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1.
An Acad Bras Cienc ; 92(1): e20181120, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32321020

RESUMO

the focus ofthis study was to testthe hypothesisthatthere would be no difference betweenthe biocompatibility of silicon dioxide nanofilms used as antimicrobial agents. Sixty male Wistar rats were divided into 4 groups (n=15): Group C (Control,Polyethylene), Group AR (Acrylic Resin), Group NP (Acrylic Resin coated with NP-Liquid), Group BG (Acrylic Resin coated with Bacterlon).the animals were sacrificed with 7,15 and 30 days and tissues analyzed as regardsthe events of inflammatory infiltrate, edema, necrosis, granulation tissue, mutinucleated giant cells, fibroblasts and collagen. Kruskal-Wallis and Dunn tests was used (P<0.05). Intense inflammatory infiltrate was shown mainly in Groups BG and AR, with significant difference from Control Group inthe time interval of 7days (P=0.004). Necrosis demonstrated significant difference between Group BG and Control Group (P<0.05) inthe time intervals of 7 days. For collagen fibers,there was significant difference betweenthe Control Group and Groups AR and BG inthe time interval of 7 days (P=0.006), and between BG and Control Groups inthe time intervals of 15 days (P=0.010).the hypothesis was rejected. Bacterlon demonstratedthe lowest level, and NP-Liquid Glassthe highest level of tissue compatibility, and best cell repair.the coating with NP-Liquid Glass was demonstrated to be highly promising for clinical use.


Assuntos
Resinas Acrílicas/farmacologia , Materiais Biocompatíveis/farmacologia , Edema/induzido quimicamente , Necrose/induzido quimicamente , Dióxido de Silício/farmacologia , Tela Subcutânea/patologia , Resinas Acrílicas/química , Animais , Materiais Biocompatíveis/química , Edema/patologia , Masculino , Teste de Materiais , Modelos Animais , Necrose/patologia , Ratos , Ratos Wistar , Dióxido de Silício/química , Tela Subcutânea/efeitos dos fármacos
2.
Chem Biol Interact ; 319: 109024, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32097614

RESUMO

Silicosis is an occupational pulmonary fibrosis that is caused by inhalation of silica (SiO2), and there are no effective drugs to treat this disease. Tanshinone IIA (Tan IIA), a natural product, has been reported to possess antioxidant and anti-fibrotic properties in various diseases. The purpose of the current study was to examine Tan IIA's protective effects against silica-induced pulmonary fibrosis and to explore the underlying mechanisms. We found that in vivo treatment with Tan IIA significantly relieved silica-induced lung fibrosis in a silicosis rat model by histological and immunohistochemical analyses. Further, in vitro mechanistic investigations, mainly using western blot and immunofluorescence analyses, revealed that Tan IIA administration markedly inhibited the silica-induced epithelial-mesenchymal transition (EMT) and transforming growth factor-ß1 (TGF-ß1)/Smad signaling pathway and also reduced silica-induced oxidative stress and activated the nuclear factor erythroid 2-related factor-2 (Nrf2) signaling pathway in A549 and human bronchial epithelial (HBE) cells. Furthermore, through transfection with siRNA, we demonstrate that Nrf2 activation partially mediates the suppression effects of Tan IIA on EMT and TGF-ß1/Smad signaling pathway activation induced by silica exposure, thus mediating the anti-fibrotic effects of Tan IIA against silica-induced pulmonary fibrosis. In our study, Tan IIA has been identified as a possible anti-oxidative and anti-fibrotic drug for silicosis.


Assuntos
Abietanos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Células A549 , Animais , Antioxidantes/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Ratos , Ratos Sprague-Dawley , Dióxido de Silício/farmacologia
3.
Ecotoxicol Environ Saf ; 192: 110253, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32059163

RESUMO

Silica particles can cause a systemic disease in workers termed lung silicosis, characterized by diffuse fibrosis. The development of lung silicosis involves various signaling pathway networks comprising numerous cell types and cytokines. As an important medium for communication between cells, exosomes have emerged as a hot research topic; however, the role of exosomal microRNAs (miRNAs) in silicosis remains unclear. In this study, we conducted high-throughput sequencing to generate exosomal miRNAs profiles from macrophages that were either exposed to silica or not. A total of 298 miRNAs were differentially expressed, with 155 up-regulated and 143 down-regulated. Highly conserved differentially expressed miRNAs were functionally annotated and analyzed to predict target genes. Among target interactions associated with the TGF-ß signaling pathway, miR-125a-5p and its putative target gene, Smurf1, were subjected to further research. As expected, levels of miR-125a-5p were upregulated in human serous exosomes and vitro, and inhibit the exosomal miR-125a-5p suppressed the expression of the fibrosis hallmarks. Besides, high levels of the miRNA led to upregulation of smooth muscle actin alpha and repression of Smurf1 in NIH-3T3 and MRC-5 cells. ID1 and SMAD1, downstream of TGF-ß signaling, were upregulated, indicating potential activation of this signaling pathway. These results contribute to understanding of the intercellular communication mediated by exosomal miRNAs and its critical role in fibroblast to myofibroblast transition and silicosis.


Assuntos
Transdiferenciação Celular/efeitos dos fármacos , Poluentes Ambientais/farmacologia , Exossomos/genética , Fibroblastos/metabolismo , Macrófagos/efeitos dos fármacos , MicroRNAs/metabolismo , Dióxido de Silício/farmacologia , Animais , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Macrófagos/metabolismo , Camundongos , Células NIH 3T3 , Análise de Sequência de RNA , Transdução de Sinais/fisiologia , Ubiquitina-Proteína Ligases , Regulação para Cima
4.
Chem Biol Interact ; 315: 108900, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31738905

RESUMO

Synthetic amorphous silica nanoparticles (SAS) are used widely in industrial applications. These nanoparticles are not classified for their carcinogenicity in humans. However, some data still demonstrate a potential carcinogenic risk of these compounds in humans. The Bhas 42 cell line was developed to screen chemicals, as tumor-initiators or -promoters according to their ability to trigger cell-to-cell transformation, in a cell transformation assay. In the present study, we performed unsupervised transcriptomic analysis after exposure of Bhas 42 cells to NM-203 SAS as well as to positive (Min-U-Sil 5® crystalline silica microparticles, and 12-O-tetradecanoylphorbol-13-acetate) and negative (diatomaceous earth) control compounds. We identified a common gene signature for 21 genes involved in the early stage of the SAS- Min-U-Sil 5®- or TPA-induced cell transformation. These genes were related to cell proliferation (over expression) and cell adhesion (under expression). Among them, 12 were selected on the basis of their potential impact on cell transformation. RT-qPCR and western blotting were used to confirm the transcriptomic data. Moreover, similar gene alterations were found when Bhas 42 cells were treated with two other transforming SAS. In conclusion, the results obtained in the current study highlight a 12-gene signature that could be considered as a potential early "bio-marker" of cell transformation induced by SAS and perhaps other chemicals.


Assuntos
Transformação Celular Neoplásica/efeitos dos fármacos , Nanopartículas/administração & dosagem , Dióxido de Silício/farmacologia , Transcriptoma/efeitos dos fármacos , Animais , Biomarcadores Tumorais/genética , Adesão Celular/efeitos dos fármacos , Adesão Celular/genética , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Camundongos , Transcriptoma/genética
5.
Proc Natl Acad Sci U S A ; 117(1): 285-291, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31871161

RESUMO

The impact of ultrasmall nanoparticles (<10-nm diameter) on the immune system is poorly understood. Recently, ultrasmall silica nanoparticles (USSN), which have gained increasing attention for therapeutic applications, were shown to stimulate T lymphocytes directly and at relatively low-exposure doses. Delineating underlying mechanisms and associated cell signaling will hasten therapeutic translation and is reported herein. Using competitive binding assays and molecular modeling, we established that the T cell receptor (TCR):CD3 complex is required for USSN-induced T cell activation, and that direct receptor complex-particle interactions are permitted both sterically and electrostatically. Activation is not limited to αß TCR-bearing T cells since those with γδ TCR showed similar responses, implying that USSN mediate their effect by binding to extracellular domains of the flanking CD3 regions of the TCR complex. We confirmed that USSN initiated the signaling pathway immediately downstream of the TCR with rapid phosphorylation of both ζ-chain-associated protein 70 and linker for activation of T cells protein. However, T cell proliferation or IL-2 secretion were only triggered by USSN when costimulatory anti-CD28 or phorbate esters were present, demonstrating that the specific impact of USSN is in initiation of the primary, nuclear factor of activated T cells-pathway signaling from the TCR complex. Hence, we have established that USSN are partial agonists for the TCR complex because of induction of the primary T cell activation signal. Their ability to bind the TCR complex rapidly, and then to dissolve into benign orthosilicic acid, makes them an appealing option for therapies targeted at transient TCR:CD3 receptor binding.


Assuntos
Ativação Linfocitária/efeitos dos fármacos , Nanopartículas/química , Complexo Receptor-CD3 de Antígeno de Linfócitos T/efeitos dos fármacos , Complexo Receptor-CD3 de Antígeno de Linfócitos T/metabolismo , Dióxido de Silício/química , Dióxido de Silício/farmacologia , Antígenos CD28/metabolismo , Complexo CD3/química , Complexo CD3/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Interleucina-2/metabolismo , Modelos Moleculares , Fosforilação , Complexo Receptor-CD3 de Antígeno de Linfócitos T/química , Complexo Receptor-CD3 de Antígeno de Linfócitos T/genética , Transdução de Sinais/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo
6.
Nanoscale ; 11(39): 18031-18036, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31570915

RESUMO

A theranostic nanosystem based on indocyanine green (ICG) covalently conjugated to mesoporous silica nanoparticles (MSNs) loaded with the anticancer drug mitoxantrone (MTX) is proposed as an innovative photoacoustic probe. Taking advantage of the characteristic PA signal displayed by both ICG and MTX, a PA-ratiometric approach was applied to assess the drug release profile from the MSNs. After complete in vitro characterization of the nanoprobe, a proof-of-concept study has been carried out in tumour-bearing mice to evaluate in vivo its effectiveness for cancer imaging and chemotherapeutic agent delivery.


Assuntos
Antineoplásicos , Meios de Contraste , Mitoxantrona , Nanopartículas , Neoplasias Experimentais , Técnicas Fotoacústicas , Fototerapia , Dióxido de Silício , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Meios de Contraste/química , Meios de Contraste/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacologia , Humanos , Verde de Indocianina/química , Verde de Indocianina/farmacologia , Camundongos , Mitoxantrona/química , Mitoxantrona/farmacologia , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Dióxido de Silício/química , Dióxido de Silício/farmacologia , Nanomedicina Teranóstica
7.
Mater Sci Eng C Mater Biol Appl ; 105: 110103, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31546357

RESUMO

Synergistic therapy of chemotherapy and photothermal therapy exhibits great potential to improve the therapeutic efficiency for cancer therapy. In this study, a new biocompatible multiple sensitive drug delivery system (DDS) was synthesized by covering a polydopamine (PDA) layer on doxorubicin (DOX)-loaded mesoporous silica nanoparticle (MSN) via disulfide bonds (MSN-SS-PDA/DOX). PDA worked as a photothermal therapy (PTT) agent and also a gate keeper to control drug release, which was highly sensitive to pH and could prolong the residence time, simultaneously increase water solubility and biocompatibility of the nanoparticles. The DDS exhibited excellent monodispersity, redox/pH/NIR-multi-dependent release characteristics, remarkable photothermal conversion property (photothermal conversion efficiency η = 40.21%) and outstanding tumor cell synergistic killing efficiency of chemotherapy and photothermal therapy (combination index CI = 0.175). The biodistribution and pharmacodynamics experiments of MSN-SS-PDA/DOX in 4T1 tumor models indicated that MSN-SS-PDA made more DOX accumulate in tumor tissue than free DOX, extend circulation time of DOX in the body, and exhibit a significant synergistic antitumor efficacy. Meanwhile, the tumor growth was remarkably inhibited, which was much more obvious than any monotherapy effect. Thus, the novel nanoplatform presents a promising future as a drug delivery system for combination therapy.


Assuntos
Materiais Revestidos Biocompatíveis , Doxorrubicina , Sistemas de Liberação de Medicamentos , Hipertermia Induzida , Indóis , Nanopartículas , Neoplasias/terapia , Fototerapia , Polímeros , Dióxido de Silício , Animais , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Feminino , Humanos , Indóis/química , Indóis/farmacologia , Masculino , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias/metabolismo , Neoplasias/patologia , Polímeros/química , Polímeros/farmacologia , Ratos , Ratos Sprague-Dawley , Dióxido de Silício/química , Dióxido de Silício/farmacologia
8.
Nanoscale ; 11(36): 17041-17051, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31506653

RESUMO

Small interfering RNA (siRNA) is a promising tool for the treatment of skin disorders including skin squamous cell carcinoma (SCC). This article develops a topical formulation for the transdermal delivery of siRNA. The formulation is built on mesoporous silica nanoparticles (MSNPs) with a loading capacity of 1.4 µg of oligonucleotide per mg of MSNPs. Cell experiments are employed to study the functionality of the formulation including the cellular uptake, the qualitative and quantitative detection of specific gene biomarkers. The clinical potential of this system is examined by topically delivering siRNA targeting TGFßR-1 (TGFßR-1) to the SCC in a mouse xenograft model. In comparison to the controls, MSNPs containing TGFßR-1 siRNA show a 2-fold suppression of TGFßR-1.


Assuntos
Carcinoma de Células Escamosas , Sistemas de Liberação de Medicamentos , Nanopartículas , Oligonucleotídeos , RNA Interferente Pequeno , Dióxido de Silício , Neoplasias Cutâneas , Administração Cutânea , Animais , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Humanos , Camundongos , Camundongos SCID , Nanopartículas/química , Nanopartículas/uso terapêutico , Oligonucleotídeos/química , Oligonucleotídeos/farmacologia , Porosidade , RNA Interferente Pequeno/química , RNA Interferente Pequeno/farmacologia , Dióxido de Silício/química , Dióxido de Silício/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
ACS Appl Mater Interfaces ; 11(38): 34755-34765, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31474108

RESUMO

Radiation dosage constraints and hypoxia-associated resistance lead to the failure of radiotherapy (RT), especially in hypoxic liver cancer. Therefore, the intricate use of combined strategies for potentiating and complementing RT is especially important. In this work, we fabricated multifunctional Janus-structured gold triangle-mesoporous silica nanoparticles (NPs) as multifunctional platforms to deliver the hypoxia-activated prodrug tirapazamine (TPZ) for extrinsic radiosensitization, local photothermal therapy, and hypoxia-specific chemotherapy. The subsequent conjugation of folic acid-linked poly(ethylene glycol) provided the Janus nanoplatforms with liver cancer targeting and minimized opsonization properties. In vitro and in vivo experiments revealed the combined radiosensitive and photothermal antitumor effects of the Janus nanoplatforms. Importantly, the TPZ-loaded Janus nanoplatforms exhibited pH-responsive release behavior, which effectively improved the cellular internalization and therapeutic efficiency in hypoxic rather than normoxic liver cancer cells. Hypoxia-specific chemotherapy supplemented the ineffectiveness of radio-photothermal therapy in hypoxic tumor tissues, resulting in remarkable tumor growth inhibition without systematic toxicity. Therefore, our Janus nanoplatforms integrated radio-chemo-photothermal therapy in a hypoxia-activated manner, providing an efficient and safe strategy for treating liver cancer.


Assuntos
Quimiorradioterapia , Sistemas de Liberação de Medicamentos , Ouro , Hipertermia Induzida , Neoplasias Hepáticas Experimentais , Fototerapia , Pró-Fármacos , Dióxido de Silício , Tirapazamina , Animais , Hipóxia Celular , Linhagem Celular Tumoral , Ouro/química , Ouro/farmacologia , Humanos , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Neoplasias Hepáticas Experimentais/terapia , Camundongos , Camundongos Nus , Nanopartículas/química , Nanopartículas/uso terapêutico , Porosidade , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Dióxido de Silício/química , Dióxido de Silício/farmacologia , Tirapazamina/química , Tirapazamina/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Mater Sci Eng C Mater Biol Appl ; 104: 109897, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31500019

RESUMO

Bisphosphonates are a class of drugs widely used in the clinical treatment of disorders of bone metabolism, such as osteoporosis, fibrous dysplasia, myeloma and bone metastases. Because of the negative side effects caused by oral administration of bisphosphonates, various silica mesoporous materials have been investigated for a confined and controlled release of these drugs. Here, we propose biosilica from diatoms as suitable substrate for alendronate local activation of bone cells. Following a novel strategy, sodium alendronate can be in vivo incorporated into biosilica shells of cultured Thalassiosira weissflogii diatoms, by feeding the algae with an aqueous solution of the drug. After acid/oxidative treatments for removing organic matter, the resulting bisphosphonate-functionalized mesoporous biosilica was characterized and tested as osteoinductive support. Effects on osteoblast growth and anti-osteoclast activity have been examined by evaluating SaOS-2, BMSC, J774 cell viability on the alendronate-"doped" biosilica. The loading percentage of sodium alendronate into biosilica, estimated as 1.45% w/w via TGA, was able to decrease metabolic activity of J774 osteoclasts-like cells till 5% over glass control. We demonstrated a good osteoconductive ability and activation of a tissue regeneration model together with osteoclasts inhibition of the functionalized biosilica, opening the way to interesting applications for diatom microalgae as a bioinspired mesoporous material for tissue engineering.


Assuntos
Alendronato/farmacologia , Osso e Ossos/efeitos dos fármacos , Diatomáceas/química , Dióxido de Silício/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Termogravimetria , Água/química
11.
J Colloid Interface Sci ; 555: 470-479, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31400539

RESUMO

Ultrasmall silver nanoclusters (Ag NCs) are one of the emerging and highly efficient antibacterial agents, owing to the unique features of sub-2 nm particle size and the high abundance of the active Ag+ species. However, practical applications of Ag NCs in biological environment are often hampered by silver oxidization, which results in particle aggregation and loss of antibacterial activity. In this study, for the first time, we develop a facile method to synthesize highly dispersed Ag NCs decorated mesoporous silica nanoparticles (Ag NC-MSNs) capable of long-term and efficient release of Ag+ ions. This novel Ag NC-MSNs nanocomposite was demonstrated as an effective antibacterial agent against both Gram-positive and Gram-negative pathogenic bacteria. Compared with the counterparts Ag NCs and silver nanoparticles decorated mesoporous silica nanoparticles (Ag NP-MSNs), Ag NC-MSNs exhibit 17-fold and 27-fold enhancement in antibacterial potency, respectively. The homogeneous distribution of ultrasmall Ag NCs in the mesoporous architecture of supporting MSNs matrix is crucial for the controlled release of Ag+ ions, leading to the superior broad-spectrum antimicrobial activity. Moreover, the cytotoxicity assay indicated that the effective antibacterial concentration of Ag NC-MSNs shows minimum toxicity on mammalian cells. This new Ag nanocomposite developed in this work is promising for practical applications against various microbial infections.


Assuntos
Antibacterianos/farmacologia , Nanopartículas/química , Pseudomonas aeruginosa/efeitos dos fármacos , Dióxido de Silício/farmacologia , Prata/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/química , Sobrevivência Celular/efeitos dos fármacos , Células HeLa , Humanos , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Porosidade , Espécies Reativas de Oxigênio/análise , Dióxido de Silício/química , Prata/química , Propriedades de Superfície
12.
Eur J Pharm Sci ; 138: 105038, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31398394

RESUMO

Antioxidants play a vital role in scavenging reactive oxygen species (ROS) produced by the reduction of molecular oxygen from various cellular mechanisms. Under oxidative stress, an increase in the levels of ROS overwhelms the antioxidant response, causing oxidative damage to biological molecules, and leading to the development of various diseases. Drug compounds with potent antioxidant properties are typically poorly water soluble and highly hydrophobic. An extreme case is Probucol (PB), a potent antioxidant with reported water solubility of 5 ng/ml, and oral bioavailiability of <10%. In this study, PB was loaded in mesoporous silica at various drug loadings to understand the changes to the physical properties of the loaded drug, and it's in vitro drug release. Further in vitro studies were conducted in endothelial and microglia cell models to compare the free radical scavening efficiency of ascorbic acid, PB, and PB release from mesoporous silica particles. Out of the three different mesostructured particles studied, the maximum loading of PB was achieved for large pore mesoporous particles (SBA-15) at 50 wt% drug loading, before complete pore filling was observed. For all materials, loadings above complete pore filling resulted in the recrystallization of PB on the external surface. In vitro drug release measurements showed a rapid dissolution rate at low drug loadings compared to a bimodal release profile of amorphous and crystalline drug at higher drug loadings. PB loaded in mesoporous particle was shown to enhance the antioxidant response to extracellular ROS in the endothelial cell line model, and to intracellular ROS in the microglia cell model. Our results indicate that the antioxidant properties of PB can be significantly improved by using mesoporous silica as a delivery vehicle.


Assuntos
Antioxidantes/fisiologia , Probucol/farmacologia , Dióxido de Silício/farmacologia , Animais , Antioxidantes/química , Linhagem Celular , Química Farmacêutica/métodos , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos/fisiologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Tamanho da Partícula , Porosidade , Probucol/química , Espécies Reativas de Oxigênio/metabolismo , Dióxido de Silício/química , Solubilidade/efeitos dos fármacos , Água/química
13.
ACS Appl Mater Interfaces ; 11(34): 30596-30609, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31373193

RESUMO

Biomaterials that have capacities to simultaneously induce bone regeneration and kill bacteria are in demand because bone defects face risks of severe infection in clinical therapy. To meet the demand, multifunctional biodegradable microspheres are fabricated, which contain vancomycin to provide antibacterial activity and strontium-doped apatite to provide osteocompatibility. Moreover, the strontium component shows activity in promoting angiogenesis, which further favors osteogenesis. For producing the microspheres, vancomycin is loaded into mesoporous silica and embedded in polylactide-based microspheres via the double emulsion technique and the strontium-doped apatite is deposited onto the microspheres via biomineralization in strontium-containing simulated body fluid. Sustained release behaviors of both vancomycin and Sr2+ ions are achieved. The microspheres exhibit strong antibacterial effect against Staphylococcus aureus, while demonstrating excellent cell/tissue compatibility. Studies of differentiation confirm that the introduction of strontium element strengthens the angiogenic and osteogenic expressions of mesenchymal stromal cells. Subcutaneous injection of the microspheres into rabbit's back confirms their effectiveness in inducing neovascularization and ectopic osteogenesis. Finally, an infected rabbit femoral condyle defect model is created with S. aureus infection and the multifunctional microspheres are injected, which display significant antibacterial activity in vivo and achieve efficient new bone formation in comparison with biomineralized microspheres without vancomycin loading. The vancomycin- and strontium-loaded microspheres, being biomineralized, injectable, and biodegradable, are attractive because of their flexibility in integrating multiple functions into one design, whose potentials in treating infected bone defects are highly expected.


Assuntos
Indutores da Angiogênese , Antibacterianos , Regeneração Óssea/efeitos dos fármacos , Portadores de Fármacos , Fêmur , Microesferas , Neovascularização Fisiológica/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/crescimento & desenvolvimento , Vancomicina , Indutores da Angiogênese/química , Indutores da Angiogênese/farmacocinética , Indutores da Angiogênese/farmacologia , Animais , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Fêmur/metabolismo , Fêmur/patologia , Porosidade , Coelhos , Ratos , Ratos Sprague-Dawley , Dióxido de Silício/química , Dióxido de Silício/farmacocinética , Dióxido de Silício/farmacologia , Estrôncio/química , Estrôncio/farmacocinética , Estrôncio/farmacologia , Vancomicina/química , Vancomicina/farmacocinética , Vancomicina/farmacologia
14.
Int J Nanomedicine ; 14: 5355-5368, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409992

RESUMO

Aim: Nanoparticles (NPs) have been receiving potential interests in protein delivery and cell therapy. As a matter of fact, NPs may be used as great candidates in promoting cell therapy by catalase (CAT) delivery into high oxidative stress tissues. However, for using NPs like SiO2 as carriers, the interaction of NPs with proteins and mesenchymal stem cells (MSCs) should be explored in advance. Methods: In the present study, the interaction of SiO2 NPs with CAT and human MSCs (hMSCs) was explored by various spectroscopic methods (fluorescence, circular dichroism (CD), UV-visible), molecular docking and dynamics studies, and cellular (MTT, cellular morphology, cellular uptake, lactate dehydrogenase, ROS, caspase-3, flow cytometry) assays. Results: Fluorescence study displayed that both dynamic and static quenching mechanisms and hydrophobic interactions are involved in the spontaneous interaction of SiO2 NPs with CAT. CD spectra indicated that native structure of CAT remains stable after interaction with SiO2 NPs. UV-visible study also revealed that the kinetic parameters of CAT such as Km, Vmax, Kcat, and enzyme efficiency were not changed after the addition of SiO2 NPs. Molecular docking and dynamics studies showed that Si and SiO2 clusters interact with hydrophobic residues of CAT and SiO2 cluster causes minor changes in the CAT structure at a total simulation time of 200 ps. Cellular assays depicted that SiO2 NPs induce significant cell mortality, change in cellular morphology, cellular internalization, ROS elevation, and apoptosis in hMSCs at higher concentration than 100 µg/mL (170 µM). Conclusion: The current results suggest that low concentrations of SiO2 NPs induce no substantial change or mortality against CAT and hMSCs, and potentially useful carriers in CAT delivery to hMSC.


Assuntos
Fenômenos Biofísicos , Células-Tronco Mesenquimais/citologia , Modelos Teóricos , Nanopartículas/química , Dióxido de Silício/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Catalase/metabolismo , Forma Celular/efeitos dos fármacos , Dicroísmo Circular , Endocitose/efeitos dos fármacos , Humanos , Cinética , L-Lactato Desidrogenase/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Espectrometria de Fluorescência , Termodinâmica
15.
Nanotechnology ; 30(49): 495101, 2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31422958

RESUMO

Conducive nanoparticles (NPs) were proposed to locally amplify the external electric field (EF) intensity at the cell surface to improve cell electroporation. To better understand the physical mechanisms behind this improvement, different types of NPs and several incubation conditions were applied to adherent cells in the present study. The enhancement of electroporation was observed in the presence of conductive NPs but not when non-conductive NPs were used. Experimental data demonstrate the influence of the incubation conditions between cells and NPs, which impact on the number and quality (aggregated or isolated) of the NPs surrounding the cells. While NPs can increase the number of electroporated cells, they have a more pronounced impact on the level permeabilization of each individual cell. Our results reveal the potential of conductive NPs to enhance the efficiency of electroporation via the amplification of the local EF at the cell surface as shown by numerical simulations.


Assuntos
Condutividade Elétrica , Eletroporação/métodos , Células Epiteliais/metabolismo , Nanopartículas/química , Animais , Bleomicina/farmacologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Cricetulus , Eletrodos , Campos Eletromagnéticos , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Nanopartículas/metabolismo , Nanopartículas/ultraestrutura , Platina/química , Platina/farmacologia , Dióxido de Silício/química , Dióxido de Silício/farmacologia
16.
ACS Appl Mater Interfaces ; 11(34): 31270-31282, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31348641

RESUMO

Typical aggregation-induced emission (AIE) luminogens tetraphenylethylene (TPE) and triphenylamine have been used to construct an AIE-active conjugated polymer, namely, poly(N,N-diphenyl-4-(4-(1,2,2-triphenylvinyl)styryl)aniline) (PTPA), which consist of D-π-A architecture by Wittig polymerization. We fabricated mesoporous silica hollow nanospheres (MSHNs) which were encapsulated with the AIE-active polymer for applications in cellular imaging. It exhibits a positive solvatochromism effect by increasing solvent polarity, supported by theoretical calculation using density functional theory. The structure of the monomers and polymer was confirmed by Fourier transform infrared, nuclear magnetic resonance, and high-resolution mass spectrometry techniques. Considering the advantage of high brightness in the fluorescence of PTPA, it was encapsulated into MSHNs by a noncovalent approach, and the surface was functionalized with an anti-EpCAM (antiepithelial cell adhesion molecule) aptamer through conjugation with γ-glycidoxypropyltrimethoxysilane for targeting cancer cells specifically. The aptamer-functionalized Apt-MSHNs exhibited excellent biocompatibility with the liver cancer-Huh-7 cells used for this study and was efficiently internalized by these cells. Because EpCAM are overexpressed in multiple carcinomas, including liver cancer, these aptamer-conjugated AIE MSHNs are therefore good candidates for targeted cellular imaging applications.


Assuntos
Meios de Contraste , Imagem por Ressonância Magnética , Nanosferas/química , Neoplasias , Dióxido de Silício , Meios de Contraste/química , Meios de Contraste/farmacologia , Humanos , Células MCF-7 , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Neoplasias/patologia , Dióxido de Silício/química , Dióxido de Silício/farmacologia , Espectrometria de Fluorescência
17.
Nanoscale ; 11(27): 13078-13088, 2019 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-31265049

RESUMO

Although photodynamic therapy (PDT), which uses a photosensitizer (PS) to generate toxic reactive oxygen species (ROS) upon laser irradiation to kill cancer cells, has been widely applied, the relatively high laser intensity required causes photodamage to healthy neighboring cells and limits its success. Furthermore, glutathione (GSH, an antioxidant) is overexpressed in cancer cells, which can scavenge the generated ROS, thus lowering PDT efficacy. Herein, ultralow-intensity near-infrared (NIR) light-triggered PDT was developed and enhanced through combined GSH-depletion chemotherapy (Chemo) based on exo- and endogenous synergistic effects. Highly emissive upconversion nanoparticles (UCNPs) were prepared and coated with a solid silica shell, which was used to encapsulate the PS rose bengal and bond the drug camptothecin with a disulfide-bond linker. The combination of highly emissive UCNPs and a matchable PS with an optimized loading dosage enabled ROS to be generated for PDT even upon 808 nm laser irradiation with ultralow intensity (0.30 W cm-2). According to the American National Standard, this laser intensity is below the maximum permissible exposure of skin (MPE, 0.33 W cm-2). Once the prepared nanoparticles endocytosed and encountered intracellular GSH, the disulfide-bond linker was cleaved by GSH, leading to drug release and GSH depletion. PDT was therefore simultaneously enhanced through the exogenous synergic effect of Chemo (namely, the "1 + 1 > 2" therapeutic effect) and the endogenous synergic effect as a result of GSH depletion. It was proven both in vitro and in vivo that this novel dual-synergistic Chemo/PDT system exhibits remarkable therapeutic efficacy with minimal photodamage to healthy neighboring cells.


Assuntos
Glutationa/metabolismo , Nanopartículas/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Dióxido de Silício/farmacologia , Animais , Preparações de Ação Retardada/farmacologia , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Espécies Reativas de Oxigênio/metabolismo
18.
Nanoscale ; 11(27): 12965-12972, 2019 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-31259344

RESUMO

With the wide application of Stöber silica nanoparticles and their ability to access the brain, it is crucial to evaluate their neurotoxicity. In this study, we used three in vitro model cells, i.e., N9, bEnd.3 and HT22 cells, representing microglia, microendothelial cells and neurons, respectively, to assess the neurotoxicity of Stöber silica nanoparticles with different sizes. We found that Stöber silica nanoparticles almost had no effect on the viability of bEnd.3 and HT22 cells. In contrast, they induced size-dependent toxicity in N9 cells, which represent the residential macrophages of the central nervous system. Further mechanistic study demonstrated that the toxicity in N9 cells was related to their surface silanol display. In addition, we demonstrated that Stöber silica nanoparticles induced the production of mitochondrial ROS, release of IL-1ß, cleavage of GSDMD, and occurrence of pyroptosis in N9 cells. Features of pyroptosis were also observed in primary microglia and macrophage J774A.1. In conclusion, these findings were helpful for the safety consideration of Stöber silica nanoparticles considering their wide applications in our daily life.


Assuntos
Microglia/metabolismo , Mitocôndrias/metabolismo , Nanopartículas/efeitos adversos , Piroptose/efeitos dos fármacos , Dióxido de Silício/efeitos adversos , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Microglia/patologia , Mitocôndrias/patologia , Nanopartículas/química , Espécies Reativas de Oxigênio/metabolismo , Dióxido de Silício/química , Dióxido de Silício/farmacologia
19.
Bull Exp Biol Med ; 167(3): 396-399, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31346874

RESUMO

We studied the response of neutrophils, macrophages, and mast cells to local application of silica nanoparticles (10-20 nm). Histological examination of tonsillar postoperative material from 6 patients aged 24-44 years with recurrent tonsillitis was carried out. Irrigation of the tonsillar lacunae was carried out over 5 days before bilateral tonsillectomy: on the right by Polysorb MP suspension (1 g/liter), on the left by saline. The contact of nanoparticles with the mucosa led to a decrease in the number of cells expressing myeloperoxidase (p=0.02) and an increase in the count of CD68+ cells (p=0.04); the count of mast cells remained unchanged. Local use of medical adsorbent based on silica nanoparticles induced changes in cells due to their resorption by the tissue. Positive chemotaxis of CD68+ macrophages revealed in the tonsillar lymphoid tissue attested to stimulation of non-specific immunity and inductive phase of specific immunity. The authors hypothesized that internalization of medical nanoparticles by resident phagocytes of the mucosa could support targeted biodistribution of drugs in the palatine tonsils.


Assuntos
Macrófagos/imunologia , Mastócitos/imunologia , Neutrófilos/imunologia , Tonsila Palatina/imunologia , Dióxido de Silício/farmacologia , Tonsilite/tratamento farmacológico , Adulto , Antígenos CD/biossíntese , Antígenos de Diferenciação Mielomonocítica/biossíntese , Sistemas de Liberação de Medicamentos/métodos , Humanos , Nanopartículas , Tonsila Palatina/citologia , Peroxidase/biossíntese , Tonsilectomia , Tonsilite/cirurgia
20.
Curr Med Sci ; 39(4): 551-559, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31346990

RESUMO

The dynamic variation of renin-angiotensin system (RAS) in silicosis remains unclear. Seventy Wistar rats were divided into 7 groups including control group, silicosis groups (inhaling SiO2 for 2, 4, 8, 16 and 24 weeks, respectively) and Captopril (Cap) group. Rat lung primary fibroblasts were divided into control group, SiO2-stimulated group (0, 0.5, 1, 3, 6, 12, 24 and 48 h) and Cap group. The silicotic nodules were formed and collagens were deposited gradually in silicosis group observed by haematoxylin and eosin (HE) staining and Van Gieson (VG) staining. Cap relieved the lung fibrosis and collagen deposition. Immunohistochemistry indicated the positive expression of α-smooth muscle actin (α-SMA) was increased gradually in silicotic rat lung tissue. Western blotting revealed the expression of collagen type I (Col I) and α-SMA was up-regulated in silicotic rat lung tissue and fibroblasts stimulated by SiO2. Cap decreased the expression of Col I and α-SMA in silicotic rat lung tissue and fibroblasts stimulated by SiO2. Western blotting also demonstrated the expression of angiotensin-converting enzyme (ACE) and angiotensin II type 1 receptor (AT1) was increased, and the expression of ACE2 and Mas was decreased gradually in silicotic rat lung tissue and fibroblasts stimulated by SiO2. ELISA showed the serum levels of ACE and angiotensin II (Ang II) were also increased and ACE2 and Ang (1-7) were decreased in the silicosis group. Treatment with Cap decreased the expression levels of ACE, Ang II and AT1, and increased the expression levels of ACE2, Ang (1-7) and Mas. These findings suggested that an imbalance between ACE-Ang II-AT1 axis and ACE2-Ang (1-7)-Mas axis may participate in the development of silicosis.


Assuntos
Captopril/farmacologia , Peptidil Dipeptidase A/genética , Receptor Tipo 1 de Angiotensina/genética , Silicose/tratamento farmacológico , Actinas/genética , Angiotensina II/genética , Animais , Colágeno Tipo I/genética , Fibroblastos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Cultura Primária de Células , Ratos , Ratos Wistar , Sistema Renina-Angiotensina , Dióxido de Silício/farmacologia , Silicose/genética , Silicose/patologia
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