Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 54.323
Filtrar
1.
Nat Commun ; 11(1): 4951, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009382

RESUMO

Immunogenic cell death (ICD) and tumour-infiltrating T lymphocytes are severely weakened by elevated reactive oxygen species (ROS) in the tumour microenvironment. It is therefore of critical importance to modulate the level of extracellular ROS for the reversal of immunosuppressive environment. Here, we present a tumour extracellular matrix (ECM) targeting ROS nanoscavenger masked by pH sensitive covalently crosslinked polyethylene glycol. The nanoscavenger anchors on the ECM to sweep away the ROS from tumour microenvironment to relieve the immunosuppressive ICD elicited by specific chemotherapy and prolong the survival of T cells for personalized cancer immunotherapy. In a breast cancer model, elimination of the ROS in tumour microenvironment elicited antitumour immunity and increased infiltration of T lymphocytes, resulting in highly potent antitumour effect. The study highlights a strategy to enhance the efficacy of cancer immunotherapy by scavenging extracellular ROS using advanced nanomaterials.


Assuntos
Antineoplásicos/farmacologia , Espaço Extracelular/metabolismo , Depuradores de Radicais Livres/metabolismo , Morte Celular Imunogênica , Espécies Reativas de Oxigênio/metabolismo , Animais , Linhagem Celular Tumoral , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Proteína HMGB1/metabolismo , Morte Celular Imunogênica/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Polietilenoglicóis/química , Microambiente Tumoral/efeitos dos fármacos
2.
Am J Dent ; 33(5): 251-257, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33017528

RESUMO

PURPOSE: To compare the stresses generated after the use of low elastic modulus polyetheretherketone (PEEK) as dental post and crown material with glass fiber post and metal supported ceramic crowns using finite element analysis. METHODS: First an image of a maxillary central incisor taken on micro-computed tomography (micro-CT) was uploaded to a computer program. Modeling was made of all the materials in the computer environment and 3-dimensional (3D) virtual models were obtained. Using two different post materials (glass fiber and PEEK post) and two different crown materials (metal supported ceramic and PEEK crown), the modeling of the maxillary central tooth was completed and a total of four groups were obtained. Finally, 135° and 100 N forces were applied from the midpoint of the palatal surface. RESULTS: The FEA analysis showed the use of PEEK as post material decreased the stress values in the post, post cement and composite core models and did not have any significant change in the dentin and crown cement models. The use of composite veneer with PEEK substructure as crown material reduced stress values in dentin, the post and composite core and increased stress values in both the post cement and the crown cement. CLINICAL SIGNIFICANCE: Since the elastic modulus of the PEEK material is very close to dentin tissue, finite element stress analysis, less stress formation in the tooth and post core restoration compared to other post systems was observed. In this context, PEEK post may reduce irreversible complications.


Assuntos
Técnica para Retentor Intrarradicular , Coroas , Análise de Elementos Finitos , Cetonas , Polietilenoglicóis , Microtomografia por Raio-X
3.
Medicine (Baltimore) ; 99(35): e21825, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871904

RESUMO

OBJECTIVE: To conduct a meta-analysis evaluating the effect of combining traditional Chinese medicine (TCM) with Western medicine in treating hepatitis C, and to provide an evidence-based medical strategy. METHODS: Randomized controlled trials (RCTs) comparing the effect of pegylated interferon (Peginterferon) combined with ribavirin (PR) alone and its combination with TCM were manually retrieved from the Weipu Information Resources System (VIP), Wan Fang Database, PubMed, and the Chinese Journal Full Text Database (CNKI). Studies meeting the inclusion criteria were selected and analyzed using the Review Manager 5.3 software. Suitable tests were also performed to determine the quality, heterogeneity, and sensitivity of the studies included in the meta-analysis. RESULTS: Twenty-eight RCTs met the inclusion criteria. The combination therapy or intervention group showed significantly greater HCV-RNA negative rate post-treatment compared to the monotherapy or the control group (P < .05). In addition, the serum levels of the liver function indicators alanine aminotransferase (ALT), aspartate aminotransferase (AST), and albumin (ALB) were significantly improved after the combination therapy compared to PR alone (P < .05), while total bilirubin (TB) and r-glutamyltransferase (GGT) levels were not affected by TCM (P > .05). Finally, the parameters of liver fibrosis were also reduced by the combination therapy more effectively than the monotherapy. CONCLUSION: The combination of TCM and PR can improve the Comprehensive Clinical Efficacy of hepatitis C and have a better negative rate of HCV-RNA with a better benefit in the liver function. The effect of TCM + PR is better than that of PR alone in treating hepatitis C.


Assuntos
Antivirais/uso terapêutico , Hepatite C/terapia , Medicina Tradicional Chinesa , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Bilirrubina/sangue , Terapia Combinada , Quimioterapia Combinada , Hepacivirus/genética , Humanos , Interferon-alfa/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , RNA Viral/sangue , Proteínas Recombinantes/uso terapêutico , Ribavirina/uso terapêutico , Albumina Sérica , gama-Glutamiltransferase/sangue
4.
Chem Biol Interact ; 330: 109245, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32866465

RESUMO

The calcineurin inhibitor, cyclosporin A (CsA) is one of the most common immunosuppressive agents used in organ transplantation. However, its clinical use is often limited by several unwanted effects including nephrotoxicity and hepatotoxicity. By using immunohistochemical and ELISA techniques, it was found that CsA administration causes a rapid activation of a disintegrin and metalloproteases-17 (ADAM-17), epidermal growth factor receptor (EGFR) and subsequent ERK1/2 phosphorylation in the liver and kidney of albino mice. Furthermore, this study presents mechanistic relevance of this signaling cascade involving reactive oxygen species (ROS)-mediated ADAM-17/EGFR/ERK1/2 activation as indicated by a clear reduction in ADAM-17 and EGFR activities as well as ERK1/2 phosphorylation when the animals pretreated with Polyethylene glycol-superoxide dismutase (PEG-SOD) before CsA administration. Collectively, our findings demonstrate that CsA has the ability to activate ADAM-17-mediated EGFR/ERK1/2 phosphorylation in the liver and kidney of albino mice in ROS-dependent manner. Finally, these data may support the concept of using antioxidant therapy as a valuable approach for the prevention of CsA-induced nephrotoxicity and hepatotoxicity.


Assuntos
Ciclosporina/toxicidade , Rim/metabolismo , Fígado/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Polietilenoglicóis/farmacologia , Superóxido Dismutase/farmacologia , Proteína ADAM17/metabolismo , Animais , Ciclosporina/farmacologia , Interações Medicamentosas , Receptores ErbB/metabolismo , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Camundongos , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
5.
Nat Commun ; 11(1): 4530, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913195

RESUMO

Various cancer cells have been demonstrated to have the capacity to form plasmonic gold nanoparticles when chloroauric acid is introduced to their cellular microenvironment. But their biomedical applications are limited, particularly considering the millimolar concentrations and longer incubation period of ionic gold. Here, we describe a simplistic method of intracellular biomineralization to produce plasmonic gold nanoparticles at micromolar concentrations within 30 min of application utilizing polyethylene glycol as delivery vector for ionic gold. We have characterized this process for intracellular gold nanoparticle formation, which progressively accumulates proteins as the ionic gold clusters migrate to the nucleus. This nano-vectorized application of ionic gold emphasizes its potential biomedical opportunities while reducing the quantity of ionic gold and required incubation time. To demonstrate its biomedical potential, we further induce in-situ biosynthesis of gold nanoparticles within MCF7 tumor mouse xenografts which is followed by its photothermal remediation.


Assuntos
Cloretos/administração & dosagem , Portadores de Fármacos/química , Compostos de Ouro/administração & dosagem , Ouro/química , Nanopartículas Metálicas/química , Neoplasias/tratamento farmacológico , Nanomedicina Teranóstica/métodos , Animais , Biomineralização/efeitos da radiação , Feminino , Ouro/efeitos da radiação , Humanos , Hipertermia Induzida/métodos , Íons , Células MCF-7 , Nanopartículas Metálicas/efeitos da radiação , Camundongos , Fotoquimioterapia/métodos , Polietilenoglicóis/química , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Int J Nanomedicine ; 15: 6167-6182, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922000

RESUMO

Background: Among the novel cancer treatment strategies, combination therapy is a cornerstone of cancer therapy. Materials and Methods: Here, combination therapy with targeted polymer, magnetic hyperthermia and chemotherapy was presented as an effective therapeutic technique. The DOX-loaded PLA-PEG-FA magnetic nanoparticles (nanocarrier) were prepared via a double emulsion method. The nanocarriers were characterized by particle size, zeta potential, morphology, saturation magnetizations and heat generation capacity, and the encapsulation efficiency, drug content and in-vitro drug release for various weight ratios of PLA:DOX. Then, cytotoxicity, cellular uptake and apoptosis level of nanocarrier-treated cells for HeLa and CT26 cells were investigated by MTT assay, flow cytometry, and apoptosis detection kit. Results and Conclusions: The synthesized nanoparticles were spherical in shape, had low aggregation and considerable magnetic properties. Meanwhile, the drug content and encapsulation efficiency of nanoparticles can be achieved by varying the weight ratios of PLA:DOX. The saturation magnetizations of nanocarriers in the maximum applied magnetic field were 59/447 emu/g and 28/224 emu/g, respectively. Heat generation capacity of MNPs and nanocarriers were evaluated in the external AC magnetic field by a hyperthermia device. The highest temperature, 44.2°C, was measured in the nanocarriers suspension at w/w ratio 10:1 (polymer:DOX weight ratio) after exposed to the magnetic field for 60 minutes. The encapsulation efficiency improved with increasing polymer concentration, since the highest DOX encapsulation efficiency was related to the nanocarriers' suspension at w/w ratio 50:1 (79.6 ± 6.4%). However, the highest DOX loading efficiency was measured in the nanocarriers' suspension at w/w ratio 10:1 (5.14 ± 0.6%). The uptake efficiency and apoptosis level of nanocarrier-treated cells were higher than those of nanocarriers (folic acid free) and free DOX-treated cells in both cell lines. Therefore, this targeted nanocarrier may offer a promising nanosystem for cancer-combined chemotherapy and hyperthermia.


Assuntos
Doxorrubicina/farmacologia , Ácido Fólico/farmacologia , Hipertermia Induzida , Nanopartículas de Magnetita/química , Neoplasias/terapia , Polietilenoglicóis/química , Animais , Apoptose/efeitos dos fármacos , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Células HeLa , Humanos , Nanopartículas de Magnetita/ultraestrutura , Camundongos , Tamanho da Partícula , Polietilenoglicóis/síntese química , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática
7.
Int J Nanomedicine ; 15: 6183-6200, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922001

RESUMO

Purpose: Diethylaminoethyl-chitosan (DEAE-CH) is a derivative with excellent potential as a delivery vector for gene therapy applications. The aim of this study is to evaluate its toxicological profile for potential future clinical applications. Methods: An endotoxin-free chitosan (CH) modified with DEAE, folic acid (FA) and polyethylene glycol (PEG) was used to complex small interfering RNA (siRNA) and form nanoparticles (DEAE12-CH-PEG-FA2/siRNA). Based on the guidelines from the International Organization for Standardization (ISO), the American Society for Testing and Materials (ASTM), and the Nanotechnology Characterization Laboratory (NCL), we evaluated the effects of the interaction between these nanoparticles and blood components. In vitro screening assays such as hemolysis, hemagglutination, complement activation, platelet aggregation, coagulation times, cytokine production, and reactive species, such as nitric oxide (NO) and reactive oxygen species (ROS), were performed on erythrocytes, plasma, platelets, peripheral blood mononuclear cells (PBMC) and Raw 264.7 macrophages. Moreover, MTS and LDH assays on Raw 264.7 macrophages, PBMC and MG-63 cells were performed. Results: Our results show that a targeted theoretical plasma concentration (TPC) of DEAE12-CH-PEG-FA2/siRNA nanoparticles falls within the guidelines' thresholds: <1% hemolysis, 2.9% platelet aggregation, no complement activation, and no effect on coagulation times. ROS and NO production levels were comparable to controls. Cytokine secretion (TNF-α, IL-6, IL-4, and IL-10) was not affected by nanoparticles except for IL-1ß and IL-8. Nanoparticles showed a slight agglutination. Cell viability was >70% for TPC in all cell types, although LDH levels were statistically significant in Raw 264.7 macrophages and PBMC after 24 and 48 h of incubation. Conclusion: These DEAE12-CH-PEG-FA2/siRNA nanoparticles fulfill the existing ISO, ASTM and NCL guidelines' threshold criteria, and their low toxicity and blood biocompatibility warrant further investigation for potential clinical applications.


Assuntos
Quitosana/química , Terapia Genética , Nanopartículas/química , Polietilenoglicóis/química , Polímeros/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Ácido Fólico/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Nanopartículas/administração & dosagem , Óxido Nítrico/metabolismo , Células RAW 264.7 , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Testes de Toxicidade
8.
Int J Nanomedicine ; 15: 6385-6399, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922007

RESUMO

Purpose: The mononuclear phagocyte system (MPS) presents a formidable obstacle that hampers the delivery of various nanopreparations to tumors. Therefore, there is an urgent need to improve the off-MPS targeting ability of nanomedicines. In the present study, we present a novel preconditioning strategy to substantially increase the circulation times and tumor targeting of nanoparticles by regulating nanocarrier-MPS interactions. Methods: In vitro, the effect of different vacuolar H+-ATPase inhibitors on macrophage uptake of targeted or nontargeted lipid vesicles was evaluated. Specifically, the clinically approved proton-pump inhibitor esomeprazole (ESO) was selected as a preconditioning agent. Then, we further investigated the blocking effect of ESO on the macrophage endocytosis of nanocarriers. In vivo, ESO was first intravenously administered into A549-tumor-bearing nude mice, and 24 h later, the c(RGDm7)-modified vesicles co-loaded with doxorubicin and gefitinib were intravenously injected. Results: In vitro, ESO was found to reduce the interactions between macrophages and c(RGDm7)-modified vesicles by interfering with the latter's lysosomal trafficking. Studies conducted in vivo confirmed that ESO pretreatment greatly decreased the liver and spleen distribution of the targeted vesicles, enhanced their tumor accumulation, and improved the therapeutic outcome of the drug-loaded nanomedicines. Conclusion: Our findings indicate that ESO can regulate the nanoparticle-MPS interaction, which provides a feasible option for enhancing the off-MPS targeting of nanomedicines.


Assuntos
Portadores de Fármacos/química , Esomeprazol/farmacologia , Sistema Fagocitário Mononuclear/citologia , Nanopartículas/química , Células A549 , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Transporte Biológico , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Endocitose , Esomeprazol/farmacocinética , Esomeprazol/uso terapêutico , Humanos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Células MCF-7 , Camundongos , Camundongos Nus , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Células RAW 264.7 , Distribuição Tecidual/efeitos dos fármacos , ATPases Vacuolares Próton-Translocadoras/metabolismo
9.
Int J Nanomedicine ; 15: 6433-6449, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922010

RESUMO

Background: Electrospun nanofibers based on Colocasia esculenta tuber (CET) protein are considered as a promising material for wound dressing applications. However, the use of these nanofibers in aqueous conditions has poor stability. The present study was performed to obtain insights into the crosslinked electrospun CET's protein-chitosan (CS)-poly(ethylene oxide) (PEO) nanofibers and to evaluate their potential for wound dressing applications. Methods: The electrospun nanofibers were crosslinked with glutaraldehyde (GA) vapor and heat treatment (HT) to enhance their physicochemical stability. The crosslinked nanofibers were characterized by protein profiles, morphology structures, thermal behavior, mechanical properties, and degradation behavior. Furthermore, the antibacterial properties and cytocompatibility were analyzed by antibacterial assessment and cell proliferation. Results: The protein profiles of the electrospun CET's protein-CS-PEO nanofibers before and after HT crosslinking contained one major bioactive protein with a molecular weight of 14.4 kDa. Scanning electron microscopy images of the crosslinked nanofibers indicated preservation of the structure after immersion in phosphate buffered saline. The crosslinked nanofibers resulted in higher ultimate tensile strength and lower ultimate strain compared to the non-crosslinked nanofibers. GA vapor crosslinking showed higher water stability compared to HT crosslinking. The in vitro antibacterial activity of the crosslinked nanofibers showed a stronger bacteriostatic effect on Staphylococcus aureus than on Escherichia coli. Human skin fibroblast cell proliferation on crosslinked GA vapor and HT nanofibers with 1% (w/v) CS and 2% (w/v) CET's protein demonstrated the highest among all the other crosslinked nanofibers after seven days of cell culture. Cell proliferation and cell morphology results revealed that introducing higher CET's protein concentration on crosslinked nanofibers could increase cell proliferation of the crosslinked nanofibers. Conclusion: These results are promising for the potential use of the crosslinked electrospun CET's protein-CS-PEO nanofibers as bioactive wound dressing materials.


Assuntos
Antibacterianos/farmacologia , Quitosana/química , Colocasia/química , Reagentes para Ligações Cruzadas/química , Nanofibras/química , Proteínas de Plantas/química , Tubérculos/química , Polietilenoglicóis/química , Animais , Proliferação de Células/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Células NIH 3T3 , Nanofibras/ultraestrutura , Proteínas de Plantas/ultraestrutura , Staphylococcus aureus/efeitos dos fármacos , Estresse Mecânico , Temperatura
10.
Int J Nanomedicine ; 15: 6451-6468, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922011

RESUMO

Background: Non-small cell lung cancer (NSCLC) is one of the most lethal types of cancer with highly infiltrating. Chemotherapy is far from satisfactory, vasculogenic mimicry (VM) and angiogenesis results in invasion, migration and relapse. Purpose: The objective of this study was to construct a novel CPP (mmp) modified vinorelbine and dioscin liposomes by two new functional materials, DSPE-PEG2000-MAL and CPP-PVGLIG-PEG5000, to destroy VM channels, angiogenesis, EMT and inhibit invasion and migration. Methods and Results: The targeting liposomes could be enriched in tumor sites through passive targeting, and the positively charged CPP was exposed and enhanced active targeting via electrostatic adsorption after being hydrolyzed by MMP2 enzymes overexpressed in the tumor microenvironment. We found that CPP (mmp) modified vinorelbine and dioscin liposomes with the ideal physicochemical properties and exhibited enhanced cellular uptake. In vitro and in vivo results showed that CPP (mmp) modified vinorelbine and dioscin liposomes could inhibit migration and invasion of A549 cells, destroy VM channels formation and angiogenesis, and block the EMT process. Pharmacodynamic studies showed that the targeting liposomes had obvious accumulations in tumor sites and magnificent antitumor efficiency. Conclusion: CPP (mmp) modified vinorelbine plus dioscin liposomes could provide a new strategy for NSCLC.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Microambiente Tumoral , Células A549 , Animais , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Morte Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Galinhas , Endocitose/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Hidrólise , Lipossomos , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Microambiente Tumoral/efeitos dos fármacos , Vinorelbina/farmacologia , Vinorelbina/uso terapêutico
11.
Ann Hematol ; 99(11): 2689-2698, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32974838

RESUMO

An open-label, crossover randomized study was performed to compare the pharmacokinetics (PK) of damoctocog alfa pegol and rurioctocog alfa pegol, two recombinant factor VIII (FVIII) products indicated in patients with hemophilia A, both conjugated to polyethylene glycol to reduce clearance and extend time in circulation. Adult patients (N = 18) with severe hemophilia A (FVIII < 1 IU/dL), previously treated with any FVIII product for ≥ 150 exposure days, were randomized to receive a single 50 IU/kg infusion of damoctocog alfa pegol followed by rurioctocog alfa pegol, or vice versa, with ≥ 7-day washout between doses. FVIII activity was measured using the one-stage clotting assay. PK parameters, including area under the curve from time 0 to the last data point (AUC0-tlast, primary parameter), dose-normalized AUC (AUCnorm), and time to threshold, were calculated based on 11 time points between 0.25 and 120 h post-dose and evaluated using a noncompartmental model. Due to differences in batch-specific vial content used for the study, actual administered median doses were 54.3 IU/kg for damoctocog alfa pegol and 61.4 IU/kg for rurioctocog alfa pegol. Based on actual dosing, a significantly higher geometric mean (coefficient of variation [%CV]) AUCnorm was observed for damoctocog alfa pegol (43.8 h kg/dL [44.0]) versus rurioctocog alfa pegol (36.0 h kg/dL [40.1, P < 0.001]). Based on population PK modeling, median time to reach 1 IU/dL was 16 h longer for damoctocog alfa pegol compared with rurioctocog alfa pegol. No adverse events or any immunogenicity signals were observed. Overall, damoctocog alfa pegol had a superior PK profile versus rurioctocog alfa pegol. Trial registration number: NCT04015492 ( ClinicalTrials.gov identifier). Date of registration: July 9, 2019.


Assuntos
Fator VIII , Hemofilia A , Adolescente , Adulto , Idoso , Estudos Cross-Over , Fator VIII/administração & dosagem , Fator VIII/farmacocinética , Meia-Vida , Hemofilia A/sangue , Hemofilia A/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinética
12.
Nat Commun ; 11(1): 4768, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958747

RESUMO

Detection and identification of proteins are typically achieved by analyzing protein size, charge, mobility and binding to antibodies, which are critical for biomedical research and disease diagnosis and treatment. Despite the importance, measuring these quantities with one technology and at the single-molecule level has not been possible. Here we tether a protein to a surface with a flexible polymer, drive it into oscillation with an electric field, and image the oscillation with a near field optical imaging method, from which we determine the size, charge, and mobility of the protein. We also measure antibody binding and conformation changes in the protein. The work demonstrates a capability for comprehensive protein analysis and precision protein biomarker detection at the single molecule level.


Assuntos
Proteínas/química , Proteínas/metabolismo , Imagem Individual de Molécula/métodos , Análise de Fourier , Ligantes , Polietilenoglicóis/química , Ligação Proteica , Conformação Proteica , Eletricidade Estática , Compostos de Estanho/química
13.
Zhonghua Zhong Liu Za Zhi ; 42(8): 617-623, 2020 Aug 23.
Artigo em Chinês | MEDLINE | ID: mdl-32867451

RESUMO

As a new type of anthracyclines, pegylated liposomal doxorubicin (PLD) is widely used in the treatment of a variety of malignant tumors, including soft tissue sarcoma, ovarian cancer, breast cancer, multiple myeloma, and so on. Compared with traditional anthracyclines, PLD can significantly decrease the incidences of adverse events such as cardiac toxicity and alopecia. However, the use of PLD will be accompanied with toxic side effects such as hand-foot syndrome, oral mucositis, and infusion reaction. This consensus will mainly focus on the mechanism, prevention and treatment of adverse events of PLD, in order to improve the therapeutic efficacy of PLD and life quality of patients.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Doxorrubicina/análogos & derivados , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Síndrome Mão-Pé/complicações , Neoplasias/tratamento farmacológico , Estomatite/complicações , Antibióticos Antineoplásicos/uso terapêutico , Consenso , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Feminino , Humanos , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/uso terapêutico , Guias de Prática Clínica como Assunto
14.
Zhonghua Zhong Liu Za Zhi ; 42(8): 692-696, 2020 Aug 23.
Artigo em Chinês | MEDLINE | ID: mdl-32867464

RESUMO

Objective: To evaluate the efficacy and safety of polyethylene glycol liposome doxorubicin (PLD) in the treatment of osteosarcoma. Methods: This study was a single-center retrospective clinical study. Two hundreds and seventy-six classical osteosarcoma treated in Beijing Jishuitan Hospital from 2015 to 2016 were enrolled. There were 213 patients who received combined chemotherapy of high dose methotrexate, ifosfamide, cisplatin and doxorubicin (ADM) were classified in ADM group. Other 63 patients received the same types, doses and cycles of chemotherapy drugs except ADM replaced by PLD were identified as PLD group. Clinical and imaging evaluation and surgical treatment were performed after neoadjuvant chemotherapy. Tumor necrosis rate was examined according to Huvos method. The efficacy of neoadjuvant chemotherapy was evaluated based on 90% necrosis rate. The recurrence, metastasis and survival were followed up regularly after operation. The adverse reactions of hematology, hepatorenal toxicity, gastrointestinal reaction and cardiotoxicity were evaluated. Results: There were no significant differences between PLD group and ADM group in age, sex, location, stage and surgical margin (all P>0.05). There were no significant differences in clinical symptoms and imaging evaluation between PLD group and ADM group after preoperative chemotherapy (all P>0.05). The tumor necrosis rate was detected in 134 cases. Among 27 cases of PLD group, tumor necrosis rates more than 90% were 11 cases, while among 107 cases of ADM group, tumor necrosis rates more than 90% were 45 cases. No significant difference of tumor necrosis rate between this two group was observed (P=0.901). The recurrence rates of PLD group and ADM group were 7.8% (4/51) and 7.3% (12/164), the metastasis rates were 19.6% (10/51) and 16.5% (27/164), the median progression free survival (PFS) were 42 and 37 months, respectively, without significant differences (all P>0.05). The incidence of granulocytopenia and decrease degree of granulocytes in PLD group were significantly lower than those in ADM group (P<0.001). There were no significant differences in the incidences of thrombocytopenia, anemia, gastrointestinal reaction, liver function damage and stomatitis between two groups (all P>0.05). Conclusions: PLD and ADM have similar chemotherapeutic effects in osteosarcoma. The incidences of adverse reactions of PLD are lower, especially the hematological toxicity represented by granulocytopenia is significantly reduced. PLD has a better application prospect.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/terapia , Lipossomos/uso terapêutico , Osteossarcoma/tratamento farmacológico , Neoplasias Ósseas/patologia , Cisplatino/administração & dosagem , Doxorrubicina/administração & dosagem , Extremidades , Humanos , Ifosfamida/administração & dosagem , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Recidiva Local de Neoplasia , Osteoblastos/efeitos dos fármacos , Osteoblastos/patologia , Osteossarcoma/patologia , Polietilenoglicóis , Prognóstico , Estudos Retrospectivos
15.
Int J Nanomedicine ; 15: 6503-6518, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922013

RESUMO

Objective: A non-lipolysis nanoemulsion (NNE) was designed to reduce the first-pass metabolism of raloxifene (RAL) by intestinal UDP-glucuronosyltransferases (UGTs) for increasing the oral absorption of RAL, coupled with in vitro and in vivo studies. Methods: In vitro stability of NNE was evaluated by lipolysis and the UGT metabolism system. The oral bioavailability of NNE was studied in rats and pigs. Finally, the absorption mechanisms of NNE were investigated by in situ single-pass intestinal perfusion (SPIP) in rats, Madin-Darby canine kidney (MDCK) cells model, and lymphatic blocking model. Results: The pre-NNE consisted of isopropyl palmitate, linoleic acid, Cremophor RH40, and ethanol in a weight ratio of 3.33:1.67:3:2. Compared to lipolysis nanoemulsion of RAL (RAL-LNE), the RAL-NNE was more stable in in vitro gastrointestinal buffers, lipolysis, and UGT metabolism system (p < 0.05). The oral bioavailability was significantly improved by the NNE (203.30%) and the LNE (205.89%) relative to the suspension group in rats. However, 541.28% relative bioavailability was achieved in pigs after oral NNE intake compared to the suspension and had two-fold greater bioavailability than the LNE (p < 0.05). The RAL-NNE was mainly absorbed in the jejunum and had high permeability at the intestine of rats. The results of both SPIP and MDCK cell models demonstrated that the RAL-NNE was absorbed via endocytosis mediated by caveolin and clathrin. The other absorption route, the lymphatic transport (cycloheximide as blocking agent), was significantly improved by the NNE compared with the LNE (p < 0.05). Conclusion: A NNE was successfully developed to reduce the first-pass metabolism of RAL in the intestine and enhance its lymphatic transport, thereby improving the oral bioavailability. Altogether, NNE is a promising carrier for the oral delivery of drugs with significant first-pass metabolism.


Assuntos
Absorção Fisico-Química , Emulsões/química , Lipólise , Nanopartículas/química , Cloridrato de Raloxifeno/metabolismo , Administração Oral , Animais , Disponibilidade Biológica , Transporte Biológico , Sobrevivência Celular , Cães , Emulsões/administração & dosagem , Feminino , Intestinos/fisiologia , Linfa/metabolismo , Células Madin Darby de Rim Canino , Masculino , Polietilenoglicóis , Ratos Sprague-Dawley , Tensoativos/química , Suínos
16.
Int J Nanomedicine ; 15: 4739-4752, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32753862

RESUMO

Purpose: Combined chemotherapeutic drug and protein drug has been a widely employed strategy for tumor treatment. To realize both tumor accumulation and deep tumor penetration for drugs with different pharmacokinetics, we propose a structure-transformable, thermo-pH dual responsive co-delivery system to co-load granzyme B/docetaxel (GrB/DTX). Methods: Thermo-sensitive hydrogels based on diblock copolymers (mPEG-b-PELG) were synthesized through ring opening polymerization. GrB/DTX mini micelles (GDM) was developed by co-loading these two drugs in pH-sensitive mini micelles, and the GDM-incorporated thermo-sensitive hydrogel (GDMH) was constructed. The thermo-induced gelation behavior of diblock copolymers and the physiochemical properties of GDMH were characterized. GDMH degradation and deep tumor penetration of released mini micelles were confirmed. The pH-sensitive disassembly and lysosomal escape abilities of released mini micelles were evaluated. In vitro cytotoxicity was studied using MTT assays and the in vivo antitumor efficacy study was evaluated in B16-bearing C57BL/6 mice. Results: GDMH was gelatinized at body temperature and can be degraded by proteinase to release mini micelles. The mini micelles incorporated in GDMH can achieve deep tumor penetration and escape from lysosomes to release GrB and DTX. MTT results showed that maximum synergistic antitumor efficacy of GrB and DTX was observed at mass ratio of 1:100. Our in vivo antitumor efficacy study showed that GDMH inhibited tumor growth in the subcutaneous tumor model and in the post-surgical recurrence model. Conclusion: The smart-designed transformable GDMH can facilitate tumor accumulation, deep tumor penetration, and rapid drug release to achieve synergistic chemo-protein therapy.


Assuntos
Antineoplásicos/uso terapêutico , Hidrogéis/química , Neoplasias/tratamento farmacológico , Temperatura , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Docetaxel/uso terapêutico , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Feminino , Granzimas/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Injeções , Camundongos Endogâmicos C57BL , Micelas , Neoplasias/patologia , Polietilenoglicóis/química
17.
Medicine (Baltimore) ; 99(30): e21251, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32791701

RESUMO

INTRODUCTION: Cranioplasty following decompressive craniectomy is routinely performed to restore integrity of skull and improve neurological function. However, reconstructing the cranial defect brings many challenges to neurosurgeons and search for ideal implant materials is one of the most controversial issues. Although many studies have compared the outcomes of titanium and polyetheretherketone (PEEK) cranioplasty, yet no prospective study exists to guide the choice of titanium and PEEK materials. METHODS/DESIGN: A non-randomized, partially blinded, prospective cohort study is described that comprehensively compares the long-term outcomes of titanium cranioplasty versus PEEK cranioplasty. One hundred forty-five patients for each group will be recruited. Eligible patients are those with cranial defect due to traumatic brain injury (≥ 16 years), defect size is over 25 cm and they must agree to participate in the trial. Each participant is evaluated before surgery, on discharge, 3, 6, and 12 months after cranioplasty. The primary outcome is the infection, implant failure and implant deformation requiring revision surgery within 12 months. Secondary outcomes include postoperative complication rate, neurological outcomes, motor function, and cosmetic outcome over a 6-month period. DISCUSSION: Search for ideal implant materials is throughout the history of cranioplasty. This study will provide robust evidence for the choice of cranioplasty materials. TRIAL REGISTRATION NUMBER: ChiCTR2000033406.


Assuntos
Lesões Encefálicas Traumáticas/cirurgia , Craniectomia Descompressiva/métodos , Titânio/uso terapêutico , Humanos , Cetonas/uso terapêutico , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados não Aleatórios como Assunto , Polietilenoglicóis/uso terapêutico , Estudos Prospectivos
18.
BMC Infect Dis ; 20(1): 590, 2020 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778058

RESUMO

BACKGROUND: Antiviral therapy is recommended for patients with immune-active chronic hepatitis B (CHB) to decrease the risk of liver-related complications. However, the outcomes of the pegylated IFN-α (PEG-IFN-α) therapy vary among CHB patients. We aimed to identify factors that can influence the outcomes in CHB patients who received antiviral PEG-IFN-α monotherapy. METHODS: Thirty-two CHB patients who received PEG-IFN-α monotherapy were enrolled in this study. All of the patients underwent two liver biopsies at baseline and 6 months after the initiation of the therapy. CD8+ T cells, CD4+ T cells, CD68+ mononuclear cells, and PD-1 levels in the 64 liver biopsy specimens were examined via immunofluorescence. RESULTS: The overall median frequency of CD8+ T cells in the liver tissues of 32 CHB patients significantly decreased at 6 months after the therapy initiation (p < 0.01). In the FIER (fibrosis and inflammation response with HBeAg seroconversion) group, CD8+PD-1+ T cells significantly decreased at 6 months (p < 0.05), while CD8+PD-1- T cells had no significant difference. On the contrary, in the FIENR (no fibrosis and inflammation response and HBeAg seroconversion) group, CD8+PD-1- T cells significantly decreased after 6 months of PEG-IFN-α treatment (p < 0.05), while CD8+PD-1+ T cells had no significant difference. In addition, the levels of CD68+ mononuclear cells in the FIER group showed an overall increasing trend after treatment (p < 0.05). CONCLUSIONS: The changes in the levels of CD8+PD-1+ T cells and CD68+ mononuclear cells may be related to the response to PEG-IFN-α therapy.


Assuntos
Antivirais/uso terapêutico , Linfócitos T CD8-Positivos/metabolismo , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Fígado/patologia , Polietilenoglicóis/uso terapêutico , Adulto , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Antígenos E da Hepatite B/sangue , Antígenos E da Hepatite B/imunologia , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Fígado/metabolismo , Masculino , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Recombinantes/uso terapêutico , Adulto Jovem
19.
Braz Oral Res ; 34: e099, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32785474

RESUMO

The composition of infiltrants can influence their physical properties, viscosity and depth of penetration (DP). Strategies are used to increase the DP, such as the addition of diluents or the use of heat. This study aimed to evaluate the effect of preheating and composition on physical properties and DP of infiltrants in demineralized enamel. The groups were assigned, and the following experimental formulations were made: 25%BisEMA +75%TEGDMA; 25%BisEMA +65%TEGDMA +10%ethanol; 25%BisEMA +65%TEGDMA +10%HEMA; 100%TEGDMA; 90%TEGDMA +10%ethanol; 90%TEGDMA +10%HEMA. The samples were photoactivated at two temperatures (25°C and 55°C). Degree of conversion (DC) was performed using an infrared spectrophotometer. Elastic modulus (E), flexural strength (FS) and contact angle (CA) tests were also performed. The DP of an infiltrant in demineralized enamel was determined by confocal laser scanning microscopy (CLSM) using an indirect labeling technique. The data were analyzed by two-way ANOVA and Tukey's test. DC increased after preheating in all the groups; however, 90%TEGDMA+10%ethanol showed the lowest DC for both temperatures, and the lowest E. Preheating did not influence E or FS. The CA increased at 55°C for most groups, but decreased for groups containing HEMA. Temperature did not seem to influence DP, and Icon showed the lowest DP values. The 100%TEGDMA composition showed more homogeneous penetration, whereas Icon showed heterogeneous and superficial penetration. The preheating technique does not improve all properties in all the material compositions. The composition of a material can influence and improve its properties.


Assuntos
Esmalte Dentário , Bis-Fenol A-Glicidil Metacrilato , Resinas Compostas , Módulo de Elasticidade , Teste de Materiais , Metacrilatos , Polietilenoglicóis , Ácidos Polimetacrílicos , Viscosidade
20.
Int J Nanomedicine ; 15: 5217-5226, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801687

RESUMO

Aim: Chronic use of oral nonsteroidal anti-inflammatory drugs (NSAIDs) is commonly associated with gastric irritation and gastric ulceration. Therefore, the aim of study was to develop a novel oral drug delivery system with minimum gastric effects and improved dissolution rate for aceclofenac (ACF), a model BCS class-II drug. Methods: Self-emulsifying drug delivery systems (SEDDS) were formulated to increase the solubility and ultimately the oral bioavailability of ACF. Oleic acid was used as an oil phase, Tween 80 (T80) and Kolliphor EL (KEL) were used as surfactants, whereas, polyethylene glycol 400 (PEG 400) and propylene glycol (PG) were employed as co-surfactants. Optimized formulations (F1, F2, F3 and F4) were analyzed for droplet size, poly dispersity index (PDI), cell viability studies, in vitro dissolution in both simulated gastric fluid and simulated intestinal fluid, ex vivo permeation studies and thermodynamic stability. Results: The optimized formulations showed mean droplet sizes in the range of 111.3 ± 3.2 nm and 470.9 ± 12.52 nm, PDI from 244.6 nm to 389.4 ± 6.51 and zeta-potential from -33 ± 4.86 mV to -38.5 ± 5.15 mV. Cell viability studies support the safety profile of all formulations for oral administration. The in vitro dissolution studies and ex vivo permeation analysis revealed significantly improved drug release ranging from 95.68 ± 0.02% to 98.15 ± 0.71% when compared with control. The thermodynamic stability studies confirmed that all formulations remain active and stable for a longer period. Conclusion: In conclusion, development of oral SEDDS might be a promising tool to improve the dissolution of BCS class-II drugs along with significantly reduced exposure to gastric mucosa.


Assuntos
Diclofenaco/análogos & derivados , Sistemas de Liberação de Medicamentos/métodos , Emulsões/química , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Disponibilidade Biológica , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Diclofenaco/administração & dosagem , Diclofenaco/farmacocinética , Liberação Controlada de Fármacos , Emulsões/administração & dosagem , Excipientes/química , Humanos , Masculino , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Polietilenoglicóis/química , Polissorbatos/química , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/farmacocinética , Ratos Sprague-Dawley , Solubilidade , Tensoativos/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA