RESUMEN
Mesoporous silica nanoparticles (MSNs) represent a promising avenue for targeted brain tumor therapy. However, the blood-brain barrier (BBB) often presents a formidable obstacle to efficient drug delivery. This study introduces a ligand-free PEGylated MSN variant (RMSN25-PEG-TA) with a 25 nm size and a slight positive charge, which exhibits superior BBB penetration. Utilizing two-photon imaging, RMSN25-PEG-TA particles remained in circulation for over 24 h, indicating significant traversal beyond the cerebrovascular realm. Importantly, DOX@RMSN25-PEG-TA, our MSN loaded with doxorubicin (DOX), harnessed the enhanced permeability and retention (EPR) effect to achieve a 6-fold increase in brain accumulation compared to free DOX. In vivo evaluations confirmed the potent inhibition of orthotopic glioma growth by DOX@RMSN25-PEG-TA, extending survival rates in spontaneous brain tumor models by over 28% and offering an improved biosafety profile. Advanced LC-MS/MS investigations unveiled a distinctive protein corona surrounding RMSN25-PEG-TA, suggesting proteins such as apolipoprotein E and albumin could play pivotal roles in enabling its BBB penetration. Our results underscore the potential of ligand-free MSNs in treating brain tumors, which supports the development of future drug-nanoparticle design paradigms.
Asunto(s)
Barrera Hematoencefálica , Doxorrubicina , Portadores de Fármacos , Nanopartículas , Dióxido de Silicio , Animales , Humanos , Ratones , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/administración & dosificación , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Doxorrubicina/farmacología , Doxorrubicina/química , Portadores de Fármacos/química , Glioma/tratamiento farmacológico , Glioma/metabolismo , Glioma/patología , Ligandos , Nanopartículas/química , Tamaño de la Partícula , Polietilenglicoles/química , Porosidad , Dióxido de Silicio/químicaRESUMEN
The advent of Nanotechnology has paved a way for improved disease treatment strategies, the most noteworthy being the mesoporous silica nanoparticles (MSNs) which have gained much recent attention in the field of cancer therapy and its diagnosis. The flaws of the current-day strategies can be overcome by this superior technology through its targeting ability in delivering drugs and image able agents specifically to the tumor sites. MSNs have unique biocompatibility features, its high surface area which contributes in large amount of drug loading and its facility to monitor size and shape of the nanoparticles are few of the positives which makes this technology an enormous asset for the field of Nanotechnology. This review paper is structured in such a way wherein we initially have discussed about the synthesis methods and various functionalization approaches for MSN followed by the different methods used for targeting cancer cells and the latest advances in controlled drug release. Some of the highlights of this review are the biocompatibility of MSNs, in vivo results of MSNs on cancer therapy. This review paper also shortly discuss about combined cancer therapies to overcome the challenges in current-day cancer treatment. Finally, we converge briefly on the recent advancements in the use of hybrid MSNs for obtaining multiple functions.
Asunto(s)
Materiales Biocompatibles , Nanopartículas , Neoplasias/diagnóstico , Neoplasias/terapia , Dióxido de Silicio , Portadores de Fármacos , Quimioterapia Combinada , HumanosRESUMEN
The effect of the intracellular pH of macrophages after taking up biodegradable polymer nanoparticles (NPs) on immunomodulating functions has not been explored so far. Previous studies have demonstrated that biodegradable polyurethane (PU) NPs exhibit immunosuppressive activity. Yet, the intracellular mechanism is not clearly understood. In this study, a uniquely designed pH nanosensor is employed for tracking the intracellular pH value of macrophages to reveal the intracellular journey of PU NPs and to clarify the intracellular pH effect on the corresponding inflammatory response. First, fluorescent mesoporous silica nanoparticles (FRMSNs) is used to detect the pH change in macrophages after endo/phagocytosis of PU NPs. Second, PU is coated on the external surface of FRMSNs to examine the intracellular trafficking process of PU in the macrophages. The results show that the majority of PU-coated FRMSNs remain to stay at the cytosol-early endosome/phagosome regions. The intracellular pH value and other supporting results show that the immune response of PU NPs may be correlated to their internalization journey. The retardation in the degradation process of the PU NPs may intervene with the lysosome activity and repress the immunostimulatory effect, which contributes to the low immune response of PU NPs.
Asunto(s)
Nanopartículas , Poliuretanos , Humanos , Concentración de Iones de Hidrógeno , Inflamación , Macrófagos , FagosomasRESUMEN
BACKGROUND: Application of superparamagnetic iron oxide nanoparticles (SPIOs) as the contrast agent has improved the quality of magnetic resonance (MR) imaging. Low efficiency of loading the commercially available iron oxide nanoparticles into cells and the cytotoxicity of previously formulated complexes limit their usage as the image probe. Here, we formulated new cationic lipid nanoparticles containing SPIOs feasible for in vivo imaging. METHODS: Hydrophobic SPIOs were incorporated into cationic lipid 1,2-dioleoyl-3-(trimethylammonium) propane (DOTAP) and polyethylene-glycol-2000-1,2-distearyl-3-sn-phosphatidylethanolamine (PEG-DSPE) based micelles by self-assembly procedure to form lipid-coated SPIOs (L-SPIOs). Trace amount of Rhodamine-dioleoyl-phosphatidylethanolamine (Rhodamine-DOPE) was added as a fluorescent indicator. Particle size and zeta potential of L-SPIOs were determined by Dynamic Light Scattering (DLS) and Laser Doppler Velocimetry (LDV), respectively. HeLa, PC-3 and Neuro-2a cells were tested for loading efficiency and cytotoxicity of L-SPIOs using fluorescent microscopy, Prussian blue staining and flow cytometry. L-SPIO-loaded CT-26 cells were tested for in vivo MR imaging. RESULTS: The novel formulation generates L-SPIOs particle with the average size of 46 nm. We showed efficient cellular uptake of these L-SPIOs with cationic surface charge into HeLa, PC-3 and Neuro-2a cells. The L-SPIO-loaded cells exhibited similar growth potential as compared to unloaded cells, and could be sorted by a magnet stand over ten-day duration. Furthermore, when SPIO-loaded CT-26 tumor cells were injected into Balb/c mice, the growth status of these tumor cells could be monitored using optical and MR images. CONCLUSION: We have developed a novel cationic lipid-based nanoparticle of SPIOs with high loading efficiency, low cytotoxicity and long-term imaging signals. The results suggested these newly formulated non-toxic lipid-coated magnetic nanoparticles as a versatile image probe for cell tracking.
Asunto(s)
Medios de Contraste , Ácidos Grasos Monoinsaturados , Compuestos Férricos , Imagen por Resonancia Magnética , Nanopartículas del Metal , Fosfatidiletanolaminas , Polietilenglicoles , Compuestos de Amonio Cuaternario , Adenocarcinoma/patología , Animales , Cationes , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral/efectos de los fármacos , Línea Celular Tumoral/trasplante , Neoplasias Colorrectales/patología , Medios de Contraste/síntesis química , Estudios de Factibilidad , Compuestos Férricos/toxicidad , Células HeLa/efectos de los fármacos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Masculino , Nanopartículas del Metal/toxicidad , Ratones , Ratones Endogámicos BALB C , Micelas , Neuroblastoma/patología , Tamaño de la Partícula , Neoplasias de la Próstata/patología , RodaminasRESUMEN
Mesoporous silica nanoparticles (MSNs) hold great potential as a versatile platform for biomedical applications, especially drug delivery. However, evidence shows that MSNs even when PEGylated are rapidly cleared from the bloodstream by the monocyte phagocytic system. Erythrocytes, also called red blood cells (RBCs), can serve as biocompatible carriers of various bioactive substances, including drugs, enzymes, and peptides. In this work, we synthesize a series of fluorescent PEGylated MSNs with different synthetic diameters ranging from 10 to 200 nm and investigate the size effect on their encapsulation in human RBCs (hRBCs) by a hypotonic dialysis-based method. According to fluorescence images and flow cytometry analyses, we demonstrated that a hydrodynamic diameter below 30 nm is critical for efficient MSN encapsulation. Confocal microscopy and scanning electron microscopy images further confirmed that PEGylated MSNs were successfully embedded inside RBC. PEGylation serves an important role not only for stabilizing MSNs in biological milieu but also for reducing significant hemolysis caused by bare MSNs and thus for successful encapsulation. In addition to PEGylation, we further introduce positively charged functional groups onto the MSNs to show that nanoparticle-encapsulated hRBCs could serve as depots for delivering biological molecules through electrostatic attraction or chemical conjugation with MSNs. Also, we verify the existence of CD47 membrane protein, a marker of self, on the nanoparticle-encapsulated hRBCs and assess its ability of circulation in the blood, which could act as a circulation reservoir for delivering pharmacological substances through an osmosis-based method with MSNs.
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Sistemas de Liberación de Medicamentos/métodos , Eritrocitos/metabolismo , Nanopartículas/química , Dióxido de Silicio/química , Animales , Antígeno CD47/sangre , Antígeno CD47/metabolismo , Eritrocitos/química , Colorantes Fluorescentes/química , Colorantes Fluorescentes/farmacocinética , Hemólisis/efectos de los fármacos , Humanos , Ratones , Ratones SCID , Microscopía Confocal , Nanopartículas/toxicidad , Polietilenglicoles/química , Dióxido de Silicio/farmacocinéticaRESUMEN
The biocompatibility of nanoparticles is the prerequisite for their applications in biomedicine but can be misleading due to the absence of criteria for evaluating the safety and toxicity of those nanomaterials. Recent studies indicate that mesoporous silica nanoparticles (MSNs) can easily internalize into human mesenchymal stem cells (hMSCs) without apparent deleterious effects on cellular growth or differentiation, and hence are emerging as an ideal stem cell labeling agent. The objective of this study was to thoroughly investigate the effect of MSNs on osteogenesis induction and to examine their biocompatibility in hMSCs. Uptake of MSNs into hMSCs did not affect the cell viability, proliferation and regular osteogenic differentiation of the cells. However, the internalization of MSNs indeed induced actin polymerization and activated the small GTP-bound protein RhoA. The MSN-induced cellular protein responses as believed to cause osteogenesis of hMSCs did not result in promotion of regular osteogenic differentiation as analyzed by cytochemical stain and protein activity assay of alkaline phosphatase (ALP). When the effect of MSNs on ALP gene expression was further examined by reverse transcriptase polymerase chain reaction, MSN-treated hMSCs were shown to have significantly higher mRNA expression than control cells after 1-hour osteogenic induction. The induction of ALP gene expression by MSNs, however, was absent in cells after 1-day incubation with osteogenic differentiation. Together our results show that the internalization of MSNs had a significant effect on the transient protein response and osteogenic signal in hMSCs, thereby suggesting that the effects of nanoparticles on diverse aspects of cellular activities should be carefully evaluated even though the nanoparticles are generally considered as biocompatible at present.
Asunto(s)
Materiales Biocompatibles/metabolismo , Células Madre Mesenquimatosas/metabolismo , Nanopartículas , Osteogénesis , Dióxido de Silicio/metabolismo , Actinas/metabolismo , Fosfatasa Alcalina/metabolismo , Diferenciación Celular , Supervivencia Celular , Células Cultivadas , Citoesqueleto/metabolismo , Expresión Génica , Humanos , ARN Mensajero/metabolismo , Transducción de Señal , Proteína de Unión al GTP rhoA/metabolismoRESUMEN
OBJECTIVES: Whole blood or tea was frequently used to stain the teeth for measuring the effectiveness of different bleaching materials. However, the components of blood or tea cannot be quantitatively determined and variability might exist among different brands of tea. The purpose of this study was to develop a reproducible in vitro tooth-staining model to simulate the intrinsic discoloration of teeth and evaluate the ability of two catalysts to enhance the bleaching activity of H(2)O(2). METHODS: Rhodamine B, Orange II, Fe(III) phthalocyanine, and tea were used to stain the tooth specimens for 4-72 h and subsequently bleached by H(2)O(2) for 4-72 h. The process was photographed using a digital stereoscopic microscope and a digital camera. The image was transformed to get L*, a*, b* values of CIE Lab system with image processing software. The catalytic ability of light irradiation plus addition of Fe/Sodium-Y or Mn/Sodium-Y for specimens stained by Orange II was evaluated in test tubes and in extracted tooth model. RESULTS: The color of specimens stained by Rhodamine B could not be sufficiently recovered after bleaching by H(2)O(2). In addition, the reaction of Fe(III) phthalocyanine with H(2)O(2) in test tubes was too fast to be monitored. Light activation plus use of Fe/Sodium-Y or Mn/Sodium-Y could significantly accelerate the bleaching efficiency of H(2)O(2). SIGNIFICANCE: Orange II was the most appropriate dye for tooth staining among the dyes used in this study. Addition of Fe/Sodium-Y or Mn/Sodium-Y plus light irradiation could elevate the bleaching efficacy of H(2)O(2) for those specimens stained by Orange II.
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Colorantes , Coloración y Etiquetado/métodos , Blanqueamiento de Dientes/métodos , Decoloración de Dientes , Análisis de Varianza , Compuestos Azo , Bencenosulfonatos , Compuestos Ferrosos , Humanos , Peróxido de Hidrógeno , Indoles , Hierro/química , Manganeso/química , Modelos Químicos , Oxidantes , Reproducibilidad de los Resultados , Rodaminas , TéRESUMEN
Tracking the distribution of stem cells is crucial to their therapeutic use. However, the usage of current vectors in cellular labeling is restricted by their low internalizing efficiency. Here, we reported a cellular labeling approach with a novel vector composed of mesoporous silica nanoparticles (MSNs) conjugated with fluorescein isothiocyanate in human bone marrow mesenchymal stem cells and 3T3-L1 cells, and the mechanism about fluorescein isothiocyanate-conjugated MSNs (FITC-MSNs) internalization was studied. FITC-MSNs were efficiently internalized into mesenchymal stem cells and 3T3-L1 cells even in short-term incubation. The process displayed a time- and concentration-dependent manner and was dependent on clathrin-mediated endocytosis. In addition, clathrin-dependent endocytosis seemed to play a decisive role on more internalization and longer stay of FITC-MSNs in mesenchymal stem cells than in 3T3-L1 cells. The internalization of FITC-MSNs did not affect the cell viability, proliferation, immunophenotype, and differentiation potential of mesenchymal stem cells, and 3T3-L1 cells. Finally, FITC-MSNs could escape from endolysosomal vesicles and were retained the architectonic integrity after internalization. We conclude that the advantages of biocompatibility, durability, and higher efficiency in internalization suit MSNs to be a better vector for stem cell tracking than others currently used.
Asunto(s)
Mesodermo/citología , Nanoestructuras , Células Madre/citología , Células 3T3-L1 , Animales , Materiales Biocompatibles/química , Células de la Médula Ósea/citología , Diferenciación Celular , Núcleo Celular/metabolismo , Proliferación Celular , Supervivencia Celular , Clatrina/química , Relación Dosis-Respuesta a Droga , Endocitosis , Fluoresceína-5-Isotiocianato/farmacología , Humanos , Inmunofenotipificación , Lisosomas/metabolismo , Ratones , Microscopía Confocal , Microscopía Fluorescente , Modelos Biológicos , Factores de TiempoRESUMEN
Au-Ag alloy nanoparticles supported on mesoporous aluminosilicate have been prepared by one-pot synthesis using hexadecyltrimethylammonium bromide (CTAB) both as a stabilizing agent for nanoparticles and as a template for the formation of mesoporous structure. The formation of Au-Ag alloy nanoparticles was confirmed by X-ray diffraction (XRD), ultraviolet-visible (UV-vis) spectroscopy, and transmission electron microscopy (TEM). Although the Au-Ag alloy nanoparticles have a larger particle size than the monometallic gold particles, they exhibited exceptionally high activity in catalysis for low-temperature CO oxidation. Even at a low temperature of 250 K, the reaction rate can reach 8.7 x 10(-6) mol.g(cat.)(-1).s(-1) at an Au/Ag molar ratio of 3/1. While neither monometallic Au@MCM-41 nor Ag@MCM-41 shows activity at this temperature, the Au-Ag alloy system shows a strongly synergistic effect in high catalytic activity. In this alloy system, the size effect is no longer a critical factor, whereas Ag is believed to play a key role in the activation of oxygen.
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Aleaciones/química , Monóxido de Carbono/química , Oro/química , Nanopartículas del Metal/química , Plata/química , Silicatos de Aluminio/síntesis química , Silicatos de Aluminio/química , Catálisis , Cetrimonio , Compuestos de Cetrimonio/química , Oxidación-Reducción , Tamaño de la Partícula , Porosidad , Propiedades de Superficie , Temperatura , Factores de TiempoRESUMEN
Induced pluripotent stem cells (iPSCs) have promising potential in regenerative medicine, but whether iPSCs can promote corneal reconstruction remains undetermined. In this study, we successfully reprogrammed human corneal keratocytes into iPSCs. To prevent feeder cell contamination, these iPSCs were cultured onto a serum- and feeder-free system in which they remained stable through 30 passages and showed ESC-like pluripotent property. To investigate the availability of iPSCs as bioengineered substitutes in corneal repair, we developed a thermo-gelling injectable amphiphatic carboxymethyl-hexanoyl chitosan (CHC) nanoscale hydrogel and found that such gel increased the viability and CD44+proportion of iPSCs, and maintained their stem-cell like gene expression, in the presence of culture media. Combined treatment of iPSC with CHC hydrogel (iPSC/CHC hydrogel) facilitated wound healing in surgical abrasion-injured corneas. In severe corneal damage induced by alkaline, iPSC/CHC hydrogel enhanced corneal reconstruction by downregulating oxidative stress and recruiting endogenous epithelial cells to restore corneal epithelial thickness. Therefore, we demonstrated that these human keratocyte-reprogrammed iPSCs, when combined with CHC hydrogel, can be used as a rapid delivery system to efficiently enhance corneal wound healing. In addition, iPSCs reprogrammed from corneal surgical residues may serve as an alternative cell source for personalized therapies for human corneal damage.
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Quitosano/análogos & derivados , Córnea/efectos de los fármacos , Córnea/patología , Queratocitos de la Córnea/citología , Hidrogel de Polietilenoglicol-Dimetacrilato/uso terapéutico , Células Madre Pluripotentes Inducidas/trasplante , Cicatrización de Heridas/efectos de los fármacos , Animales , Células Cultivadas , Reprogramación Celular , Quitosano/uso terapéutico , Córnea/citología , Humanos , Células Madre Pluripotentes Inducidas/citología , Estrés Oxidativo/efectos de los fármacos , RatasRESUMEN
A novel magnetic resonance (MR) angiographic method, 3DΔR2-mMRA (three dimensional and ΔR2 based microscopy magnetic resonance angiography), is developed as a clinical diagnosis for depicting the function and structure of cerebral small vessels. However, the visibility of microvasculatures and the precision of cerebral blood volume calculation greatly rely on the transverse relaxivity and intravascular half-life of contrast agent, respectively. In this work, we report a blood pool contrast agent named H-Fe3O4@SiO2-PEG where multiple Fe3O4 nanocrystals are encapsulated in a thin silica shell to enhance the T2-relaxivity (r2 = 342.8 mM⻹ s⻹) and poly(ethylene glycol) (PEG) is employed to reduce opsonization and prolong circulation time of nanoparticles. Utilization of the newly developed H-Fe3O4@SiO2-PEG with a novel MR angiographic methodology, a high-resolution MR image of rat cerebral microvasculatures is successfully obtained.
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Óxido Ferrosoférrico/química , Angiografía por Resonancia Magnética/instrumentación , Angiografía por Resonancia Magnética/métodos , Nanopartículas/química , Polietilenglicoles/química , Dióxido de Silicio/química , Animales , Circulación Cerebrovascular , Dextranos/química , Células HeLa , Humanos , Nanopartículas de Magnetita/química , Ensayo de Materiales , Ratones , Microvasos/ultraestructura , RatasRESUMEN
We present a simple experimental method to extract the van Vleck second moment of a multiple-spin system under high-resolution condition. The idea is to incorporate a double-quantum (DQ) filter into the pulse sequence of heteronuclear correlation spectroscopy so that a DQ excitation profile can be obtained by measuring a series of 2D spectra. The effects of spinning frequency and proton decoupling are demonstrated on the measurements of two model compounds, viz. hydroxyapatite and brushite. Based on the results obtained for the model compounds, the P-31 homonuclear second moment of the apatite component in rat dentin is characterized. The method is generally suited for the study of bone, enamel and dentin.
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Dentina/química , Durapatita/química , Incisivo/química , Modelos Biológicos , Modelos Químicos , Resonancia Magnética Nuclear Biomolecular/métodos , Animales , Simulación por Computador , Técnicas In Vitro , Ratas , Ratas Wistar , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Marcadores de SpinRESUMEN
For many years, octacalcium phosphate (OCP) has been postulated as the precursor phase of biological apatite in bones and teeth. In this work, we study the molecular mechanism of OCP to hydroxyapatite (HAp) transformation in vitro by several physical techniques, with particular emphasis on solid-state (31)P homonuclear double-quantum (DQ) NMR spectroscopy. The in vitro system is prepared by mixing urea, sodium phosphate monobasic dehydrate, and calcium nitrate tetrahydrate at 100 degrees C. The images obtained by scanning electron microscopy and transmission electron microscopy show that the bladelike OCP crystals will transform into hexagonal rod-shaped HAp crystals as the pH of the reaction mixture increases slowly from 4.35 to 6.69 in 12 h. Powder X-ray diffraction patterns indicate that a trace amount of monetite was also precipitated when the pH was around 5. Together with computer-assisted lattice matching, our DQ NMR data reveal that OCP crystals transform to HAp topotaxially, where the [000](HAp) and [20](HAp) axes are along the same directions as the [001](OCP) and [010](OCP) axes, respectively. On the basis of our in vitro results, the formation of the central dark line commonly found in biological hard tissues could be explained by the inherent lattice mismatch between OCP and HAp. Furthermore, the data of the (31)P{(1)H} cross-polarization NMR suggest that water molecules enter the hydration layers of OCP crystals via the hydrolysis reaction HPO(4)(2)(-) + OH(-) = PO(4)(3)(-) + H(2)O, which also accounts for the deprotonation of the HPO(4)(2)(-) ions during the transformation.