional methods for monitoring calcium‐dependent physiological and pathological processes in a dynamic manner.     

Mesoporous Silica as a Versatile Platform for Cancer Immunotherapy

Immunotherapy has been recognized for decades as a promising therapeutic method for cancer treatment. To enhance host immune responses against cancer, antigen‐presenting cells (APCs; e.g., dendritic cells) or T cells are educated using immunomodulatory agents including tumor‐associated antigens and adjuvants, and manipulated to induce a cascading adaptive immune response targeting tumor cells. Mesoporous silica materials are promising candidates to improve cancer immunotherapy based on their attractive properties that include high porosity, high biocompatibility, facile surface modification, and self‐adjuvanticity. Here, the recent progress on mesoporous‐silica‐based immunotherapies based on two material forms is summarized: 1) mesoporous silica nanoparticles (MSNs), which can be internalized into APCs, and 2) micrometer‐sized mesoporous silica rods (MSRs) that can form a 3D space to recruit APCs. Subcutaneously injected MSN‐based cancer vaccines can be taken up by peripheral APCs or by APCs in lymphoid organs to educate the immune system against cancer cells. MSR cancer vaccines can recruit immune cells into the MSR scaffold to induce cancer‐specific immunity. Both vaccine systems successfully stimulate the adaptive immune response to eradicate cancer in vivo. Thus, mesoporous silica has potential value as a material platform for the treatment of cancer or infectious diseases.     

Synthesis of biomolecule-modified mesoporous silica nanoparticles for targeted hydrophobic drug delivery to cancer cells

Synthetic methodologies integrating hydrophobic drug delivery and biomolecular targeting with mesoporous silica nanoparticles are described. Transferrin and cyclic-RGD peptides are covalently attached to the nanoparticles utilizing different techniques and provide selectivity between primary and metastatic cancer cells. The increase in cellular uptake of the targeted particles is examined using fluorescence microscopy and flow cytometry. Transferrin-modified silica nanoparticles display enhancement in particle uptake by Panc-1 cancer cells over that of normal HFF cells. The endocytotic pathway for these particles is further investigated through plasmid transfection of the transferrin receptor into the normal HFF cell line, which results in an increase in particle endocytosis as compared to unmodified HFF cells. By designing and attaching a synthetic cyclic-RGD, selectivity between primary cancer cells (BT-549) and metastatic cancer cells (MDA-MB 435) is achieved with enhanced particle uptake by the metastatic cancer cell line. Incorporation of the hydrophobic drug Camptothecin into these two types of biomolecular-targeted nanoparticles causes an increase in mortality of the targeted cancer cells compared to that caused by both the free drug and nontargeted particles. These results demonstrate successful biomolecular-targeted hydrophobic drug delivery carriers that selectively target specific cancer cells and result in enhanced drug delivery and cell mortality.     

肿瘤干细胞活体示踪的分子影像学研究进展

肿瘤干细胞(Cancer Stem Cell,CSCs)是肿瘤细胞中具有自我更新和多向分化能力的细胞,与肿瘤的发生、增殖、转移和耐药等生物学行为关系密切,CSCs的活体示踪对于实时监测CSCs在体内的生物学行为具有重要意义。目前常见CSCs活体示踪的分子影像学方法包括:超声成像、核磁共振成像(Magnetic Resonance Imaging,MRI)、光学成像、核医学成像(Positron Emission Tomography-Computed Tomography,PET-CT)、光声成像、多模态成像。这些成像方法的发展对于CSCs的研究具有重大意义,对于CSCs的研究有助于临床诊断及治疗,有利于诊疗一体化进程的发展。文章就CSCs活体示踪的分子影像学研究进展进行了综述。     

Multifunctional mesoporous silica nanospheres with cleavable Gd(III) chelates as MRI contrast agents: synthesis, characterization, target-specificity, and renal clearance

Mesoporous silica nanospheres (MSNs) are a promising material for magnetic resonance imaging (MRI) contrast agents. In this paper multifunctional MSNs with cleavable Gd(III) chelates are synthesized and characterized, and their applicability as MRI contrast agents is demonstrated both in vitro and in vivo. The MSNs contain Gd(III) chelates that are covalently linked via a redox-responsive disulfide moiety. The MSNs are further functionalized with polyethylene glycol (PEG) and an anisamide ligand to improve their biocompatibility and target specificity. The effectiveness of MSNs as an MRI imaging contrast agent and their targeting ability are successfully demonstrated in vitro using human colon adenocarcinoma and pancreatic cancer cells. Finally, the capability of this platform as an in vivo MRI contrast agent is tested using a 3T scanner. The Gd(III) chelate was quickly cleaved by the blood pool thiols and eliminated through the renal excretion pathway. Further tuning of the Gd(III) chelate release kinetics is needed before the MSN system can be used as target-specific MRI contrast agents in vivo.     

Luminescent Carbon Nanodots Doped with Gadolinium (III): Purification Criteria,Chemical and Biological Characterization of a New Dual Fluorescence/MR Imaging Agent

Carbon Dots (CDs) are luminescent quasi-spherical nanoparticles, possessing water solubility, high biocompatibility, and tunable chemical and physical properties for a wide range of applications, including nanomedicine and theranostics. The evaluation of new purification criteria, useful to achieve more reliable CDs, free from the interference of artifacts, is currently an object of debate in the field. Here, new CDs doped with gadolinium (Gd (III)), named Gd@CNDs, are presented as multifunctional probes for Magnetic Resonance Imaging (MRI). This new system is a case of study, to evaluate and/or combine different purification strategies, as a crucial approach to generate CDs with a better performance. Indeed, these new amorphous Gd@CNDs display good homogeneity, and they are free from emissive side products. Gd@CNDs (7–10 nm) contain 7% of Gd (III) w/w, display suitable and stable longitudinal relaxivity (r₁) and with emissive behavior, therefore potentially useful for both MR and fluorescence imaging. They show good biocompatibility in both cellular and in vivo studies, cell permeability, and the ability to generate contrast in cellular pellets. Finally, MRI recording T₁-weighted images on mice after intravenous injection of Gd@CNDs, show signal enhancement in the liver, spleen, and kidney 30 min postinjection.     

葡萄糖醛酸功能化双介孔硅对胆红素的高效吸附研究

胆红素是由衰老及异常红细胞被吞噬、血红蛋白分解代谢产生的一种生物活性物质。采用具有小孔径和较大孔径两种介孔孔道的双介孔硅作为基底材料,并用葡萄糖醛酸对双介孔硅进行功能化,以实现对胆红素的选择性吸附。研究了吸附时间、温度、初始浓度、血清蛋白、离子强度对胆红素吸附的影响。实验结果表明,葡萄糖醛酸化双介孔硅对胆红素的吸附快速、高效,吸附平衡为15 min,最大吸附量为(246.78.3)mg/g,血清蛋白的存在对胆红素吸附的影响不大。胆红素吸附符合二级吸附动力学模型和Langmuir等温吸附模型。     

Chitosan nanoparticles as a new delivery system for the chemotherapy agent tegafur

Background: Despite the very efficient antitumor activity of conventional chemotherapy, generally high doses of anticancer molecules must be administered to obtain the required therapeutic action, simultaneously leading to severe side effects. This is frequently a consequence of the development of multidrug resistance by cancer cells and of the poor pharmacokinetic profile of these agents. Objective: In Order to improve the antitumor effect of tegafur and overcome their important drawbacks, we have investigated its incorporation into a drug nanoplatform based on the biodegradable polymer chitosan. Materials and Methods: Two tegafur loading methods were studied: (i) absorption into the polymeric network (entrapment procedure); and (ii) surface deposition (adsorption procedure) in already formed chitosan nanoparticles. Results: Tegafur entrapment into the polymeric matrix has yielded higher drug loading values and a slower drug release profile, compared to single surface adsorption. The main factores determining the drug loading to chitosan were identified. Discussion and Conclusion: Such polymeric colloid present very interesting properties for efficient tegafur delivery to cancer.     

Tailor-made pH-sensitive polyacrylic acid functionalized mesoporous silica nanoparticles for efficient and controlled delivery of anti-cancer drug Etoposide

A multifaceted therapeutic platform has been proposed for controlled delivery of Etoposide (ETS) leading to a synergistic advantage of maximum therapeutic efficacy and diminished toxicity. A state of the art pH responsive nanoparticles (NPs) MSNs-PAA consisting of mesoporous silica nanoparticles core and polymeric shell layers, were developed for controlled release of model anti-cancer drug ETS. Graft onto strategy was employed and amination served as an interim step, laying a vital foundation for functionalization of the MSN core with hydrophilic and pH responsive polyacrylic acid (PAA). MCM-41-PAA were investigated as carriers for loading and regulated release of ETS at different pH for the first time. The PAA-MSNs contained 20.19% grafted PAA as exhibited by thermogravimetric analysis (TGA), which enormously improved the solubility of ETS in aqueous media. The synthesized PAA-MSNs were characterized by various techniques viz, SEM-EDS, TEM, BET, FT-IR and powder XRD. ETS was effectively loaded into the channels of PAA-MSN via electrostatic interactions. The cumulative release was much rapid at extracellular tumor (6.8) and endosomal pH (5.5) than that of blood pH (7.4). Hemolysis study was done for the prepared NPs. MTT assay results showed that the drug-loaded ETS-MCM-41-PAA NPs were more cytotoxic to both prostate cancer cells namely PC-3 and LNCaP than free ETS, which was attributed to their slow and sustained release behavior. The above results confirmed that PAA-MSN hold a great potential as pH responsive carriers with promising future in the field of cancer therapy.