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1.
Phys Rev Lett ; 126(13): 138004, 2021 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-33861109

RESUMEN

While the interplay between liquid-liquid phase separation (LLPS) and glass formation in biological systems is highly relevant for their structure formation and thus function, the exact underlying mechanisms are not well known. The kinetic arrest originates from the slowdown at the molecular level, but how this propagates to the dynamics of microscopic phase domains is not clear. Since with diffusion, viscoelasticity, and hydrodynamics, distinctly different mechanisms are at play, the dynamics needs to be monitored on the relevant time and length scales and compared to theories of phase separation. Using x-ray photon correlation spectroscopy, we determine the LLPS dynamics of a model protein solution upon low temperature quenches and find distinctly different dynamical regimes. We observe that the early stage LLPS is driven by the curvature of the free energy and speeds up upon increasing quench depth. In contrast, the late stage dynamics slows down with increasing quench depth, fingerprinting a nearby glass transition. The dynamics observed shows a ballistic type of motion, implying that viscoelasticity plays an important role during LLPS. We explore possible explanations based on the Cahn-Hilliard theory with nontrivial mobility parameters and find that these can only partially explain our findings.


Asunto(s)
Modelos Químicos , gammaglobulinas/química , Transición de Fase , Espectroscopía de Fotoelectrones , Polietilenglicoles/química , Soluciones
2.
Int J Nanomedicine ; 16: 2357-2372, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33790554

RESUMEN

Purpose: Non-small cell lung cancer (NSCLC) is an aggressive tumor with high mortality and poor prognosis. In this study, we designed a liposome encapsulating polymeric micelles (PMs) loaded with vinorelbine (NVB) and cis-diamminedichloroplatinum (II) (cisplatin or CDDP) for the treatment of NSCLC. Materials and Methods: Sodium poly(α-l-glutamic acid)-graft-methoxy-polyethylene glycol (PLG-G-PEG5K) was used to prepare NVB-loaded NVB-PMs and CDDP-loaded CDDP-PMs that were co-encapsulated into liposomes by a reverse evaporation method, yielding NVB and CDDP co-delivery liposomes (CoNP-lips) composed of egg phosphatidyl lipid-80/cholesterol/DPPG/DSPE-mPEG2000 at a molar ratio of 52:32:14:2. The CoNP-lips were characterized in terms of particle size, zeta potential, drug content, encapsulation efficiency, and structural properties. Drug release by the CoNP-lips as well as their stability and cytotoxicity was evaluated in vitro, and their antitumor efficacy was assessed in a mouse xenograft model of Lewis lung carcinoma cell-derived tumors. Results: CoNP-lips had a spherical shape with uniform size distribution; the average particle size was 162.97±9.06 nm, and the average zeta potential was -13.02±0.22 mV. In vitro cytotoxicity analysis and the combination index demonstrated that the CoNP-lips achieved a synergistic cytotoxic effect at an NVB:CDDP weight ratio of 2:1 in an NSCLC cell line. There was sustained release of both drugs from CoNP-lips. The pharmacokinetic analysis showed that CoNP-lips had a higher plasma half-life than NP solution, with 6.52- and 8.03-fold larger areas under the receiver operating characteristic curves of NVB and CDDP. CoNP-lips showed antitumor efficacy in tumor-bearing C57BL/6 mice and drug accumulation in tumors via the enhanced permeability and retention effect. Conclusion: CoNP-lips are a promising formulation for targeted therapy in NSCLC.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Cisplatino/uso terapéutico , Sistemas de Liberación de Medicamentos , Neoplasias Pulmonares/tratamiento farmacológico , Micelas , Polímeros/química , Vinorelbina/uso terapéutico , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cisplatino/administración & dosificación , Cisplatino/farmacocinética , Cisplatino/farmacología , Liberación de Fármacos , Humanos , Liposomas , Neoplasias Pulmonares/patología , Masculino , Ratones Endogámicos C57BL , Nanopartículas/ultraestructura , Tamaño de la Partícula , Polietilenglicoles/química , Ratas Sprague-Dawley , Distribución Tisular , Vinorelbina/farmacocinética , Vinorelbina/farmacología
3.
Molecules ; 26(5)2021 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-33670890

RESUMEN

Prostate cancer is one of the most common cancers in men. Cell invasion is an important step in the process of cancer metastasis. Herein, gold nanorods (GNRs) and polyethylene glycol (PEG)-coated GNRs were conjugated with polydopamine (PDA). The PDA-nanoconjugates demonstrated excellent colloidal stability upon lyophilization and dispersion in cell culture media with or without the addition of fetal bovine albumin (FBS), compared to unconjugated GNRs. PDA-nanoconjugates exhibited a considerable cytotoxicity against DU-145 and PC3 prostate cancer cell lines over a concentration range of 48 µg/mL-12 µg/mL, while they were biocompatible over a concentration range of 3.0 µg/mL-0.185 µg/mL. Furthermore, PDA-nanoconjugates demonstrated possible anti-invasion activity towards prostate cancer cell lines, particularly DU-145 cell line, by reducing cell migration and cell adhesion properties. The PDA-nanoconjugates could be considered a promising nano-platform toward cancer treatment by reducing the invasion activity; it could also be considered a drug delivery system for chemotherapeutic agents.


Asunto(s)
Antineoplásicos/química , Oro/química , Indoles/química , Nanoconjugados/química , Nanotubos/química , Polímeros/química , Neoplasias de la Próstata/tratamiento farmacológico , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Materiales Biocompatibles/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Masculino , Polietilenglicoles/química , Propiedades de Superficie
4.
Int J Nanomedicine ; 16: 2283-2295, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33776433

RESUMEN

Background: Paclitaxel (PTX) has interesting anticancer activity. However, it is insoluble in water, which seriously hinders its use in clinical. Superparamagnetic iron oxide nanoparticles (SPIONs) are used as an ideal drug delivery system. Therefore, we proposed a folic acid (FA) targeting drug-loaded SPIONs to reduce its adverse reaction. Methods: To improve the hydrophilicity of PTX, the structure of PTX was modified by succinic anhydride to obtain 2'-succinate paclitaxel (SPTX). FA conjugated Polyethylene glycol (PEG)/polyethyleneimine (PEI)-SPIONs SPTX-loaded nanoparticles (SPTX@FA@PEG/PEI-SPIONs) were prepared by solvent volatilization and hydrogen bond adsorption, and the nano-formulation was optimized by response surface methodology (RSM). The characteristics, antitumor effect in vitro, pharmacokinetics, and biodistribution of SPTX@FA@PEG/PEI-SPIONs were evaluated. Results: SPTX was successfully loaded on the surface of FA@PEG/PEI-SPIONs. The formation of SPTX@FA@PEG/PEI-SPIONs was exhibited water-dispersive monodispersity with high stability by RSM, and dynamic light scattering (DLS) was 178.1±3.12 nm, particle size observed in the transmission electron microscope (TEM) was 13.01±1.10 nm, and the encapsulation efficiency (EE) and loading efficiency (LE) were 81.1±1.66% and 14.8±1.46%, respectively. It enhanced the stability in normal physiological condition, accelerated drug release at tumorous pH, and preferentially prolonged the circulation time. In vitro, the SPTX@FA@PEG/PEI-SPIONs significantly targeted to folate receptor (FR) positive cancers cell (HNE-1) via the receptor-ligand mediated pathway, resulting in effective cytotoxic activity. Pharmacokinetic results demonstrated that SPTX@FA@PEG/PEI-SPIONs (t1/2=3.41 h) had longer than free SPTX or PTX (t1/2=1.67 h) in rats in vivo. Tissue distribution studies showed that SPTX@FA@PEG/PEI-SPIONs were present at high levels in the liver and help in targeting the folate receptors present on the kidneys. Conclusion: These results suggest that SPTX@FA@PEG/PEI-SPIONs offer a highly promising approach to control drug release, improve drug pharmacokinetics and actively target the nasopharyngeal carcinoma.


Asunto(s)
Ácido Fólico/química , Paclitaxel/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Liberación de Fármacos , Humanos , Iminas/química , Concentración 50 Inhibidora , Carcinoma Nasofaríngeo/tratamiento farmacológico , Carcinoma Nasofaríngeo/patología , Paclitaxel/sangre , Paclitaxel/farmacocinética , Paclitaxel/uso terapéutico , Tamaño de la Partícula , Polietilenglicoles/química , Polietilenos/química , Ratas , Espectrofotometría Ultravioleta , Espectroscopía Infrarroja por Transformada de Fourier , Electricidad Estática , Succinatos/química , Distribución Tisular/efectos de los fármacos
5.
Int J Nanomedicine ; 16: 1943-1960, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33727808

RESUMEN

Introduction: The overexpression of Human Epidermal Growth Factor Receptor 2 (HER2) is usually associated with aggressive and infiltrating breast cancer (BC) phenotype, and metastases. Functionalized silica-based nanocarriers (SiNPs) can be labeled for in vivo imaging applications and loaded with chemotherapy drugs, making possible the simultaneous noninvasive diagnosis and treatment (theranostic) for HER2-positive BC. Methods: Firstly, FITC-filled SiNPs, were engineered with two different amounts of Hc-TZ (trastuzumab half-chain) per single nanoparticle (1:2 and 1:8, SiNPs to Hc-TZ ratio), which was 99mTc-radiolabeled at histidine residues for ex vivo and in vivo biodistribution evaluations. Secondly, nanoparticles were loaded with DOX and their in vitro and ex vivo/in vivo delivery was assessed, in comparison with liposomal Doxorubicin (Caelyx). Finally, the treatment efficacy of DOX-SiNPs-TZ (1:8 Hc-TZ) was evaluated in vivo by PET and supported by MS-based proteomics profiling of tumors. Results: SiNPs-TZ (1:8 Hc-TZ) tumor uptake was significantly greater than that of SiNPs-TZ (1:2 Hc-TZ) at 6 hours post-injection (p.i.) in ex vivo biodistribution experiment. At 24 h p.i., radioactivity values remained steady. Fluorescence microscopy, confirmed the presence of radiolabeled SiNPs-TZ (1:8 Hc-TZ) within tumor even at later times. SiNPs-TZ (1:8 Hc-TZ) nanoparticles loaded with Doxorubicin (DOX-SiNPs-TZ) showed a similar DOX delivery capability than Caelyx (at 6 h p.i.), in in vitro and ex vivo assays. Nevertheless, at the end of treatment, tumor volume was significantly reduced by DOX-SiNPs-TZ (1:8 Hc-TZ), compared to Caelyx and DOX-SiNPs treatment. Proteomics study identified 88 high stringent differentially expressed proteins comparing the three treatment groups with controls. Conclusion: These findings demonstrated a promising detection specificity and treatment efficacy for our system (SiNPs-TZ, 1:8 Hc-TZ), encouraging its potential use as a new theranostic agent for HER2-positive BC lesions. In addition, proteomic profile confirmed that a set of proteins, related to tumor aggressiveness, were positively affected by targeted nanoparticles.


Asunto(s)
Neoplasias de la Mama/diagnóstico , Portadores de Fármacos/química , Nanopartículas/química , Radiofármacos/química , Receptor ErbB-2/metabolismo , Dióxido de Silicio/química , Tecnecio/química , Animales , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Doxorrubicina/análogos & derivados , Doxorrubicina/química , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Endocitosis , Femenino , Fluoresceína-5-Isotiocianato/química , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Polietilenglicoles/química , Polietilenglicoles/farmacología , Polietilenglicoles/uso terapéutico , Proteoma/metabolismo , Proteómica , Radiofármacos/farmacocinética , Tecnecio/farmacocinética , Distribución Tisular/efectos de los fármacos , Tomografía Computarizada de Emisión de Fotón Único , Resultado del Tratamiento
6.
Carbohydr Polym ; 260: 117823, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33712164

RESUMEN

A bio-based pressure-responsive sensor with adjustable structural color is prepared by combining aerogel skeleton of cellulose nanocrystals (CNCs)/poly(ethylene glycol) (PEG) obtained via the ice-templating method with flexible polyacrylamide (PAAM) elastomer. The white aerogel is composed of consecutive ribbons, demonstrating chiral nematic structure. These ribbons are rearranged to be vertical to the force direction, leading to immediate appearance of the structural color when the 3D aerogel transforms to a 2D plane. Helical pitches are regulated by the PEG content that the wavelength of structural color covers up to 178 nm. There is an excellent linear correlation between pressure and transmittance of reflectance peak, and the sensitivity to pressure can be regulated by changing solid content of PAAM. Furthermore, the pressure-responsive color is still vivid after 16 cycles of compression. This flexible material with pressure-responsive structural color is promising in sensing, intelligent display, information transmission, and etc.


Asunto(s)
Técnicas Biosensibles/métodos , Geles/química , Presión , Resinas Acrílicas/química , Celulosa/química , Fuerza Compresiva , Nanopartículas/química , Polietilenglicoles/química
7.
Nat Commun ; 12(1): 1673, 2021 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-33723263

RESUMEN

There are increasing efforts to engineer functional compartments that mimic cellular behaviours from the bottom-up. One behaviour that is receiving particular attention is motility, due to its biotechnological potential and ubiquity in living systems. Many existing platforms make use of the Marangoni effect to achieve motion in water/oil (w/o) droplet systems. However, most of these systems are unsuitable for biological applications due to biocompatibility issues caused by the presence of oil phases. Here we report a biocompatible all aqueous (w/w) PEG/dextran Pickering-like emulsion system consisting of liposome-stabilised cell-sized droplets, where the stability can be easily tuned by adjusting liposome composition and concentration. We demonstrate that the compartments are capable of negative chemotaxis: these droplets can respond to a PEG/dextran polymer gradient through directional motion down to the gradient. The biocompatibility, motility and partitioning abilities of this droplet system offers new directions to pursue research in motion-related biological processes.


Asunto(s)
Liposomas/química , Quimiotaxis , Dextranos/química , Emulsiones , Movimiento (Física) , Tamaño de la Partícula , Polietilenglicoles/química , Agua
8.
Int J Nanomedicine ; 16: 1575-1586, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33664572

RESUMEN

Background: Exosomes are a type of membrane vesicles secreted by living cells. Recent studies suggest exosome-like nanovesicles (ELNVs) from fruits and vegetables are involved in tissue renewal process and functional regulation against inflammatory diseases or cancers. However, there are few reports on ELNVs derived from medicinal plants. Methods: ELNVs derived from Asparagus cochinchinensis (Lour.) Merr. (ACNVs) were isolated and characterized. Cytotoxicity, antiproliferative and apoptosis-inducing capacity of ACNVs against hepatoma carcinoma cell were assessed. The endocytosis mechanism of ACNVs was evaluated on Hep G2 cells in the presence of different endocytosis inhibitors. In vivo distribution of ACNVs was detected in healthy and tumor-bearing mice after scavenger receptors (SRs) blockade. PEG engineering of ACNVs was achieved through optimizing the pharmacokinetic profiles. In vivo antitumor activity and toxicity were evaluated in Hep G2 cell xenograft model. Results: ACNVs were isolated and purified using a differential centrifugation method accompanied by sucrose gradient ultracentrifugation. The optimized ACNVs had an average size of about 119 nm and showed a typical cup-shaped nanostructure containing lipids, proteins, and RNAs. ACNVs were found to possess specific antitumor cell proliferation activity associated with an apoptosis-inducing pathway. ACNVs could be internalized into tumor cells mainly via phagocytosis, but they were quickly cleared once entering the blood. Blocking the SRs or PEGylation decoration prolonged the blood circulation time and increased the accumulation of ACNVs in tumor sites. In vivo antitumor results showed that PEGylated ACNVs could significantly inhibit tumor growth without side effects. Conclusion: This study provides a promising functional nano platform derived from edible Asparagus cochinchinensis that can be used in antitumor therapy with negligible side effects.


Asunto(s)
Asparagaceae/química , Carcinoma Hepatocelular/patología , Exosomas/metabolismo , Neoplasias Hepáticas/patología , Nanopartículas/química , Nanotecnología , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Endocitosis/efectos de los fármacos , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/efectos adversos , Nanopartículas/ultraestructura , Polietilenglicoles/química , Distribución Tisular/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Carbohydr Polym ; 259: 117710, 2021 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-33673989

RESUMEN

Harmful algal blooms induce severe environmental problems. It is challenging to remove algae by the current available treatments involving complicate process and costly instruments. Here, we developed a CaO2@PEG-loaded water-soluble self-branched chitosan (CP-SBC) system, which can remove algae from water in one-step without additional instrumentation. This approach utilizes a novel flocculant (self-branched chitosan) integrated with flotation function (induced by CaO2@PEG). CP-SBC exhibited better flocculation performance than commercial flocculants, which is attributed to the enhanced bridging and sweeping effect of branched chitosan. CP-SBC demonstrated outstanding biocompatibility, which was verified by zebrafish test and algae activity test. CaO2@PEG-loaded self-branched chitosan can serve as an "Air flotation system" to spontaneous float the flocs after flocculation by sustainably released O2. Furthermore, CP-SBC can improve water quality through minimizing dissolved oxygen depletion and reducing total phosphorus concentrations.


Asunto(s)
Quitosano/química , Floraciones de Algas Nocivas/fisiología , Animales , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Compuestos de Calcio/química , Floculación/efectos de los fármacos , Floraciones de Algas Nocivas/efectos de los fármacos , Cinética , Larva/efectos de los fármacos , Óxidos/química , Oxígeno/química , Fósforo/química , Polietilenglicoles/química , Porosidad , Pez Cebra/crecimiento & desarrollo , Pez Cebra/fisiología
10.
Molecules ; 26(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652827

RESUMEN

The application of physiologically based pharmacokinetic models to nanoparticles is still very restricted and challenging, owing to the complicated in vivo transport mechanisms involving nanoparticles, including phagocytosis, enhanced permeability and retention effects, cellular recognition, and internalisation, enzymatic degradation, lymphatic transport, and changes in physical properties. In our study, five nanoparticle formulations were synthesised using polycaprolactone as a framework material and methoxy poly (ethylene glycol)-poly(ε-caprolactone) as a long-circulating decorating material, as well as types of environmentally responsive near-infrared aza-boron-dipyrromethene dyes. According to quantification data and direct visualisation involving specific organs, a phagocytosis physiologically based pharmacokinetic model was developed to describe the dynamics of nanoparticles within and between organs in mice, considering cellular mechanisms involving phagocytosis and enhanced permeability and retention effects. Our results offer a better understanding of the in vivo fate of polymeric nanoparticles.


Asunto(s)
Colorantes/química , Sistemas de Liberación de Medicamentos , Nanopartículas/química , Farmacocinética , Animales , Simulación por Computador , Humanos , Ratones , Poliésteres/química , Polietilenglicoles/química , Polímeros/química
11.
Molecules ; 26(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652957

RESUMEN

Multidrug resistance (MDR) remains a major problem in cancer therapy and is characterized by the overexpression of p-glycoprotein (P-gp) efflux pump, upregulation of anti-apoptotic proteins or downregulation of pro-apoptotic proteins. In this study, an Apolipoprotein A1 (ApoA1)-modified cationic liposome containing a synthetic cationic lipid and cholesterol was developed for the delivery of a small-molecule chemotherapeutic drug, doxorubicin (Dox) to treat MDR tumor. The liposome-modified by ApoA1 was found to promote drug uptake and elicit better therapeutic effects than free Dox and liposome in MCF-7/ADR cells. Further, loading Dox into the present ApoA1-liposome systems enabled a burst release at the tumor location, resulting in enhanced anti-tumor effects and reduced off-target effects. More importantly, ApoA1-lip/Dox caused fewer adverse effects on cardiac function and other organs in 4T1 subcutaneous xenograft models. These features indicate that the designed liposomes represent a promising strategy for the reversal of MDR in cancer treatment.


Asunto(s)
Apolipoproteína A-I/química , Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/análogos & derivados , Apolipoproteína A-I/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/química , Doxorrubicina/farmacología , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Células MCF-7 , Polietilenglicoles/química , Polietilenglicoles/farmacología
12.
Phys Rev Lett ; 126(8): 088102, 2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33709739

RESUMEN

The interaction between proteins and hydration water stabilizes protein structure and promotes functional dynamics, with water translational motions enabling protein flexibility. Engineered solvent-free protein-polymer hybrids have been shown to preserve protein structure, function, and dynamics. Here, we used neutron scattering, protein and polymer perdeuteration, and molecular dynamics simulations to explore how a polymer dynamically replaces water. Even though relaxation rates and vibrational properties are strongly modified in polymer coated compared to hydrated proteins, liquidlike polymer dynamics appear to plasticize the conjugated protein in a qualitatively similar way as do hydration-water translational motions.


Asunto(s)
Polímeros/química , Proteínas/química , Diaminas/química , Glicolatos/química , Enlace de Hidrógeno , Simulación de Dinámica Molecular , Mioglobina/química , Difracción de Neutrones , Polietilenglicoles/química , Conformación Proteica , Termodinámica , Agua/química
13.
Int J Nanomedicine ; 16: 1457-1472, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33654396

RESUMEN

Purpose: Rheumatoid arthritis is an autoimmune disorder that directly affects joints. However, other body organs including heart, eyes, skin, blood vessels and lungs may also be affected. The purpose of this study was to design and evaluate a nanoemulgel formulation of diflunisal (DIF) and solubility enhanced diflunisal (DIF-IC) for enhanced topical anti-inflammatory activity. Methodology: Nanoemulsion formulations of both DIF and DIF-IC were prepared and incorporated in three different gelling agents, namely carboxymethylcellulose sodium (CMC-Na), sodium alginate (Na-ALG) and xanthan gum (XG). All the formulations were evaluated in term of particle size, pH, conductivity, viscosity, zeta potential and in vitro drug release. The formulation 2 (NE2) of both DIF and DIF-IC which expressed optimum release and satisfactory physicochemical properties was incorporated with gelling agents to produce final nanoemulgel formulations. The optimized nanoemulgel formulation was subjected to three different in vivo anti-inflammatory models including carrageenan-induced paw edema model, histamine-induced paw edema model and formalin-induced paw edema model. Results: DIF-IC-loaded nanoemulgel formulations yielded significantly enhanced in vitro skin permeation than DIF-loaded nanoemulgel. The nanoemulgel formulation of DIF-IC formulated with XG produced improved in vivo anti-inflammatory activity. Conclusion: It was recommended that DIF-IC-based nanoemulgel formulation prepared with XG could be a better option for effective topical treatment of inflammatory conditions.


Asunto(s)
Diflunisal/administración & dosificación , Sistemas de Liberación de Medicamentos , Emulsiones/química , Nanogeles/química , Polietilenglicoles/química , Polietileneimina/química , Administración Tópica , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Carragenina , Diflunisal/química , Diflunisal/farmacología , Diflunisal/uso terapéutico , Modelos Animales de Enfermedad , Composición de Medicamentos , Liberación de Fármacos , Edema/tratamiento farmacológico , Edema/patología , Conductividad Eléctrica , Concentración de Iones de Hidrógeno , Masculino , Tamaño de la Partícula , Permeabilidad , Transición de Fase , Ratas , Piel/efectos de los fármacos , Absorción Cutánea/efectos de los fármacos , Solubilidad , Tensoactivos/química , Viscosidad
14.
Int J Nanomedicine ; 16: 1473-1485, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33654397

RESUMEN

Purpose: The near-infrared fluorescent dye indocyanine green (ICG) has shown great potential in the photodynamic therapy (PDT) and photothermal therapy (PTT) of cancer. However, its disadvantages of instability in aqueous solution, short half-life, and non-targeting accumulation limit the effectiveness of ICG PDT/PTT. To overcome the disadvantages of ICG in tumor treatment, we designed PEGylated-human serum albumin (PHSA)-ICG-TAT. In this nanoparticle, PEG4000, the HSA package, and nuclear targeting peptide TAT (human immunodeficiency virus 1 [HIV-1]-transactivator protein) were used to improve the water solubility of ICG, prolong the life span of ICG in vivo, and target the nuclei of tumor cells, respectively. Methods: The PHSA-ICG-TAT was characterized in terms of morphology and size, ultraviolet spectrum, dispersion stability, singlet oxygen and cellular uptake, and colocalization using transmission electron microscopy and dynamic light scattering, and fluorescence assay, respectively. Subsequently, the anti-tumor effect of PHSA-ICG-TAT was investigated via in vitro and in vivo experiments, including cell viability, apoptosis, comet assays, histopathology, and inhibition curves. Results: The designed ICG-loaded nanoparticle had a higher cell uptake rate and stronger PDT/PTT effect than free ICG. The metabolism of PHSA-ICG-TAT in normal mice revealed that there was no perceptible toxicity. In vivo imaging of mice showed that PHSA-ICG-TAT had a good targeting effect on tumors. PHSA-ICG-TAT was used for the phototherapy of tumors, and significantly suppressed the tumor growth. The tumor tissue sections showed that the cell gap and morphology of the tumor tissue had been obviously altered after treatment with PHSA-ICG-TAT. Conclusion: These results indicate that the PHSA-ICG-TAT had a significant therapeutic effect against tumors.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Núcleo Celular/metabolismo , Nanopartículas/química , Fotoquimioterapia , Fármacos Fotosensibilizantes/uso terapéutico , Animales , Neoplasias de la Mama/patología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Dispersión Dinámica de Luz , Femenino , Fluorescencia , Colorantes Fluorescentes/química , Humanos , Verde de Indocianina/química , Ratones Endogámicos BALB C , Nanopartículas/ultraestructura , Fármacos Fotosensibilizantes/farmacología , Polietilenglicoles/química , Albúmina Sérica Humana/química
15.
Int J Mol Sci ; 22(4)2021 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-33546481

RESUMEN

Antibody drug conjugates (ADCs) have become an important modality of clinical cancer treatment. However, traditional ADCs have some limitations, such as reduced permeability in solid tumors due to the high molecular weight of monoclonal antibodies, difficulty in preparation and heterogeneity of products due to the high drug/antibody ratio (4-8 small molecules per antibody). Miniaturized ADCs may be a potential solution, although their short circulation half-life may lead to new problems. In this study, we propose a novel design strategy for miniaturized ADCs in which drug molecules and small ligand proteins are site-specifically coupled via a bifunctional poly(ethylene glycol) (PEG) chain. The results showed that the inserted PEG chains significantly prolonged the circulation half-life but also obviously reduced the cytotoxicity of the conjugates. Compared with the conjugate ZHER2-SMCC-MMAE (HM), which has no PEG insertion, ZHER2-PEG4K-MMAE (HP4KM) and ZHER2-PEG10K-MMAE (HP10KM) with 4 or 10 kDa PEG insertions have 2.5- and 11.2-fold half-life extensions and 4.5- and 22-fold in vitro cytotoxicity reductions, respectively. The combined effect leads to HP10KM having the most ideal tumor therapeutic ability at the same dosages in the animal model, and its off-target toxicity was also reduced by more than 4 times compared with that of HM. These results may indicate that prolonging the half-life is very helpful in improving the therapeutic capacity of miniaturized ADCs. In the future, the design of better strategies that can prolong half-life without affecting cytotoxicity may be useful for further improving the therapeutic potential of these molecules.


Asunto(s)
Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/farmacología , Antineoplásicos Inmunológicos/química , Antineoplásicos Inmunológicos/farmacología , Inmunoconjugados/química , Inmunoconjugados/farmacología , Polietilenglicoles/química , Animales , Anticuerpos Monoclonales/efectos adversos , Especificidad de Anticuerpos , Antineoplásicos Inmunológicos/efectos adversos , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Técnicas de Química Sintética , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunoconjugados/efectos adversos , Estructura Molecular , Unión Proteica , Relación Estructura-Actividad
16.
AAPS PharmSciTech ; 22(2): 69, 2021 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-33565009

RESUMEN

Encapsulating genetic material into biocompatible polymeric microparticles is a means to improving gene transfection while simultaneously decreasing the tendency for inflammatory responses; and can be advantageous in terms of delivering material directly to the lungs via aerosolization for applications such as vaccinations. In this study, we investigated the advantages of using polymeric microparticles carrying the luciferase reporter gene in increasing transfection efficiency in the readily transfectable HEK293 cell line and the difficult to transfect RAW264.7 cell line. The results indicated that there was a limit to the ratio of nitrogen in polyethylenimine (PEI) to phosphate in DNA (N/P ratio) beyond which further increases in transgene expression no longer, or only marginally, occurred. Microparticles encapsulating PEI:DNA nanoplexes induced cellular toxicity in a dose-dependent manner. PEGylation increased transgene expression, likely related to enhanced degradation of particles. Furthermore, intra-tracheal instillation in rats allowed us to investigate the inflammatory response in the lung as a function of PEGylation, porosity, and size. Porosity did not influence cell counts in bronchoalveolar lavage fluid in the absence of PEG, but in particles containing PEG, non-porous particles recruited fewer inflammatory cells than their porous counterparts. Finally, both 1 µm and 10 µm porous PLA-PEG particles recruited more neutrophils than 4 µm particles. Thus, we have shown that PEGylation and lack of porosity are advantageous for faster release of genetic cargo from microparticles and a reduced inflammatory response, respectively.


Asunto(s)
ADN/química , Inflamación/prevención & control , Lactatos/química , Polietilenglicoles/química , Polietileneimina/química , Transgenes , Animales , Células HEK293 , Humanos , Ratones , Células RAW 264.7 , Ratas , Transfección
17.
Nat Commun ; 12(1): 1124, 2021 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-33602928

RESUMEN

Clay-based nanomaterials, especially 2:1 aluminosilicates such as vermiculite, biotite, and illite, have demonstrated great potential in various fields. However, their characteristic sandwiched structures and the lack of effective methods to exfoliate two-dimensional (2D) functional core layers (FCLs) greatly limit their future applications. Herein, we present a universal wet-chemical exfoliation method based on alkali etching that can intelligently "capture" the ultrathin and biocompatible FCLs (MgO and Fe2O3) sandwiched between two identical tetrahedral layers (SiO2 and Al2O3) from vermiculite. Without the sandwich structures that shielded their active sites, the obtained FCL nanosheets (NSs) exhibit a tunable and appropriate electron band structure (with the bandgap decreased from 2.0 eV to 1.4 eV), a conductive band that increased from -0.4 eV to -0.6 eV, and excellent light response characteristics. The great properties of 2D FCL NSs endow them with exciting potential in diverse applications including energy, photocatalysis, and biomedical engineering. This study specifically highlights their application in cancer theranostics as an example, potentially serving as a prelude to future extensive studies of 2D FCL NSs.


Asunto(s)
Silicatos de Aluminio/química , Nanopartículas/química , Neoplasias/diagnóstico , Neoplasias/terapia , Nanomedicina Teranóstica , Animales , Antineoplásicos/farmacología , Células Hep G2 , Humanos , Luz , Ratones Endogámicos C57BL , Nanopartículas/ultraestructura , Neoplasias/patología , Fotoquimioterapia , Polietilenglicoles/química , Especies Reactivas de Oxígeno/química , Temperatura , Distribución Tisular/efectos de los fármacos
18.
Nucleic Acids Res ; 49(5): 2790-2802, 2021 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-33589919

RESUMEN

The RNA polymerase (RNAP) clamp, a mobile structural element conserved in RNAP from all domains of life, has been proposed to play critical roles at different stages of transcription. In previous work, we demonstrated using single-molecule Förster resonance energy transfer (smFRET) that RNAP clamp interconvert between three short-lived conformational states (lifetimes ∼ 0.3-0.6 s), that the clamp can be locked into any one of these states by small molecules, and that the clamp stays closed during initial transcription and elongation. Here, we extend these studies to obtain a comprehensive understanding of clamp dynamics under conditions RNAP may encounter in living cells. We find that the RNAP clamp can populate long-lived conformational states (lifetimes > 1.0 s) and can switch between these long-lived states and the previously observed short-lived states. In addition, we find that clamp motions are increased in the presence of molecular crowding, are unchanged in the presence of elevated monovalent-cation concentrations, and are reduced in the presence of elevated divalent-cation concentrations. Finally, we find that RNAP bound to non-specific DNA predominantly exhibits a closed clamp conformation. Our results raise the possibility of additional regulatory checkpoints that could affect clamp dynamics and consequently could affect transcription and transcriptional regulation.


Asunto(s)
ARN Polimerasas Dirigidas por ADN/química , Cationes Bivalentes , Cationes Monovalentes , ADN/metabolismo , ARN Polimerasas Dirigidas por ADN/metabolismo , Escherichia coli/enzimología , Transferencia Resonante de Energía de Fluorescencia , Polietilenglicoles/química , Conformación Proteica
20.
Int J Mol Sci ; 22(3)2021 Jan 26.
Artículo en Inglés | MEDLINE | ID: mdl-33530445

RESUMEN

Amphiphilic copolymers containing polydimethylsiloxane (PDMS) and polyethylene glycol methyl ether (MPEG) were obtained via an azide-alkyne cycloaddition reaction between alkyne-functionalized copolymer of MPEG methacrylate and azide-functionalized PDMS. "Click" reactions were carried out with an efficiency of 33-47% increasing grafting degrees. The grafted copolymers were able to carry out the micellization and encapsulation of active substances, such as vitamin C (VitC), ferulic acid (FA) and arginine (ARG) with drug loading content (DLC) in the range of 2-68% (VitC), and 51-89% (FA or ARG). In vitro release studies (phosphate buffer saline, PBS; pH = 7.4 or 5.5) demonstrated that the maximum release of active substances was mainly after 1-2 h. The permeability of released active substances through membrane mimicking skin evaluated by transdermal tests in Franz diffusion cells indicated slight diffusion into the solution (2-16%) and their remaining in the membrane. Studies on the selected carrier with FA showed no negative effect on cell viability, proliferation capacity or senescence, as well as cell apoptosis/necrosis differences or cell cycle interruption in comparison with control cells. These results indicated that the presented micellar systems are good candidates for carriers of cosmetic substances according to physicochemical characterization and biological studies.


Asunto(s)
Dimetilpolisiloxanos/química , Portadores de Fármacos/química , Micelas , Polietilenglicoles/química , Polímeros/química , Apoptosis , Materiales Biocompatibles/química , Ciclo Celular , Fenómenos Químicos , Técnicas de Química Sintética , Permeabilidad , Polimerizacion , Polímeros/síntesis química , Piel/metabolismo , Absorción Cutánea , Análisis Espectral
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