Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 48.785
Filtrar
1.
Int J Mol Sci ; 22(9)2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064412

RESUMO

Epidermal growth factor receptor (EGFR) is one of the most promising molecular targets for anticancer therapy. We used boron clusters as a platform for generation of new materials. For this, functional DNA constructs conjugated with boron clusters (B-ASOs) were developed. These B-ASOs, built from 1,2-dicarba-closo-dodecaborane linked with two anti-EGFR antisense oligonucleotides (ASOs), form with their complementary congeners torus-like nanostructures, as previously shown by atomic force microscope (AFM) and transmission electron cryo-microscopy (cryo-TEM) imaging. In the present work, deepened studies were carried out on B-ASO's properties. In solution, B-ASOs formed four dominant complexes as confirmed by non-denaturing polyacrylamide gel electrophoresis (PAGE). These complexes exhibited increased stability in cell lysate comparing to the non-modified ASO. Fluorescently labeled B-ASOs localized mostly in the cytoplasm and decreased EGFR expression by activating RNase H. Moreover, the B-ASO complexes altered the cancer cell phenotype, decreased cell migration rate, and arrested the cells in the S phase of cell cycle. The 1,2-dicarba-closo-dodecaborane-containing nanostructures did not activate NLRP3 inflammasome in human macrophages. In addition, as shown by inductively coupled plasma mass spectrometry (ICP MS), these nanostructures effectively penetrated the human squamous carcinoma cells (A431), showing their potential applicability as anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Boranos/farmacologia , Regulação Neoplásica da Expressão Gênica , Nanopartículas/química , Oligonucleotídeos Antissenso/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Boranos/síntese química , Boranos/metabolismo , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Movimento Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Células HeLa , Humanos , Cinética , Células MCF-7 , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/metabolismo , Fase S/efeitos dos fármacos , Fase S/genética , Transdução de Sinais
2.
Nat Commun ; 12(1): 3453, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103484

RESUMO

A once every eight-week cabotegravir (CAB) long-acting parenteral is more effective than daily oral emtricitabine and tenofovir disoproxil fumarate in preventing human immunodeficiency virus type one (HIV-1) transmission. Extending CAB dosing to a yearly injectable advances efforts for the elimination of viral transmission. Here we report rigor, reproducibility and mechanistic insights for a year-long CAB injectable. Pharmacokinetic (PK) profiles of this nanoformulated CAB prodrug (NM2CAB) are affirmed at three independent research laboratories. PK profiles in mice and rats show plasma CAB levels at or above the protein-adjusted 90% inhibitory concentration for a year after a single dose. Sustained native and prodrug concentrations are at the muscle injection site and in lymphoid tissues. The results parallel NM2CAB uptake and retention in human macrophages. NM2CAB nanocrystals are stable in blood and tissue homogenates. The long apparent drug half-life follows pH-dependent prodrug hydrolysis upon slow prodrug nanocrystal dissolution and absorption. In contrast, solubilized prodrug is hydrolyzed in hours in plasma and tissues from multiple mammalian species. No toxicities are observed in animals. These results affirm the pharmacological properties and extended apparent half-life for a nanoformulated CAB prodrug. The report serves to support the mechanistic design for drug formulation safety, rigor and reproducibility.


Assuntos
Liberação Controlada de Fármacos , Lipídeos/química , Nanopartículas/química , Pró-Fármacos/farmacologia , Piridonas/farmacocinética , Animais , Composição de Medicamentos , Endocitose , Humanos , Cinética , Masculino , Camundongos Endogâmicos BALB C , Piridonas/administração & dosagem , Piridonas/sangue , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Distribuição Tecidual
3.
Nat Commun ; 12(1): 3460, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103491

RESUMO

Lack or dysfunction of the lymphatics leads to secondary lymphedema formation that seriously reduces the function of the affected organs and results in degradation of quality of life. Currently, there is no definitive treatment option for lymphedema. Here, we utilized nucleoside-modified mRNA encapsulated in lipid nanoparticles (LNPs) encoding murine Vascular Endothelial Growth Factor C (VEGFC) to stimulate lymphatic growth and function and reduce experimental lymphedema in mouse models. We demonstrated that administration of a single low-dose of VEGFC mRNA-LNPs induced durable, organ-specific lymphatic growth and formation of a functional lymphatic network. Importantly, VEGFC mRNA-LNP treatment reversed experimental lymphedema by restoring lymphatic function without inducing any obvious adverse events. Collectively, we present a novel application of the nucleoside-modified mRNA-LNP platform, describe a model for identifying the organ-specific physiological and pathophysiological roles of the lymphatics, and propose an efficient and safe treatment option that may serve as a novel therapeutic tool to reduce lymphedema.


Assuntos
Linfangiogênese/genética , Vasos Linfáticos/patologia , Linfedema/patologia , Nucleosídeos/metabolismo , Fator C de Crescimento do Endotélio Vascular/genética , Animais , Vasos Sanguíneos/patologia , Proliferação de Células/efeitos dos fármacos , Toxina Diftérica/farmacologia , Modelos Animais de Doenças , Células HEK293 , Humanos , Imunidade/efeitos dos fármacos , Injeções Intradérmicas , Lipídeos/administração & dosagem , Lipídeos/química , Vasos Linfáticos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Nanopartículas/administração & dosagem , Nanopartículas/química , Especificidade de Órgãos , Poli C/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tamoxifeno/farmacologia , Fator C de Crescimento do Endotélio Vascular/administração & dosagem , Fator C de Crescimento do Endotélio Vascular/metabolismo
4.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34066280

RESUMO

We previously designed a Carbopol gel formulation (N-IND/MEN) based on a combination of indomethacin solid nanoparticles (IND-NPs) and l-menthol, and we reported that the N-IND/MEN showed high transdermal penetration. However, the detailed mechanism for transdermal penetration of IND-NPs was not clearly defined. In this study, we investigated whether endocytosis in the skin tissue of rat and Göttingen minipig is related to the transdermal penetration of IND-NPs using pharmacological inhibitors of endocytosis. The pharmacological inhibitors used in this study are as follows: 54 µM nystatin, a caveolae-mediated endocytosis (CavME) inhibitor; 40 µM dynasore, a clathrin-mediated endocytosis (CME) inhibitor; and 2 µM rottlerin, a micropinocytosis (MP) inhibitor. The N-IND/MEN was prepared by a bead mill method, and the particle size of solid indomethacin was 79-216 nm. In both rat and Göttingen minipig skin, skin penetration of approximately 80% IND-NPs was limited by the stratum corneum (SC), although the penetration of SC was improved by the combination of l-menthol. On the other hand, the treatment of nystatin and dynasore decreased the transdermal penetration of indomethacin in rats and Göttingen minipigs treated with N-IND/MEN. Moreover, in addition to nystatin and dynasore, rottlerin attenuated the transdermal penetration of IND-NPs in the Göttingen minipigs' skin. In conclusion, we found that l-menthol enhanced the SC penetration of IND-NPs. In addition, this study suggests that the SC-passed IND-NPs are absorbed into the skin tissue by energy-dependent endocytosis (CavME, CME, and/or MP pathways) on the epidermis under the SC, resulting in an enhancement in transdermal penetration of IND-NPs. These findings provide significant information for the design of nanomedicines in transdermal formulations.


Assuntos
Endocitose , Indometacina/administração & dosagem , Mentol/administração & dosagem , Nanopartículas/administração & dosagem , Absorção Cutânea , Pele/efeitos dos fármacos , Administração Cutânea , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Antipruriginosos/administração & dosagem , Composição de Medicamentos , Metabolismo Energético , Masculino , Nanopartículas/química , Ratos , Suínos , Porco Miniatura
5.
Biosensors (Basel) ; 11(5)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064591

RESUMO

This study proposes a non-enzymatic glucose sensor fabricated by synthesizing high-purity TiO2 nanoparticles in thermal plasma and depositing it directly on a substrate and then depositing chitosan-polypyrrole (CS-PPy) conductive polymer films by electrochemical method. The structural properties of the deposited TiO2 nanoparticles were analyzed by X-ray diffraction (XRD) and dynamic light scattering (DLS) system. The chemical composition and structural properties of the TiO2 nanoparticle layer and the conductive polymer films were confirmed by X-ray photoelectron spectroscopy (XPS) spectra and scanning electron microscope (SEM). The glucose detection characteristics of the fabricated biosensor were determined by cyclic voltammetry (CV). CS-PPy/TiO2 biosensor showed high sensitivity of 302.0 µA mM-1 cm-2 (R2 = 0.9957) and low detection limit of 6.7 µM. The easily manufactured CS-PPy/TiO2 biosensor showed excellent selectivity and reactivity.


Assuntos
Técnicas Biossensoriais , Glucose/química , Nanopartículas/química , Quitosana/química , Técnicas Eletroquímicas , Polímeros , Pirróis , Titânio
6.
Biosensors (Basel) ; 11(5)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068452

RESUMO

Lanthanide-doped upconversion nanoparticles (UCNPs) are promising bioimaging nanoprobes due to their excellent photostability. As one of the most commonly used lanthanide activators, Tm3+ ions have perfect ladder-type electron configuration and can be directly excited by bio-friendly near-infrared-II (NIR-II) wavelengths. Here, the emission characteristics of Tm3+-doped nanoparticles under laser excitations of different near-infrared-II wavelengths were systematically investigated. The 1064 nm, 1150 nm, and 1208 nm lasers are proposed to be three excitation strategies with different response spectra of Tm3+ ions. In particular, we found that 1150 nm laser excitation enables intense three-photon 475 nm emission, which is nearly 100 times stronger than that excited by 1064 nm excitation. We further optimized the luminescence brightness after investigating the luminescence quenching mechanism of bare NaYF4: Tm (1.75%) core. After growing an inert shell, a ten-fold increase of emission intensity was achieved. Combining the advantages of NIR-II wavelength and the higher-order nonlinear excitation, a promising facile excitation strategy was developed for the application of thulium-doped upconversion nanoparticles in nanoparticles imaging and cancer cell microscopic imaging.


Assuntos
Técnicas Biossensoriais , Nanopartículas/química , Lasers , Luz , Luminescência , Neoplasias/diagnóstico por imagem , Análise Espectral , Túlio
7.
Int J Nanomedicine ; 16: 3581-3598, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34079251

RESUMO

Background: BF211, a derivative of bufalin (BF), shows significantly improved solubility and potent antitumor efficiency compared to BF. Unfortunately, the unwanted toxicity such as cardiotoxicity caused by unspecific distribution has hindered its clinical use. Methods: PEGylated BF211 liposomes (BF211@Lipo) were designed and optimizely prepared based on the pre-prescription research. In vitro and in vivo cardiotoxicity was evaluated. In vivo pharmacokinetics and biodistribution of BF211@Lipo were investigated. In vivo antitumor activity and toxicity were evaluated in HepG2 cell xenograft models. The rapid-release triggered by Poloxamer 188 (P188) was assessed in vitro and in vivo. Results: The optimized BF211@Lipo displayed a spherical morphology with a size of (164.6 ± 10.3) nm and a high encapsulation efficiency of (93.24 ± 2.15) %. The in vivo concentration-time curves of BF211 loaded in liposomes showed a prolonged half-life in plasma and increased tumor accumulation. No obvious abnormality in electrocardiograms was observed in guinea pigs even at 9 mg/kg. Moreover, to improve the efficient release of BF211@Lipo, a surfactant-assisted rapid-release strategy was developed, and the release-promoting mechanism was revealed by the fluorescence resonance energy transfer (FRET) and fluorescence nanoparticle tracking analysis (fl-NTA) technology. Sequential injection of BF211@Lipo and P188 could ignite the "cold" liposomes locally in tumor regions, facilitating the burst release of BF211 and enhancing the therapeutic index. Conclusion: Our progressive efforts that begin with preparation technology and dosage regimen enable BF211 to like a drug, providing a promising nano platform to deliver the cardiac glycosides and alleviate the side effects by decreasing unspecific biodistribution.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Bufanolídeos/administração & dosagem , Bufanolídeos/farmacologia , Coração/efeitos dos fármacos , Tensoativos/química , Animais , Antineoplásicos/química , Antineoplásicos/toxicidade , Bufanolídeos/química , Bufanolídeos/toxicidade , Cobaias , Células Hep G2 , Humanos , Lipossomos , Nanopartículas/química , Poloxâmero/química , Solubilidade , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Int J Nanomedicine ; 16: 3173-3183, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34007172

RESUMO

Aim: Cerebral ischemic injury is one of the debilitating diseases showing that inflammation plays an important role in worsening ischemic damage. Therefore, studying the effects of some potential anti-inflammatory compounds can be very important in the treatment of cerebral ischemic injury. Methods: This study investigated anti-inflammatory effects of triblock copolymer nanomicelles loaded with curcumin (abbreviated as NC) in the brain of rats following transient cerebral ischemia/reperfusion (I/R) injury in stroke. After preparation of NC, their protective effects against bilateral common carotid artery occlusion (BCCAO) were explored by different techniques. Concentrations of free curcumin (C) and NC in liver, kidney, brain, and heart organs, as well as in plasma, were measured using a spectrofluorometer. Western blot analysis was then used to measure NF-κB-p65 protein expression levels. Also, ELISA assay was used to examine the level of cytokines IL-1ß, IL-6, and TNF-α. Lipid peroxidation levels were assessed using MDA assay and H&E staining was used for histopathological examination of the hippocampus tissue sections. Results: The results showed a higher level of NC compared to C in plasma and organs including the brain, heart, and kidneys. Significant upregulation of NF-κB, IL-1ß, IL-6, and TNF-α expressions compared to control was observed in rats after induction of I/R, which leads to an increase in inflammation. However, NC was able to downregulate significantly the level of these inflammatory cytokines compared to C. Also, the level of lipid peroxidation in pre-treated rats with 80mg/kg NC was significantly reduced. Conclusion: Our findings in the current study demonstrate a therapeutic effect of NC in an animal model of cerebral ischemia/reperfusion (I/R) injury in stroke through the downregulation of NF-κB-p65 protein and inflammatory cytokines.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Inflamação/tratamento farmacológico , Micelas , NF-kappa B/metabolismo , Nanopartículas/química , Polímeros/química , Transdução de Sinais , Animais , Anti-Inflamatórios/farmacologia , Encéfalo/patologia , Isquemia Encefálica/sangue , Isquemia Encefálica/complicações , Curcumina/farmacologia , Citocinas/sangue , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Inflamação/complicações , Inflamação/patologia , Lactatos/química , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Nanopartículas/ultraestrutura , Fosforilação/efeitos dos fármacos , Polietilenoglicóis/química , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Distribuição Tecidual/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo
9.
Int J Nanomedicine ; 16: 3241-3254, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34007176

RESUMO

Purpose: Immune checkpoint inhibitors (ICIs) and sonodynamic therapy (SDT) are types of immunotherapy. In order to combine soluble programmed cell death protein 1 (sPD-1)-mediated immune checkpoint therapy and chlorin e6 (Ce6)-assisted SDT, nanobubbles (NBs) were generated to simultaneously load sPD-1 and Ce6. Materials and Methods: The sPD-1/Ce6-NBs, which were prepared by thin-film hydration and mechanical oscillation, had a stable physical condition, and delivered sPD-1 and Ce6 in a targeted manner. NBs could strengthen tumor suppression by increasing tumor-targeting accumulation of Ce6 and sPD-1, and by inducing ultrasound-targeted NB destruction. A mouse H22 cell hepatoma xenograft model was used to evaluate the synergetic immunotherapeutic effect and mechanism of sPD-1/Ce6-NBs. Results: By observing the tumor inhibition rate, tissue and cell apoptosis, apoptosis-related genes and protein expression, the best immunotherapeutic effect was exhibited by the sPD-1/Ce6-NBs group. The immunotherapeutic mechanism initially demonstrated that when tumor cells were transfected by sPD-1 delivered by NBs, which downregulated the expression of programmed death-ligand 1 (PD-L1) in tumor cells, and blocked the PD-1/PD-L1 signaling pathway, which improved T-cell-mediated tumor inhibition. Furthermore, ICIs combined with SDT induced immunogenic cell death by translocating calreticulin to the cell surface and then synergistically enhancing antitumor immune responses. Conclusion: In conclusion, sPD-1/Ce6-NBs were successfully designed. Ultrasound-mediated sPD-1/Ce6-NBs are potentially effective delivery systems for combination immunotherapy of hepatocellular carcinoma.


Assuntos
Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/terapia , Imunoterapia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/terapia , Nanopartículas/química , Porfirinas/uso terapêutico , Receptor de Morte Celular Programada 1/metabolismo , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos BALB C , Nanopartículas/ultraestrutura , Porfirinas/farmacocinética , Porfirinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Carga Tumoral
10.
Bioconjug Chem ; 32(5): 1034-1046, 2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-33951913

RESUMO

SARS-CoV-2 caused the COVID-19 pandemic that lasted for more than a year. Globally, there is an urgent need to use safe and effective vaccines for immunization to achieve comprehensive protection against SARS-CoV-2 infection. Focusing on developing a rapid vaccine platform with significant immunogenicity as well as broad and high protection efficiency, we designed a SARS-CoV-2 spike protein receptor-binding domain (RBD) displayed on self-assembled ferritin nanoparticles. In a 293i cells eukaryotic expression system, this candidate vaccine was prepared and purified. After rhesus monkeys are immunized with 20 µg of RBD-ferritin nanoparticles three times, the vaccine can elicit specific humoral immunity and T cell immune response, and the neutralizing antibodies can cross-neutralize four SARS-CoV-2 strains from different sources. In the challenge protection test, after nasal infection with 2 × 105 CCID50 SARS-CoV-2 virus, compared with unimmunized control animals, virus replication in the vaccine-immunized rhesus monkeys was significantly inhibited, and respiratory pathology observations also showed only slight pathological damage. These analyses will benefit the immunization program of the RBD-ferritin nanoparticle vaccine in the clinical trial design and the platform construction to present a specific antigen domain in the self-assembling nanoparticle in a short time to harvest stable, safe, and effective vaccine candidates for new SARS-CoV-2 isolates.


Assuntos
/imunologia , Nanopartículas/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Linfócitos T/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Sítios de Ligação , Linfócitos T CD8-Positivos/imunologia , Ferritinas/química , Ferritinas/metabolismo , Imunidade Humoral , Macaca mulatta , Masculino , Nanopartículas/metabolismo , /fisiologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Linfócitos T/metabolismo , Ultracentrifugação
11.
Int J Nanomedicine ; 16: 3091-3103, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33953557

RESUMO

Objective: To synthesize and determine the antifungal activity of AgBr-nanoparticles (NP) @CTMAB (cetyltrimethyl-ammonium bromide) against Candida albicans (C. albicans) for use in the field of denture cleaning. Methods: The morphology and structure of AgBr-NP@CTMAB were characterized by IR, UV-Vis, XRD and SEM. The antifungal potential of AgBr-NP@CTMAB against C. albicans was determined by colony formation assay and growth curve analysis. PMMA containing AgBr-NP@CTMAB was prepared, and the long-term antifungal efficacy was analyzed. The effect against C. albicans biofilm was analyzed by SEM and OD600 , and the color changes of the specimens were observed by stereomicroscopy after 1 week of incubation. Cytotoxicity to human oral gingival fibroblasts and oral mucosal epithelial cells was detected by Cell Counting Kit-8 (CCK-8) in vitro. Results: The compound showed a good crystalline phase, the presence of AgBr nanoparticles and the hybridization of CTMAB+ with AgBr-NPs. AgBr-NP@CTMAB showed significant antifungal activity against C. albicans at concentrations of 10 µg/mL and 20 µg/mL. PMMA specimens containing AgBr-NP@CTMAB showed no long-term antifungal effect against C. albicans biofilm. The clearance rate of C. albicans attached to PMMA was 44.73% after soaking in 10 µg/mL AgBr-NP@CTMAB solution for 30 min and 91.35% for 8 h. There was no significant residual cytotoxicity or visual color change after soaking. Significance: AgBr-NP@CTMAB showed promising potential treatment for denture cleaners.


Assuntos
Antifúngicos/síntese química , Antifúngicos/farmacologia , Cetrimônio/química , Nanopartículas/química , Polimetil Metacrilato/química , Antifúngicos/química , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Candida albicans/fisiologia , Técnicas de Química Sintética , Humanos , Nanotecnologia
12.
Int J Nanomedicine ; 16: 3041-3057, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33948084

RESUMO

Background: The dentin exposure always leads to dentin hypersensitivity and/or caries. Given the dentin's tubular structure and low mineralization degree, reestablishing an effective biobarrier to stably protect dentin remains significantly challenging. This study reports a versatile dentin surface biobarrier consisting of a mesoporous silica-based epigallocatechin-3-gallate (EGCG)/nanohydroxyapatite delivery system and evaluates its stability on the dentinal tubule occlusion and the Streptococcus mutans (S. mutans) biofilm inhibition. Materials and Methods: The mesoporous delivery system was fabricated and characterized. Sensitive dentin discs were prepared and randomly allocated to three groups: 1, control group; 2, casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) group; and 3, the mesoporous delivery system group. The dentin permeability, dentinal tubule occlusion, acid and abrasion resistance, and S. mutans biofilm inhibition were determined for 1 week and 1 month. The in vitro release profiles of EGCG, Ca, and P were also monitored. Results: The mesoporous delivery system held the ability to sustainably release EGCG, Ca, and P and could persistently occlude dentinal tubules with acid and abrasion resistance, reduce the dentin permeability, and inhibit the S. mutans biofilm formation for up to 1 month compared with the two other groups. The system provided prolonged stability to combat oral adverse challenges and served as an effective surface biobarrier to protect the exposed dentin. Conclusion: The establishment of the dentin surface biobarrier consisting of a mesoporous delivery system indicates a promising strategy for the prevention and the management of dentin hypersensitivity and caries after enamel loss.


Assuntos
Biofilmes/crescimento & desenvolvimento , Dentina/química , Streptococcus mutans/fisiologia , Ácidos , Adsorção , Biofilmes/efeitos dos fármacos , Cálcio/análise , Caseínas/farmacologia , Catequina/análogos & derivados , Catequina/química , Catequina/farmacologia , Morte Celular/efeitos dos fármacos , Contagem de Colônia Microbiana , Polpa Dentária/citologia , Humanos , Nanopartículas/química , Nanopartículas/ultraestrutura , Nitrogênio/química , Permeabilidade , Fósforo/análise , Porosidade , Dióxido de Silício/química , Streptococcus mutans/ultraestrutura
13.
Int J Nanomedicine ; 16: 3275-3292, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34007177

RESUMO

Purpose: Neuropathic pain causes great distress among patients; however, its response to traditional analgesia techniques remains sub-optimal. There has been progress in stem cell research for neuropathic pain treatment; however, effective homing remains problematic. This study aimed to establish Fe3O4@polydopamine(PDA)-labeled mesenchymal stem cells (MSCs); moreover, we aimed to guide MSCs using a magnetic field to the spinal cord segments showing pain-related responses to allow MSC homing and gathering, in advance, in order to fully employ their repair function. Materials and Methods: Fe3O4@PDA-labeled MSCs were characterized using transmission electron microscopy. We analyzed the characteristics of MSCs, as well as the nanoparticle effects on MSC activity, differentiation, and proliferation, using the CCK-8 method, flow cytometry, and staining. Using rats, we performed behavioral tests of mechanical and thermal pain hypersensitivity. Serum inflammatory markers were detected using ELISA. Finally, changes in proteins associated with spinal cord pain were detected through quantitative reverse transcription PCR, histology, and immunohistochemistry. Results: Fe3O4@PDA did not affect the characteristics and viability of MSCs. The magnetic field guidance improved the therapeutic effect of Fe3O4@PDA-labeled MSCs as indicated by the paw withdrawal threshold. Fe3O4@PDA-labeled MSCs decreased spinal nerve demyelination and c-Fos expression (a pain molecule); moreover, they inhibited microglia and astrocyte activation. Conclusion: Fe3O4@PDA-labeled MSCs showed better homing to the spinal cord under magnetic field guidance. Moreover, they inhibited microglial and astrocyte activation, as well as played an early and continuous role in neuropathic pain treatment.


Assuntos
Portadores de Fármacos/química , Compostos Férricos/química , Indóis/química , Campos Magnéticos , Células-Tronco Mesenquimais/química , Células-Tronco Mesenquimais/citologia , Neuralgia/terapia , Polímeros/química , Animais , Diferenciação Celular , Masculino , Transplante de Células-Tronco Mesenquimais , Microglia/patologia , Nanopartículas/química , Neuralgia/patologia , Ratos , Medula Espinal/patologia
14.
Biomed Res Int ; 2021: 6693585, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33969124

RESUMO

Purpose: The purpose of this retrospective study was to evaluate the advantages of carbon nanoparticles in neck dissection and to conclude its application in the treatment of clinically node-negative papillary thyroid carcinoma (CN0PTC). Methods: As a retrospective cohort study, we divided the enrolled patients into two groups, the carbon nanoparticle (CN) group and the control group according to the usage of CN. In the CN group, CN was applied to reveal drainage lymph nodes and the picked LNs were sent for fast frozen testing. If metastasis exits, modified radical lateral lymph node dissection (LLND) was performed. For both groups, prophylactic central lymph node dissection was routinely done. Finally, the demographic information, tumor characteristics, postoperative pathological results, and laboratory data were collected for analysis. Results: A total of 61 CN0PTC were enrolled in this study, 33 in the CN group and 28 in the control group. The black-stained rate for CN was 29/40 (72.5%) with a positive prediction rate of 34.5%. The mainly black-stained region in the lateral neck was level III and possesses the highest lymph node ratio (17.5%). The metastasis that occurred in level VI was 30% and 11.8% in the CN and control groups, respectively (p = 0.058). During the available follow-up, no one showed recurrence. Statistical analysis showed that the CN suspension can significantly reduce the risk of damage to the parathyroid gland (p = 0.001 for hypocalcemia, <0.05; p = 0.047 for hypoparathyroidism, <0.05). Conclusion: The lateral neck metastasis in patients with papillary thyroid microcarcinoma in clinical stage cT1aN0 is not rare. CN can help surgeons to distinguish the real person who actually needs LLND. In prophylactic CLND, CN acts as a tracer which makes the parathyroid gland more identifiable and avoids risks of injuries to nerves and glands.


Assuntos
Carbono/química , Linfonodos/patologia , Nanopartículas/química , Esvaziamento Cervical , Câncer Papilífero da Tireoide/cirurgia , Neoplasias da Glândula Tireoide/cirurgia , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino
15.
Nat Commun ; 12(1): 2633, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976149

RESUMO

Ebola virus (EBOV) glycoprotein (GP) can be recognized by neutralizing antibodies (NAbs) and is the main target for vaccine design. Here, we first investigate the contribution of the stalk and heptad repeat 1-C (HR1C) regions to GP metastability. Specific stalk and HR1C modifications in a mucin-deleted form (GPΔmuc) increase trimer yield, whereas alterations of HR1C exert a more complex effect on thermostability. Crystal structures are determined to validate two rationally designed GPΔmuc trimers in their unliganded state. We then display a modified GPΔmuc trimer on reengineered protein nanoparticles that encapsulate a layer of locking domains (LD) and a cluster of helper T-cell epitopes. In mice and rabbits, GP trimers and nanoparticles elicit cross-ebolavirus NAbs, as well as non-NAbs that enhance pseudovirus infection. Repertoire sequencing reveals quantitative profiles of vaccine-induced B-cell responses. This study demonstrates a promising vaccine strategy for filoviruses, such as EBOV, based on GP stabilization and nanoparticle display.


Assuntos
Vacinas contra Ebola/administração & dosagem , Glicoproteínas/administração & dosagem , Doença pelo Vírus Ebola/terapia , Proteínas Virais/administração & dosagem , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Antígenos Virais/administração & dosagem , Antígenos Virais/genética , Antígenos Virais/imunologia , Antígenos Virais/ultraestrutura , Linfócitos B/imunologia , Cristalografia por Raios X , Modelos Animais de Doenças , Vacinas contra Ebola/genética , Vacinas contra Ebola/imunologia , Ebolavirus/genética , Ebolavirus/imunologia , Epitopos de Linfócito T/administração & dosagem , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/ultraestrutura , Feminino , Glicoproteínas/genética , Glicoproteínas/imunologia , Glicoproteínas/ultraestrutura , Doença pelo Vírus Ebola/sangue , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/virologia , Humanos , Camundongos , Nanopartículas/química , Domínios Proteicos/genética , Domínios Proteicos/imunologia , Engenharia de Proteínas , Multimerização Proteica/genética , Multimerização Proteica/imunologia , Estabilidade Proteica , Coelhos , Linfócitos T Auxiliares-Indutores/imunologia , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/genética , Vacinas de Subunidades/imunologia , Proteínas Virais/genética , Proteínas Virais/imunologia , Proteínas Virais/ultraestrutura
16.
Nat Commun ; 12(1): 2614, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33972525

RESUMO

The differentiation of neural stem cells (NSCs) into neurons is proposed to be critical in devising potential cell-based therapeutic strategies for central nervous system (CNS) diseases, however, the determination and prediction of differentiation is complex and not yet clearly established, especially at the early stage. We hypothesize that deep learning could extract minutiae from large-scale datasets, and present a deep neural network model for predictable reliable identification of NSCs fate. Remarkably, using only bright field images without artificial labelling, our model is surprisingly effective at identifying the differentiated cell types, even as early as 1 day of culture. Moreover, our approach showcases superior precision and robustness in designed independent test scenarios involving various inducers, including neurotrophins, hormones, small molecule compounds and even nanoparticles, suggesting excellent generalizability and applicability. We anticipate that our accurate and robust deep learning-based platform for NSCs differentiation identification will accelerate the progress of NSCs applications.


Assuntos
Aprendizado Profundo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurogênese/genética , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Células Cultivadas , Simulação por Computador , Imunofluorescência , Hormônios/farmacologia , Microscopia Eletrônica de Transmissão , Nanopartículas/química , Nanopartículas/ultraestrutura , Fatores de Crescimento Neural/farmacologia , Redes Neurais de Computação , Células-Tronco Neurais/efeitos dos fármacos , Neurônios/citologia , Neurônios/metabolismo , Oligodendroglia/citologia , Oligodendroglia/metabolismo , Ratos
17.
Nat Commun ; 12(1): 3187, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-34045459

RESUMO

Failure of conventional clinical therapies such as tumor resection and chemotherapy are mainly due to the ineffective control of tumor metastasis. Metastasis consists of three steps: (i) tumor cells extravasate from the primary sites into the circulation system via epithelial-mesenchymal transition (EMT), (ii) the circulating tumor cells (CTCs) form "micro-thrombi" with platelets to evade the immune surveillance in circulation, and (iii) the CTCs colonize in the pre-metastatic niche. Here, we design a systemic metastasis-targeted nanotherapeutic (H@CaPP) composed of an anti-inflammatory agent, piceatannol, and an anti-thrombotic agent, low molecular weight heparin, to hinder the multiple steps of tumor metastasis. H@CaPP is found efficiently impeded EMT, inhibited the formation of "micro-thrombi", and prevented the development of pre-metastatic niche. When combined with surgical resection or chemotherapy, H@CaPP efficiently inhibits tumor metastasis and prolonged overall survival of tumor-bearing mice. Collectively, we provide a simple and effective systemic metastasis-targeted nanotherapeutic for combating tumor metastasis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Portadores de Fármacos/química , Neoplasias Mamárias Experimentais/terapia , Metástase Neoplásica/terapia , Nanomedicina Teranóstica/métodos , Animais , Anti-Inflamatórios/administração & dosagem , Anticoagulantes/administração & dosagem , Linhagem Celular Tumoral/transplante , Quimioterapia Adjuvante/métodos , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Heparina de Baixo Peso Molecular/administração & dosagem , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Glândulas Mamárias Animais/patologia , Glândulas Mamárias Animais/cirurgia , Neoplasias Mamárias Experimentais/patologia , Camundongos , Nanopartículas/química , Células Neoplásicas Circulantes/efeitos dos fármacos , Paclitaxel/administração & dosagem , Estudo de Prova de Conceito , Ratos , Estilbenos/administração & dosagem
18.
Int J Nanomedicine ; 16: 3457-3472, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34045853

RESUMO

Purpose: Malignant melanoma is one of the most devastating types of cancer with rapid relapse and low survival rate. Novel strategies for melanoma treatment are currently needed to enhance therapeutic efficiency for this disease. In this study, we fabricated a multifunctional drug delivery system that incorporates dacarbazine (DTIC) and indocyanine green (ICG) into manganese-doped mesoporous silica nanoparticles (MSN(Mn)) coupled with magnetic resonance imaging (MRI) and photothermal imaging (PI), for achieving the superior antitumor effect of combined chemo-photothermal therapy. Materials and Methods: MSN(Mn) were characterized in terms of size and structural properties, and drug loading and release efficiency MSN(Mn)-ICG/DTIC were analyzed by UV spectra. Photothermal imaging effect and MR imaging effect of MSN(Mn)-ICG/DTIC were detected by thermal imaging system and 3.0 T MRI scanner, respectively. Then, the combined chemo-phototherapy was verified in vitro and in vivo by morphological evaluation, ultrasonic and pathological evaluation. Results: The as-synthesized MSN(Mn) were characterized as mesoporous spherical nanoparticles with 125.57±5.96 nm. MSN(Mn)-ICG/DTIC have the function of drug loading-release which loading ratio of ICG and DTIC could reach to 34.25±2.20% and 50.00±3.24%, and 32.68±2.10% of DTIC was released, respectively. Manganese doping content could reach up to 65.09±2.55 wt%, providing excellent imaging capability in vivo which the corresponding relaxation efficiency was 14.33 mM-1s-1. And outstanding photothermal heating ability and stability highlighted the potential biomedical applicability of MSN(Mn)-ICG/DTIC to kill cancer cells. Experiments by A375 melanoma cells and tumor-bearing mice demonstrated that the compound MSN(Mn)-ICG/DTIC have excellent biocompatibility and our combined therapy platform delivered a superior antitumor effect compared to standalone treatment in vivo and in vitro. Conclusion: Our findings demonstrate that composite MSN(Mn)-ICG/DTIC could serve as a multifunctional platform to achieve a highly effective chemo-photothermal combined therapy for melanoma treatment.


Assuntos
Imageamento por Ressonância Magnética , Melanoma/diagnóstico por imagem , Melanoma/terapia , Terapia Fototérmica , Animais , Linhagem Celular Tumoral , Terapia Combinada , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Doxorrubicina/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Humanos , Verde de Indocianina/química , Melanoma/tratamento farmacológico , Melanoma/patologia , Camundongos , Nanopartículas/química , Dióxido de Silício/química
19.
Mol Pharm ; 18(6): 2448-2453, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33983745

RESUMO

Nanomedicine has demonstrated a substantial role in vaccine development against severe acute respiratory syndrome coronavirus (SARS-CoV-2 and COVID-19). Although nanomedicine-based vaccines have now been validated in millions of individuals worldwide in phase 4 and tracking of sex-disaggregated data on COVID-19 is ongoing, immune responses that underlie COVID-19 disease outcomes have not been clarified yet. A full understanding of sex-role effects on the response to nanomedicine products is essential to building an effective and unbiased response to the pandemic. Here, we exposed model lipid nanoparticles (LNPs) to whole blood of 18 healthy donors (10 females and 8 males) and used flow cytometry to measure cellular uptake by circulating leukocytes. Our results demonstrated significant differences in the uptake of LNP between male and female natural killer (NK) cells. The results of this proof-of-concept study show the importance of recipient sex as a critical factor which enables researchers to better consider sex in the development and administration of vaccines for safer and more-efficient sex-specific outcomes.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Nanopartículas/química , SARS-CoV-2/imunologia , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/química , Composição de Medicamentos/métodos , Ácidos Graxos Monoinsaturados/química , Feminino , Voluntários Saudáveis , Humanos , Imunogenicidade da Vacina , Lipossomos , Masculino , Pandemias/prevenção & controle , Compostos de Amônio Quaternário/química , Fatores Sexuais , Resultado do Tratamento
20.
Nat Commun ; 12(1): 2934, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006860

RESUMO

Immunometabolic intervention has been applied to treat cancer via inhibition of certain enzymes associated with intratumoral metabolism. However, small-molecule inhibitors and genetic modification often suffer from insufficiency and off-target side effects. Proteolysis targeting chimeras (PROTACs) provide an alternative way to modulate protein homeostasis for cancer therapy; however, the always-on bioactivity of existing PROTACs potentially leads to uncontrollable protein degradation at non-target sites, limiting their in vivo therapeutic efficacy. We herein report a semiconducting polymer nano-PROTAC (SPNpro) with phototherapeutic and activatable protein degradation abilities for photo-immunometabolic cancer therapy. SPNpro can remotely generate singlet oxygen (1O2) under NIR photoirradiation to eradicate tumor cells and induce immunogenic cell death (ICD) to enhance tumor immunogenicity. Moreover, the PROTAC function of SPNpro is specifically activated by a cancer biomarker (cathepsin B) to trigger targeted proteolysis of immunosuppressive indoleamine 2,3-dioxygenase (IDO) in the tumor of living mice. The persistent IDO degradation blocks tryptophan (Trp)-catabolism program and promotes the activation of effector T cells. Such a SPNpro-mediated in-situ immunometabolic intervention synergizes immunogenic phototherapy to boost the antitumor T-cell immunity, effectively inhibiting tumor growth and metastasis. Thus, this study provides a polymer platform to advance PROTAC in cancer therapy.


Assuntos
Imunoterapia/métodos , Neoplasias Mamárias Experimentais/terapia , Nanopartículas/química , Polímeros/química , Animais , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Transmissão , Terapia de Alvo Molecular/métodos , Nanopartículas/ultraestrutura , Fotoquimioterapia/métodos , Semicondutores , Espectrofotometria/métodos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...