RESUMEN
While investigating the possible synergistic effect of the conventional anticancer therapies, which, taken individually, are often ineffective against critical tumors, such as central nervous system (CNS) ones, the design of a theranostic nanovector able to carry and deliver chemotherapy drugs and magnetic hyperthermic agents to the target radiosensitizers (oxygen) was pursued. Alongside the original formulation of polymeric biodegradable oxygen-loaded nanostructures, their properties were fine-tuned to optimize their ability to conjugate therapeutic doses of drugs (doxorubicin) or antitumoral natural substances (curcumin). Oxygen-loaded nanostructures (diameter = 251 ± 13 nm, ζ potential = -29 ± 5 mV) were finally decorated with superparamagnetic iron oxide nanoparticles (SPIONs, diameter = 18 ± 3 nm, ζ potential = 14 ± 4 mV), producing stable, effective and non-agglomerating magnetic nanovectors (diameter = 279 ± 17 nm, ζ potential = -18 ± 7 mV), which could potentially target the tumoral tissues under magnetic driving and are monitorable either by US or MRI imaging.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Quitosano/química , Hipertermia Inducida/métodos , Nanopartículas de Magnetita/química , Fármacos Sensibilizantes a Radiaciones/farmacología , Nanomedicina Teranóstica/métodos , Antibióticos Antineoplásicos/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Medios de Contraste/síntesis química , Medios de Contraste/farmacología , Curcumina/química , Curcumina/farmacología , Sulfato de Dextran/química , Doxorrubicina/química , Doxorrubicina/farmacología , Composición de Medicamentos/métodos , Humanos , Cinética , Nanopartículas de Magnetita/ultraestructura , Oxígeno/química , Oxígeno/farmacología , Fármacos Sensibilizantes a Radiaciones/síntesis químicaRESUMEN
Antibiotic-polyelectrolyte nanoparticle complex (or nanoplex in short) has been recently demonstrated as a superior antibiotic delivery system to the native antibiotic in bronchiectasis therapy owed to its ability to overcome the lung's mucus barrier and generate high localized antibiotic exposure in the infected sites. The present work aimed to further improve the mucus permeability, hence the antibacterial efficacy of the nanoplex, by incorporating mucolytic enzyme papain (PAP) at the nanoplex formation step to produce PAP-decorated antibiotic-polyelectrolyte nanoplex exhibiting built-in mucolytic capability. Ciprofloxacin (CIP) and dextran sulfate (DXT) were used as the models for antibiotics and polyelectrolyte, respectively. The results showed that the PAP inclusion had minimal effects on the physical characteristics, preparation efficiency, and dissolution of the CIP-DXT nanoplex. The optimal CIP-(DXT-PAP) nanoplex exhibited size and zeta potential of approximately 200â¯nm and -50â¯mV with CIP and PAP payloads of 60% and 32% (w/w), respectively. The nanoplex was prepared at high efficiency with larger than 80% CIP and PAP utilization rates. The CIP-(DXT-PAP) nanoplex exhibited tenfold improvement in the mucus permeability compared to its CIP-DXT nanoplex counterpart, resulting in the former's superior bactericidal activity against clinical Pseudomonas aeruginosa biofilm in the presence of mucus barrier. A trade-off, nevertheless, existed between antibacterial efficacy and cytotoxicity towards human lung epithelium cells upon the incorporation of PAP above a certain concentration threshold. Therefore, the optimal dosing of the CIP-(DXT-PAP) nanoplex must be carefully determined.
Asunto(s)
Antibacterianos/farmacología , Bronquiectasia/tratamiento farmacológico , Ciprofloxacina/farmacología , Sulfato de Dextran/farmacología , Nanopartículas/química , Papaína/química , Polielectrolitos/farmacología , Antibacterianos/química , Antibacterianos/metabolismo , Biopelículas/efectos de los fármacos , Bronquiectasia/microbiología , Ciprofloxacina/química , Ciprofloxacina/metabolismo , Sulfato de Dextran/química , Sulfato de Dextran/metabolismo , Sistemas de Liberación de Medicamentos , Humanos , Pruebas de Sensibilidad Microbiana , Nanopartículas/metabolismo , Papaína/metabolismo , Tamaño de la Partícula , Polielectrolitos/química , Polielectrolitos/metabolismo , Pseudomonas aeruginosa/efectos de los fármacos , Propiedades de SuperficieRESUMEN
Salmon calcitonin (sCT) is a potent calcium-regulating peptide hormone and widely applied for the treatment of some bone diseases clinically. However, the therapeutic usefulness of sCT is hindered by the frequent injection required, owing to its short plasma half-life and therapeutic need for a high dose. Oral delivery is a popular modality of administration for patients because of its convenience to self-administration and high patient compliance, while orally administered sCT remains a great challenge currently due to the existence of multiple barriers in the gastrointestinal (GI) tract. Here, we introduced an orally targeted delivery system to increase the transport of sCT across the intestine through both the paracellular permeation route and the bile acid pathway. In this system, sCT-based glycol chitosan-taurocholic acid conjugate (GC-T)/dextran sulfate (DS) ternary nanocomplexes (NC-T) were produced by a flash nanocomplexation (FNC) process in a kinetically controlled mode. The optimized NC-T exhibited well-controlled properties with a uniform and sub-60 nm hydrodynamic diameter, high batch-to-batch reproducibility, good physical or chemical stability, as well as sustained drug release behaviors. The studies revealed that NC-T could effectively improve the intestinal uptake and permeability, owing to its surface functionalization with the taurocholic acid ligand. In the rat model, orally administered NC-T showed an obvious hypocalcemia effect and a relative oral bioavailability of 10.9%. An in vivo assay also demonstrated that NC-T induced no observable side effect after long-term oral administration. As a result, the orally targeted nanocomplex might be a promising candidate for improving the oral transport of therapeutic peptides.
Asunto(s)
Calcitonina/administración & dosificación , Hormonas y Agentes Reguladores de Calcio/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Absorción Intestinal/efectos de los fármacos , Nanocompuestos/química , Administración Oral , Animales , Disponibilidad Biológica , Transporte Biológico , Células CACO-2/efectos de los fármacos , Células CACO-2/metabolismo , Calcitonina/efectos adversos , Calcitonina/sangre , Calcitonina/farmacocinética , Calcio/sangre , Hormonas y Agentes Reguladores de Calcio/efectos adversos , Hormonas y Agentes Reguladores de Calcio/sangre , Hormonas y Agentes Reguladores de Calcio/farmacocinética , Quitosano/química , Sulfato de Dextran/química , Liberación de Fármacos , Estabilidad de Medicamentos , Semivida , Humanos , Hipocalcemia/inducido químicamente , Inyecciones Subcutáneas , Masculino , Ratas , Ratas Sprague-Dawley , Ácido Taurocólico/químicaRESUMEN
Porous microparticles (MPs) have been regarded as a promising vehicle for drug delivery. Herein, porous MPs and their counterparts (nonporous MPs) were produced by a conventional emulsion-solvent evaporation method in the presence and absence of ammonium bicarbonate, and curcumin was encapsulated into these MPs during the preparation process. The obtained MPs possessed desirable diameters of around 1.2 µm and negative zeta potentials of approximately -28 mV. It was found that the release rate of curcumin was remarkably increased with the introduction of pores in MPs. Furthermore, orally administered porous MPs achieved statistically significantly better therapeutic outcomes against ulcerative colitis mouse model induced by dextran sulfate sodium, in comparison to nonporous MPs. These findings confirmed that porous MPs could be served as a promising platform for the treatment of ulcerative colitis via oral route.
Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Curcumina/química , Curcumina/farmacología , Nanopartículas/química , Polímeros/química , Administración Oral , Animales , Bicarbonatos/química , Sulfato de Dextran/química , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Femenino , Ratones , Tamaño de la Partícula , PorosidadRESUMEN
Layer-by-Layer assembled polyelectrolyte films offer the opportunity to control cell attachment and behavior on solid surfaces. In the present study, multilayer films based on negatively charged biopolymers (pectin, dextran sulfate, carboxymethylcellulose) and positively charged polysaccharide chitosan or synthetic polyelectrolyte polyethyleneimine has been prepared and evaluated. Physico-chemical properties of the formed multilayer films, including their growth, morphology, wettability, stability, and mechanical properties, have been studied. We demonstrated that chitosan-containing films are characterized by the linear growth, the defect-free surface, and predominantly viscoelastic properties. When chitosan is substituted for the polyethyleneimine in the multilayer system, the properties of the formed films are significantly altered: the rigidity and surface roughness increases, the film growth acquires the exponential character. The multilayer films were subsequently used for culturing mesenchymal stem cells. It has been determined that stem cells effectively adhered to chitosan-containing films and formed on them the monolayer culture of fibroblast-like cells with high viability. Our results show that cell attachment is a complex process which is not only governed by the surface functionality because one of the key parameter effects on cell adhesion is the stiffness of polyelectrolyte multilayer films. We therefore propose our Layer-by-Layer films for applications in tissue engineering. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2093-2104, 2018.
Asunto(s)
Células Madre Mesenquimatosas/citología , Polisacáridos/química , Adsorción , Animales , Adhesión Celular , Supervivencia Celular , Células Cultivadas , Sulfato de Dextran/química , Módulo de Elasticidad , Pectinas/química , Polietileneimina/química , Ratas Wistar , Andamios del Tejido/químicaRESUMEN
In this study, the anti-inflammatory effects of mangosteen extract (MGE) on dextran sulfate sodium (DSS)-induced colitis in mice and nuclear factor (NF)-κB pathway modulation were investigated. Acute colitis was induced by administering 3% DSS in drinking water for 7 days, and three groups of Institute of Cancer Research mice were treated with 30 and 120 mg/kg MGE or 5-aminosalicylic acid for 7 days; an additional two groups of mice served as healthy and disease controls. The results indicated that MGE significantly prevented weight loss, reduced disease activity index scores, and preserved colon length compared with the findings in the untreated colitis group. MGE downregulated the NF-κB pathway by inhibiting the phosphorylation of IκB and IKK in a dose-dependent manner. These findings suggest that MGE alleviates ulcerative colitis by modulating the NF-κB pathway.
Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Sulfato de Dextran/química , Garcinia mangostana/química , FN-kappa B/inmunología , Extractos Vegetales/administración & dosificación , Animales , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/genética , Colitis Ulcerosa/inmunología , Sulfato de Dextran/efectos adversos , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Ratones Endogámicos ICR , FN-kappa B/genética , Transducción de SeñalRESUMEN
AIM: To investigate the therapeutic effect of Jianpi Qingchang decoction (JPQCD) on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice. METHODS: C57BL/c mice were injected intragastrically with 5% DSS instead of drinking water for 7 d, and their body weight, diarrhea severity and fecal bleeding were monitored, while the mice in the control group were treated with standard drinking water, without DSS. After 7 d, the DSS drinking water was changed to normal water and the DSS group continued with DSS water. The control and DSS groups were given normal saline by intragastric injection. The 5-aminosalicylic acid (5-ASA) group was treated orally with 5-ASA at a dose of 100 mg/kg daily. The JPQCD group was treated orally with JPQCD at a dose of 17.1 g/kg daily. On day 14, the colon length was measured, the colorectal histopathological damage score was assessed, and protein levels of interleukin (IL)-1ß, IL-8 and tumor necrosis factor-alpha (TNF-α) in colon supernatants were measured by enzyme-linked immunosorbent assay. mRNA expression of IL-1ß, IL-8, TNF-α and nuclear factor-kappa B (NF-κB) was detected by real-time quantitative polymerase chain reaction. Western blotting was used to detect the protein expression of NF-κB and inhibitor of kappa B. RESULTS: Acute inflammation occurred in the mice administered DSS, including the symptoms of losing body weight, loose feces/watery diarrhea and presence of fecal blood; all these symptoms worsened at 7 d. The colons of mice treated with DSS were assessed by histological examination, and the results confirmed that acute inflammation had occurred, as evidenced by loss of colonic mucosa and chronic inflammatory cell infiltration, and these features extended into the deeper layer of the colon walls. The expression levels of IL-1ß, IL-8 and TNF-α in the DSS group were higher than those in the control group (P < 0.05), and the expression levels of IL-1ß, IL-8 and TNF-α in the JPQCD and 5-ASA groups were lower than those in the DSS group after treating with JPQCD and 5-ASA. Comparing with the DSS group, the mRNA level of IL-1ß, IL-8, TNF-α and NF-κB was significantly reduced by 5-ASA and JPQCD. The difference between JPQCD and 5-ASA groups was not statistically significant (P > 0.05). Comparing with the DSS group, due to using JPQCD and 5-ASA, significant suppression of activation in DSS-induced NF-κB and increased phosphorylation of IκB in mice with experimental colitis occurred (P < 0.05). The difference between the JPQCD group and the 5-ASA group was not statistically significant (P > 0.05). CONCLUSION: Activation of the NF-κB signaling pathway is inhibited by JPQCD, which shows the potential mechanism by which JPQCD treats UC.
Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Colitis/tratamiento farmacológico , Sulfato de Dextran/química , Medicamentos Herbarios Chinos/uso terapéutico , FN-kappa B/metabolismo , Animales , Colon/metabolismo , Inflamación , Interleucina-1beta/metabolismo , Interleucina-8/metabolismo , Masculino , Mesalamina/química , Ratones , Ratones Endogámicos C57BL , FN-kappa B/antagonistas & inhibidores , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Colorectal cancer (CRC) is one of the most common cancers leading to high mortality. However, long-term administration of anti-tumor therapy for CRC is not feasible due to the side effects. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), particularly DHA and EPA, exert protection against CRC, but the mechanisms are unclear. Here, we show that ω-3 PUFAs inhibit proliferation and induce apoptosis of CRC cells in vitro and alleviate AOM/DSS-induced mice colorectal cancer in vivo. Moreover, ω-3 PUFAs promote phosphorylation and cytoplasmic retention of YAP and this effect was mediated by MST1/2 and LATS1, suggesting that the canonical Hippo Pathway is involved in ω-3 PUFAs function. We further confirmed that increase of pYAP by ω-3 PUFAs was mediated by GPRs, including GPR40 and GPR120, which subsequently activate PKA via Gαs, thus inducing the Hippo pathway activation. These data provide a novel DHA/EPA-GPR40/120-Gαs-PKA-MST1/2-LATS1-YAP signaling pathway which is linked to ω-3 PUFAs-induced inhibition of cell proliferation and promotion of apoptosis in CRC cells, indicating a mechanism that could explain the anti-cancer action of ω-3 PUFAs.
Asunto(s)
Neoplasias Colorrectales/metabolismo , Ácidos Grasos Omega-3/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis , Azoximetano/química , Proteínas de Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/terapia , Citoplasma/metabolismo , Sulfato de Dextran/química , Células HT29 , Vía de Señalización Hippo , Humanos , Ratones , Ratones Endogámicos BALB C , Fosfoproteínas/metabolismo , Fosforilación , Transporte de Proteínas , Proteínas Señalizadoras YAPRESUMEN
To improve the stability and antioxidant activity of anthocyanins (ATC), complexes of dextran sulfate (DESU) and ATC extracted from Vaccinium myrtillus were formed during electrostatic interaction between sulfo groups of DESU and cationic moieties of ATC. At the optimal weight ratio DESU/ATC=0.4 g/g, the amount of ATC introduced into a complex depended on the total concentration of the reagents. About 1.7 g of ATC per g of DESU could be incorporated into a complex. The formation of DESU/ATC complexes was confirmed by HPLC and FT-IR spectroscopy. According to HPLC analysis, the amount of individual ATC incorporated into a complex varied from 73.7% in the case of malvidin-3-O-glucoside to 90.8% in the case of delphinidin-3-arabinoside.
Asunto(s)
Antocianinas/química , Sulfato de Dextran/química , Vaccinium myrtillus/química , Antioxidantes/farmacología , Cromatografía Líquida de Alta Presión , Depuradores de Radicales Libres/farmacología , Iones , Peso Molecular , Extractos Vegetales/química , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
We evaluated an analytical setup to identify optimal preparation conditions for nanoplex formation of small molecule drugs and polyelectrolytes using ciprofloxacin (CIP) and dextran sulfate (DS) as model compounds. The suitability of isothermal titration calorimetry (ITC) as a screening tool for rational formulation optimization was assessed. Besides ITC, static and dynamic light scattering, zeta potential measurements and scanning electron microscopy were applied to analyze the influence of different salt types and ionic strengths on CIP/DS nanoplex formation. The addition of low amounts of salt, especially 0.1M NaCl, improved the formation of CIP/DS nanoplexes. The presence of low amounts of salt led to smaller and more numerous particles of higher uniformity but had no influence on the release of CIP from nanoplexes. Furthermore, the molar range, within which efficient complexation was achieved, was broader in the presence of 0.1M NaCl than in the absence of salt with overall comparable complexation efficiency. Importantly, binding affinity correlated with particle shape and morphology, potentially enabling optimization of critical quality attributes based on ITC data. Altogether, ITC along with supplemental methods is a versatile screening tool for the evaluation of nanoplex formulation conditions regarding mixing ratio, salt type and ionic strength.
Asunto(s)
Antibacterianos/química , Ciprofloxacina/química , Sulfato de Dextran/química , Nanopartículas/química , Cloruro de Sodio/química , Cloruro de Calcio/química , Calorimetría , Química Farmacéutica , Liberación de Fármacos , Microscopía Electrónica de Rastreo , Nanopartículas/ultraestructura , Concentración Osmolar , Cloruro de Potasio/químicaRESUMEN
Salmonella Paratyphi A is a food-borne Gram-negative pathogen and a major public health challenge in the developing world. Upon reaching the intestine, S. Paratyphi A penetrates the intestinal epithelial barrier; and infects phagocytes such as macrophages and dendritic cells. S. Paratyphi A surviving within macrophages is protected from the lethal action of antibiotics due to their poor penetration into the intracellular compartments. Hence we have developed chloramphenicol loaded chondroitin sulfate (CS-Cm Nps) and dextran sulfate (DS-Cm Nps) nanoparticles through ionotropic-gelation method for the intracellular delivery of chloramphenicol. The size of these nanoparticles ranged between 100 and 200 nm in diameter. The encapsulation efficiency of both the nanoparticles was found to be around 65%. Both the nanoparticles are found to be non-hemolytic and non-toxic to fibroblast and epithelial cells. The prepared nanoparticles exhibited sustained release of the drug of up to 40% at pH 5 and 20-25% at pH 7.0 after 168 h. The anti-microbial activities of both nanoparticles were tested under in vitro and ex vivo conditions. The delivery of DS-Cm Nps into the intracellular compartments of the macrophages was 4 fold more compared to the CS-Cm Nps which lead to the enhanced intracellular antimicrobial activity of Ds-Cm Nps. Enhanced anti-microbial activity of Ds-Cm Nps was further confirmed in an ex vivo chicken intestine infection model. Our results showed that Cm loaded DS Nps can be used to treat intracellular Salmonella infections.
Asunto(s)
Cloranfenicol/uso terapéutico , Sulfatos de Condroitina/química , Sulfato de Dextran/química , Espacio Intracelular/microbiología , Nanopartículas/química , Infecciones por Salmonella/tratamiento farmacológico , Animales , Antibacterianos/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular , Cloranfenicol/farmacología , Endocitosis/efectos de los fármacos , Hemólisis/efectos de los fármacos , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana/efectos de los fármacos , Nanopartículas/ultraestructura , Ratas , Espectroscopía Infrarroja por Transformada de Fourier , Resultado del TratamientoRESUMEN
With the prevalence of inflammatory bowel disease (IBD) and its associated risk for development of colorectal cancer, it is of great importance to prevent and treat IBD. However, due to the complexity of etiology and potentially serious adverse effects, treatment options for IBD are relatively limited. Thus, the purpose of this study was to identify a safe food-based approach for the prevention and treatment of IBD. In this study, we tested the effects of cranberry products on preventing dextran sulphate sodium-induced murine colitis. Our results suggest that both cranberry extract and dried cranberries-fed groups had a significantly reduced disease activity index, where dried cranberries were more effective in preventing colitis than cranberry extract. Shortening of colon length, colonic myeloperoxidase activity and production of pro-inflammatory cytokines were attenuated in animals fed dried cranberries compared to the controls. The current report suggests that cranberries can be applied to prevent and reduce the symptoms of IBD.
Asunto(s)
Colitis/inducido químicamente , Sulfato de Dextran/química , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Vaccinium macrocarpon/química , Animales , Masculino , RatonesRESUMEN
Mucoadhesive polyethylenimine-dextran sulfate nanoparticles (PDNPs) were developed for local oral mucosa delivery. Punica granatum peel extract (PGE) was loaded into PDNPs for oral malodor reduction and caries prevention. PDNPs were constructed using the polyelectrolyte complexation technique employing oppositely charged polymers polyethylenimine (PEI) and dextran sulfate (DS), with PEG 400 as a stabilizer. Under optimal conditions, spherical particles of â¼ 500 nm with a zeta potential of â¼+28 mV were produced. Up to 98%, drug entrapment efficiency was observed. The mass ratio of PEI:DS played a significant role in controlling particle size and entrapment efficacy. PDNPs shown to be a good mucoadhesive drug delivery system as confirmed by ex vivo wash off test. In vitro dissolution studies revealed that PGE-loaded PDNPs manifested a prolong release characteristic with a burst release within 5 min. In addition, they remained effectively against oral bacteria.
Asunto(s)
Antiinfecciosos/administración & dosificación , Preparaciones de Acción Retardada/química , Sulfato de Dextran/química , Lythraceae/química , Nanopartículas/química , Polietileneimina/química , Administración Oral , Animales , Antiinfecciosos/farmacocinética , Antiinfecciosos/farmacología , Bacterias/efectos de los fármacos , Infecciones Bacterianas/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Mucosa Bucal/metabolismo , Tamaño de la Partícula , Extractos Vegetales/química , PorcinosRESUMEN
We report a simple method to fabricate multifunctional polyelectrolyte thin films to load and deliver the therapeutic drugs. The multilayer thin films were assembled by the electrostatic adsorption of poly (allylamine hydrochloride) (PAH) and dextran sulfate (DS). The silver nanoparticles (Ag NPs) biosynthesized from novel Hybanthus enneaspermus leaf extract as the reducing agent were successfully incorporated into the film. The biosynthesized Ag NPs showed excellent antimicrobial activity against the range of enteropathogens, which could be significantly enhanced when used with commercial antibiotics. The assembled silver nano composite multilayer films showed rupture and deformation when they are exposed to laser. The Ag NPs act as an energy absorption center, locally heat up the film and rupture it under laser treatment. The antibacterial drug, moxifloxacin hydrochloride (MH) was successfully loaded into the multilayer films. The total amount of MH release observed was about 63% which increased to 85% when subjected to laser light exposure. Thus, the polyelectrolyte thin film reported in our study has significant potential in the field of remote activated drug delivery, antibacterial coatings and wound dressings.
Asunto(s)
Antibacterianos/química , Compuestos Aza/química , Sistemas de Liberación de Medicamentos , Nanopartículas del Metal/química , Quinolinas/química , Plata/química , Violaceae , Combinación Amoxicilina-Clavulanato de Potasio/química , Combinación Amoxicilina-Clavulanato de Potasio/farmacología , Antibacterianos/farmacología , Compuestos Aza/farmacología , Bacterias/efectos de los fármacos , Sulfato de Dextran/química , Eritromicina/química , Eritromicina/farmacología , Fluoroquinolonas , Rayos Láser , Moxifloxacino , Extractos Vegetales/química , Hojas de la Planta , Poliaminas/química , Quinolinas/farmacología , Plata/farmacologíaRESUMEN
Single-walled carbon nanotubes (SWNTs) have shown promise as in vivo contrast nanoagents for medical theranostics, in particular photoacoustic and photothermal imaging and therapy, as well as targeted drug delivery systems. However, SWNTs have not proved able to evade biological obstacles, such as opsonization and phagocytosis by macrophage and nonspecific attachments to cells and other biological components in the bloodstream, before reaching target tissues and cells in vivo. Here, we demonstrate the stealth character of dextran sulfate (DS) coated SWNTs (DS-SWNTs) towards human macrophages and other biological barriers using Staphylococcus aureus, a bacterial pathogen, as a model. DS-SWNTs were compared to PEGylated SWNTs, a commonly accepted standard for rendering nanoparticles immune to opsonization. Also a new site-specific conjugation strategy was developed to functionalize antibody (Ab) on DS-SWNT in an upright way, enhancing their targeting efficiency. DS coating was proved to be resistant to opsonins and bacterial cells, demonstrating its potential to provide considerable stealth.character to SWNTs with excellent immunity versus macrophages and other biological barriers, and achieve prolonged blood circulation times. Moreover, the hybrid nanoagents could not only selectively bind to target pathogenic cells upon the controlled Ab attachment but also effectively eradicate pathogens after near-infrared laser irradiation.
Asunto(s)
Materiales Biocompatibles Revestidos/síntesis química , Sulfato de Dextran/química , Macrófagos/química , Nanocápsulas , Nanotubos de Carbono/química , Staphylococcus aureus/química , Staphylococcus aureus/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Hipertermia Inducida , Luz , Macrófagos/fisiología , Ensayo de Materiales , Nanocápsulas/química , Nanocápsulas/uso terapéutico , Nanotubos , Fagocitosis/fisiología , Fototerapia , Polietilenglicoles , Staphylococcus aureus/fisiologíaRESUMEN
Inflammatory bowel disease (IBD) is a risk factor for the development of colon cancer. Environmental factors including diet and the microflora influence disease outcome. Folate and homocysteine have been associated with IBD-mediated colon cancer but their roles remain unclear. We used a model of chemically induced ulcerative colitis (dextran sodium sulphate (DSS)) with or without the colon carcinogen azoxymethane (AOM) to determine the impact of dietary folic acid (FA) on colonic microflora and the development of colon tumours. Male mice (n 15 per group) were fed a FA-deficient (0 mg/kg), control (2 mg/kg) or FA-supplemented (8 mg/kg) diet for 12 weeks. Folate status was dependent on the diet (P< 0·001) and colitis-induced treatment (P= 0·04) such that mice with colitis had lower circulating folate. FA had a minimal effect on tumour initiation, growth and progression, although FA-containing diets tended to be associated with a higher tumour prevalence in DSS-treated mice (7-20 v. 0%, P= 0·08) and the development of more tumours in the distal colon of AOM-treated mice (13-83% increase, P= 0·09). Folate deficiency was associated with hyperhomocysteinaemia (P< 0·001) but homocysteine negatively correlated with tumour number (r - 0·58, P= 0·02) and load (r - 0·57, P= 0·02). FA had no effect on the intestinal microflora. The present data indicate that FA intake has no or little effect on IBD or IBD-mediated colon cancer in this model and that hyperhomocysteinaemia is a biomarker of dietary status and malabsorption rather than a cause of IBD-mediated colon cancer.
Asunto(s)
Dieta , Ácido Fólico/química , Inflamación/patología , Microbiota , Neoplasias/prevención & control , Animales , Azoximetano/química , Biomarcadores/metabolismo , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/microbiología , Colon/microbiología , Neoplasias del Colon/complicaciones , Neoplasias del Colon/microbiología , Sulfato de Dextran/química , Dextranos/química , Progresión de la Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , ARN Ribosómico 16S/genética , Sulfatos/químicaRESUMEN
Lipid-polymer hybrid nanoparticles have emerged as promising nanoscale carriers of therapeutics as they combine the attractive characteristics of liposomes and polymers. Herein we develop dry powder inhaler (DPI) formulation of hybrid nanoparticles composed of poly(lactic-co-glycolic acid) and soybean lecithin as the polymer and lipid constituents, respectively. The hybrid nanoparticles are transformed into inhalable microscale nanocomposite structures by a novel technique based on electrostatically-driven adsorption of nanoparticles onto polysaccharide carrier particles, which eliminates the drawbacks of conventional techniques based on controlled drying (e.g. nanoparticle-specific formulation, low yield). First, we engineer polysaccharide carrier particles made up of chitosan cross-linked with tripolyphosphate and dextran sulphate to exhibit the desired aerosolization characteristics and physical robustness. Second, we investigate the effects of nanoparticle to carrier mass ratio and salt inclusion on the adsorption efficiency, in terms of the nanoparticle loading and yield, from which the optimal formulation is determined. Desorption of the nanoparticles from the carrier particles in phosphate buffer saline is also examined. Lastly, we characterize aerosolization efficiency of the nanocomposite product in vitro, where the emitted dose and respirable fraction are found to be comparable to the values of conventional DPI formulations.
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Portadores de Fármacos/química , Ácido Láctico/química , Lecitinas/química , Nanopartículas , Ácido Poliglicólico/química , Adsorción , Aerosoles , Quitosano/química , Reactivos de Enlaces Cruzados/química , Sulfato de Dextran/química , Composición de Medicamentos , Inhaladores de Polvo Seco , Excipientes/química , Lecitinas/aislamiento & purificación , Nanocompuestos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Polifosfatos/química , Glycine max/química , Electricidad Estática , Tecnología Farmacéutica/métodosRESUMEN
Nanoscale antibiotic delivery has emerged as a promising therapeutic means to treat lung biofilm infection owed to its sputum penetrating ability. Due to the high antibiotic dosage requirement in anti-biofilm therapy, the most suitable formulation for this purpose is the antibiotic nanoparticles themselves, instead of the more extensively studied antibiotic-loaded nano-carriers, which often exhibit low drug loading. The present work details the preparation and characterization of antibiotic nanoparticle complex (or nanoplex) by self-assembly amphiphile-polyelectrolyte complexation process. Ofloxacin (OFX) and levofloxacin (LEV) are used as the antibiotics with dextran sulfate (DXT) as the polyelectrolyte. The nanoplex possesses high drug loading (up to 80%) and size<400nm ideal for sputum penetration. Unlike existing methods to prepare drug nanoparticles, the present method is fast, energy-minimal, solvent-free, and highly efficient as manifested in nearly 100% of drug is transformed into nanoplex. The effects of drug-to-polyelectrolyte charge ratio, pH, drug, and salt concentrations on the nanoplex characteristics (i.e. size, stability, drug loading) are investigated from which the optimal preparation conditions have been identified. Higher complexation efficiency and stronger agglomeration tendency are observed for LEV nanoplex owed to its higher hydrophobicity. The antibiotics are completely released from the nanoplex in aqueous salt solution within 3h and their antimicrobial activity is preserved upon complexation. The nanoplex is readily transformed into amorphous dry powders that remain stable after one-month storage owed to the high glass transition temperature. The antibiotic nanoplexes are highly charged enabling their subsequent functionalization for targeted delivery and controlled drug release purposes.
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Antibacterianos/farmacología , Biopelículas/efectos de los fármacos , Sulfato de Dextran/química , Electrólitos/química , Tecnología Química Verde/métodos , Nanopartículas/química , Tensoactivos/química , Antiinfecciosos/farmacología , Rastreo Diferencial de Calorimetría , Levofloxacino , Pruebas de Sensibilidad Microbiana , Nanopartículas/ultraestructura , Ofloxacino/farmacología , Tamaño de la Partícula , Polvos , Pseudomonas aeruginosa/efectos de los fármacos , Cloruro de Sodio/química , Termogravimetría , Difracción de Rayos XRESUMEN
Complementary imaging modalities provide more information than either method alone can yield and we have developed a dual-mode imaging probe for combined magnetic resonance (MR) and positron emission tomography (PET) imaging. We have developed dual-mode PET/MRI active probes targeted to vascular inflammation and present synthesis of (1) an aliphatic amine polystyrene bead and (2) a novel superparamagnetic iron oxide nanoparticle targeted to macrophages that were both coupled to positron-emitting copper-64 isotopes. The amine groups of the polystyrene beads were directly conjugated with an amine-reactive form (isothiocyanate) of aza-macrocycle 1,4,7,10-tetraazacyclo-dodecane-1,4,7,10-tetraacetic acid (DOTA). Iron oxide nanoparticles are dextran sulfate coated, and the surface was modified to contain aldehyde groups to conjugate to an amine-activated DOTA. Incorporation of chelated Cu-64 to nanoparticles under these conditions, which is routinely used to couple DOTA to macromolecules, was unexpectedly difficult and illustrates that traditional conjugation methods do not always work in a nanoparticle environment. Therefore, we developed new methods to couple Cu-64 to nanoparticles and demonstrate successful labeling to a range of nanoparticle types. We obtained labeling yields of 24% for the amine polystyrene beads and 21% radiolabeling yield for the anionic dextran sulfate iron oxide nanoparticles. The new coupling chemistry can be generalized for attaching chelated metals to other nanoparticle platforms.
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Compuestos Férricos/síntesis química , Magnetismo , Nanopartículas/química , Coloración y Etiquetado/métodos , Aminación , Quelantes/química , Radioisótopos de Cobre , Reactivos de Enlaces Cruzados/química , Sulfato de Dextran/química , Compuestos Férricos/química , Compuestos Heterocíclicos con 1 Anillo/química , Imagen por Resonancia Magnética , Microesferas , Poliestirenos/química , Tomografía de Emisión de PositronesRESUMEN
The absorption optical system of a Beckman XL-I ultracentrifuge has been used to monitor the Donnan distribution of ions in polysaccharide solutions dialyzed against sodium phosphate buffer (pH 6.8, I 0.08) supplemented with 0.2 mM chromate as an indicator ion. For dextran sulfate, heparin, and polygalacturonate, the effective net charges are shown to be only one-third of those deduced from the chemical structures--a reflection of charge screening (counterion condensation) in aqueous polyelectrolyte solutions. Whereas the extent of charge screening for the first two polysaccharides agrees well with theoretical prediction, the disparity in the corresponding comparison for polygalacturonate reflects partial esterification of carboxyl groups, whereupon the experimental parameter refers to the effective charge per hexose residue rather than the effective fractional charge of each carboxyl group.