RESUMEN
Biomimetic scaffolds with transparent, biocompatible, and in situ-forming properties are highly desirable for corneal tissue engineering, which can deeply fill corneal stromal defects with irregular shapes and support tissue regeneration. We here engineer a novel class of corneal scaffolds from oligoethylene glycol (OEG)-based dendronized chitosans (DCs), whose aqueous solutions show intriguing sol-gel transitions triggered by physiological temperature, resulting in highly transparent hydrogels. Gelling points of these hydrogels can be easily tuned, and furthermore, their mechanical strengths can be significantly enhanced when injected into PBS at 37 °C instead of pure water. In vitro tests indicate that these DC hydrogels exhibit excellent biocompatibility and can promote proliferation and migration of keratocyte. When applied in the rabbit eyes with corneal stromal defects, in situ formed DC hydrogels play a positive effect for new tissue regeneration. Overall, this thermo-gelling DCs possess appealing features as corneal tissue substitutes with their excellent biocompatibility and unprecedented thermoresponsiveness.
Asunto(s)
Materiales Biomiméticos/química , Quitosano/análogos & derivados , Córnea/metabolismo , Dendrímeros/química , Andamios del Tejido/química , Animales , Materiales Biomiméticos/toxicidad , Movimiento Celular/efectos de los fármacos , Quitosano/toxicidad , Córnea/citología , Córnea/cirugía , Dendrímeros/toxicidad , Inflamación/metabolismo , Queratectomía , Polietilenglicoles/química , Polietilenglicoles/toxicidad , Conejos , Células del Estroma/efectos de los fármacos , Ingeniería de Tejidos/métodos , Cicatrización de Heridas/efectos de los fármacosRESUMEN
The design of catalysts with greater control over catalytic activity and stability is a major challenge with substantial impact on fundamental chemistry and industrial applications. Due to their unparalleled diversity, selectivity, and efficiency, enzymes are promising models for next-generation catalysts, and considerable efforts have been devoted to incorporating the principles of their mechanisms of action into artificial systems. We report a heretofore undocumented catalyst design that introduces fullerenes to the field of biocatalysis, which we refer to as fullerene nanocatalysts, and that emulates enzymatic active sites through multifunctional self-assembled nanostructures. As a proof-of-concept, we mimicked the reactivity of hydrolases using fullerene nanocatalysts functionalized with the basic components of the parent enzyme with remarkable activity. Owing to the versatile amino acid-based functionalization repertoire of fullerene nanocatalysts, these next-generation carbon/biomolecule hybrids have potential to mimic the activity of other families of enzymes and, therefore, offer new perspectives for the design of biocompatible, high-efficiency artificial nanocatalysts.
Asunto(s)
Materiales Biomiméticos/química , Fulerenos/química , Nanoestructuras/química , Aminoácidos/química , Aminoácidos/toxicidad , Materiales Biomiméticos/toxicidad , Catálisis , Fulerenos/toxicidad , Humanos , Cinética , Células MCF-7 , Simulación de Dinámica Molecular , Nanoestructuras/toxicidad , Oxidación-ReducciónRESUMEN
Drug resistance of Klebsiella pneumoniae severely threatens human health. Overcoming the mechanisms of K. pneumoniae resistance to develop novel vaccines against drug-resistant K. pneumoniae is highly desired. Here, we report a technology platform that uses high pressure to drive drug-resistant K. pneumoniae to pass through a gap, inducing the formation of stable artificial bacterial biomimetic vesicles (BBVs). These BBVs had little to no bacterial intracellular protein or nucleic acid and had high yields. BBVs were efficiently taken up by dendritic cells to stimulate their maturation. BBVs as K. pneumoniae vaccines had the dual functions of inducing bacteria-specific humoral and cellular immune responses to increase animals' survival rate and reduce pulmonary inflammation and bacterial loads. We believe that BBVs are new-generation technology for bacterial vesicle preparation. Establishment of this BBV vaccine platform can maximally expand preparation technology for vaccines against drug-resistant K. pneumoniae.
Asunto(s)
Vacunas Bacterianas/uso terapéutico , Materiales Biomiméticos/uso terapéutico , Vesículas Extracelulares/inmunología , Infecciones por Klebsiella/terapia , Klebsiella pneumoniae/inmunología , Animales , Vacunas Bacterianas/síntesis química , Vacunas Bacterianas/inmunología , Vacunas Bacterianas/toxicidad , Materiales Biomiméticos/síntesis química , Materiales Biomiméticos/toxicidad , Fraccionamiento Celular/métodos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Femenino , Inmunidad Celular/efectos de los fármacos , Inmunidad Humoral/efectos de los fármacos , Klebsiella pneumoniae/química , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , PresiónRESUMEN
Injectable hydrogels have received much attention because of the advantages of simulation of the natural extracellular matrix, microinvasive implantation, and filling and repairing of complex shape defects. Yet, for bone repair, the current injectable hydrogels have shown significant limitations such as the lack of tissue adhesion, deficiency of self-healing ability, and absence of osteogenic activity. Herein, a strategy to construct mussel-inspired bisphosphonated injectable nanocomposite hydrogels with adhesive, self-healing, and osteogenic properties is developed. The nano-hydroxyapatite/poly(l-glutamic acid)-dextran (nHA/PLGA-Dex) dually cross-linked (DC) injectable hydrogels are fabricated via Schiff base cross-linking and noncovalent nHA-BP chelation. The chelation between bisphosphonate ligands (alendronate sodium, BP) and nHA favors the uniform dispersion of the latter. Moreover, multiple adhesion ligands based on catechol motifs, BP, and aldehyde groups endow the hydrogels with good tissue adhesion. The hydrogels possess excellent biocompatibility and the introduction of BP and nHA both can effectively promote viability, proliferation, migration, and osteogenesis differentiation of MC3T3-E1 cells. The incorporation of BP groups and HA nanoparticles could also facilitate the angiogenic property of endothelial cells. The nHA/PLGA-Dex DC hydrogels exhibited considerable biocompatibility despite the presence of a certain degree of inflammatory response in the early stage. The successful healing of a rat cranial defect further proves the bone regeneration ability of nHA/PLGA-Dex DC injectable hydrogels. The developed tissue adhesive osteogenic injectable nHA/PLGA-Dex hydrogels show significant potential for bone regeneration application.
Asunto(s)
Materiales Biomiméticos/química , Regeneración Ósea/efectos de los fármacos , Hidrogeles/química , Nanocompuestos/química , Osteogénesis/efectos de los fármacos , Andamios del Tejido/química , Adhesivos/síntesis química , Adhesivos/química , Adhesivos/toxicidad , Alendronato/análogos & derivados , Alendronato/toxicidad , Animales , Materiales Biocompatibles/síntesis química , Materiales Biocompatibles/química , Materiales Biocompatibles/toxicidad , Materiales Biomiméticos/síntesis química , Materiales Biomiméticos/toxicidad , Huesos/efectos de los fármacos , Línea Celular , Fenómenos Fisiológicos Celulares/efectos de los fármacos , Dextranos/síntesis química , Dextranos/química , Dextranos/toxicidad , Durapatita/síntesis química , Durapatita/química , Durapatita/toxicidad , Femenino , Hidrogeles/síntesis química , Hidrogeles/toxicidad , Masculino , Ratones , Nanocompuestos/toxicidad , Ácido Poliglutámico/síntesis química , Ácido Poliglutámico/química , Ácido Poliglutámico/toxicidad , Ratas Sprague-Dawley , Porcinos , Ingeniería de Tejidos/métodosRESUMEN
Surface modification techniques are often used to enhance the properties of Ti-based materials as hard-tissue replacements. While the microstructure of the coating and the quality of the interface between the substrate and coating are essential to evaluate the reliability and applicability of the surface modification. In this study, both a hydroxyapatite (HA) coating and a collagen-hydroxyapatite (Col-HA) composite coating were deposited onto a Ti-6Al-4V substrate using a biomimetic coating process. Importantly, a gradient cross-sectional structure with a porous coating toward the surface, while a dense layer adjacent to the interface between the coating and substrate was observed in three-dimensional (3D) from both the HA and Col-HA coatings via a dual-beam focused ion beam-scanning electron microscope (FIB-SEM). Moreover, the pore distributions within the entire coatings were reconstructed in 3D using Avizo, and the pores size distributions along the coating depth were calculated using RStudio. By evaluating the mechanical property and biocompatibility of these materials and closely observing the cross-sectional cell-coating-substrate interfaces using FIB-SEM, it was revealed that the porous surface created by both coatings well supports osteoblast cell adhesion while the dense inner layer facilitates a good bonding between the coating and the substrate. Although the mechanical property of the coating decreased with the addition of collagen, it is still strong enough for implant handling and the biocompatibility was promoted.
Asunto(s)
Materiales Biomiméticos/química , Biomimética/métodos , Materiales Biocompatibles Revestidos/química , Células 3T3 , Adhesivos , Aleaciones , Animales , Materiales Biomiméticos/toxicidad , Materiales Biocompatibles Revestidos/toxicidad , Colágeno Tipo I , Durapatita , Procesamiento de Imagen Asistido por Computador , Imagenología Tridimensional , Ensayo de Materiales , Ratones , Microscopía Electrónica de Rastreo , Porosidad , Resistencia a la Tracción , TitanioRESUMEN
Conductive hydrogel-based epidermal strain sensors can generate repeatable electrical changes upon mechanical deformations for indication of the skin's physiological condition. However, this remains challenging for many conductive hydrogel sensors due to biomechanical mismatch with skin tissues and an unstable resistance variation response, resulting in non-conformable deformations with the epidermis and dermis, and consequently generating inaccurate monitoring of human movements. Herein, a conductive hydrogel that highly matches the skin is fabricated from dynamically hydrogen-bonded nanocrystallites of polydopamine-modified reduced graphene oxide (PDA-rGO) nanosheets composited with polyvinyl alcohol, namely the PDA-rGO/PVA hydrogel. PDA-rGO provides a large number of dynamic hydrogen-bonding interactions in the hydrogel, resulting in a skin-matching modulus (78 kPa) and stretchability. Moreover, the resultant hydrogel possesses excellent cytocompatibility and conductivity (0.87 S m-1), high sensitivity (gauge factor of compression: 20) at low strain and outstanding linearity at high strain as well as a stable resistance variation response. These desirable properties enable the application of the PDA-rGO/PVA hydrogel as a skin-friendly wearable sensor for real-time and accurate detection of both large-scale joint movements and tiny physiological signals, including the bending and relaxing of fingers, the wrist, elbow and knee joints, and wrist pulse and swallowing. Moreover, this hydrogel is integrated into a 2D sensor array that monitors strains or pressures in two dimensions, which is promising for electronic skin, biosensors, human-machine interfaces, and wearable electronic devices.
Asunto(s)
Grafito/química , Hidrogeles/química , Monitoreo Fisiológico/métodos , Movimiento/fisiología , Alcohol Polivinílico/química , Dispositivos Electrónicos Vestibles , Animales , Materiales Biomiméticos/síntesis química , Materiales Biomiméticos/química , Materiales Biomiméticos/toxicidad , Fuerza Compresiva , Deglución , Conductividad Eléctrica , Grafito/síntesis química , Grafito/toxicidad , Humanos , Hidrogeles/síntesis química , Hidrogeles/toxicidad , Indoles/síntesis química , Indoles/química , Indoles/toxicidad , Células Madre Mesenquimatosas/efectos de los fármacos , Monitoreo Fisiológico/instrumentación , Polímeros/síntesis química , Polímeros/química , Polímeros/toxicidad , Alcohol Polivinílico/síntesis química , Alcohol Polivinílico/toxicidad , Ratas , Estrés MecánicoRESUMEN
Chitosan sulfates have demonstrated the ability to mimic heparan sulfate (HS) function. In this context, it is crucial to understand how the specific structural properties of HS domains determine their functionalities and biological activities. In this study, several HS-mimicking chitosans have been prepared to mimic the structure of HS domains that have proved to be functionally significant in cell processes. The results presented herein are in concordance with the hypothesis that sulfated chitosan-growth factor (GF) interactions are controlled by a combination of two effects: the electrostatic interactions and the conformational adaptation of the polysaccharide. Thus, we found that highly charged O-sulfated S-CS and S-DCS polysaccharides with a low degree of contraction interacted more strongly with GFs than N-sulfated N-DCS, with a higher degree of contraction and a low charge. Finally, the evidence gathered suggests that N-DCS would be able to bind to an allosteric zone and is likely to enhance GF signaling activity. This is because the bound protein remains able to bind to its cognate receptor, promoting an effect on cell proliferation as has been shown for PC12 cells. However, S-CS and S-DCS would sequester the protein, decreasing the GF signaling activity by depleting the protein or locally blocking its active site.
Asunto(s)
Materiales Biomiméticos/farmacología , Quitosano/farmacología , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Materiales Biomiméticos/síntesis química , Materiales Biomiméticos/metabolismo , Materiales Biomiméticos/toxicidad , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Quitosano/síntesis química , Quitosano/metabolismo , Quitosano/toxicidad , Heparitina Sulfato/química , Células PC12 , Unión Proteica , RatasRESUMEN
The management of thrombosis and bacterial infection is critical to ensure the functionality of medical devices. While administration of anticoagulants is the current antithrombotic clinical practice, a variety of complications, such as uncontrolled hemorrhages or heparin-induced thrombocytopenia, can occur. Additionally, infection rates remain a costly and deadly complication associated with use of these medical devices. It has been hypothesized that if a synthetic surface could mimic the biochemical mechanisms of the endothelium of blood vessels, thrombosis could be reduced, anticoagulant use could be avoided, and infection could be prevented. Herein, the interfacial biochemical effects of the endothelium were mimicked by altering the surface of medical grade silicone rubber (SR). Surface modification was accomplished via heparin surface immobilization (Hep) and the inclusion of a nitric oxide (NO) donor into the SR polymeric matrix to achieve synergistic effects (Hep-NO-SR). An in vitro bacteria adhesion study revealed that Hep-NO-SR exhibited a 99.46 ± 0.17% reduction in viable bacteria adhesion compared to SR. An in vitro platelet study revealed Hep-NO-SR reduced platelet adhesion by 84.12 ± 6.19% compared to SR, while not generating a cytotoxic response against fibroblast cells. In a 4 h extracorporeal circuit model without systemic anticoagulation, all Hep-NO-SR samples were able to maintain baseline platelet count and device patency; whereas 66% of SR samples clotted within the first 2 h of study. Results indicate that Hep-NO-SR creates a more hemocompatible and antibacterial surface by mimicking two key biochemical functions of the native endothelium.
Asunto(s)
Materiales Biomiméticos/química , Fármacos Hematológicos/uso terapéutico , Heparina/uso terapéutico , Donantes de Óxido Nítrico/uso terapéutico , S-Nitroso-N-Acetilpenicilamina/uso terapéutico , Animales , Adhesión Bacteriana/efectos de los fármacos , Materiales Biomiméticos/toxicidad , Coagulación Sanguínea/efectos de los fármacos , Plaquetas/metabolismo , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/toxicidad , Endotelio/química , Fármacos Hematológicos/farmacología , Fármacos Hematológicos/toxicidad , Heparina/farmacología , Heparina/toxicidad , Proteínas Inmovilizadas/farmacología , Proteínas Inmovilizadas/uso terapéutico , Proteínas Inmovilizadas/toxicidad , Ratones , Óxido Nítrico/metabolismo , Donantes de Óxido Nítrico/farmacología , Donantes de Óxido Nítrico/toxicidad , Adhesividad Plaquetaria/efectos de los fármacos , Conejos , S-Nitroso-N-Acetilpenicilamina/farmacología , S-Nitroso-N-Acetilpenicilamina/toxicidad , Elastómeros de Silicona/química , Elastómeros de Silicona/toxicidad , Staphylococcus aureus/efectos de los fármacos , Propiedades de SuperficieRESUMEN
Inhibition of phospholipaseâ A2 (PLA2) has long been considered for treating various diseases associated with an elevated PLA2 activity. However, safe and effective PLA2 inhibitors remain unavailable. Herein, we report a biomimetic nanoparticle design that enables a "lure and kill" mechanism designed for PLA2 inhibition (denoted "L&K-NP"). The L&K-NPs are made of polymeric cores wrapped with modified red blood cell membrane with two inserted key components: melittin and oleyloxyethyl phosphorylcholine (OOPC). Melittin acts as a PLA2 attractant that works together with the membrane lipids to "lure" in-coming PLA2 for attack. Meanwhile, OOPC acts as inhibitor that "kills" PLA2 upon enzymatic attack. Both compounds are integrated into the L&K-NP structure, which voids toxicity associated with free molecules. In the study, L&K-NPs effectively inhibit PLA2-induced hemolysis. In mice administered with a lethal dose of venomous PLA2, L&K-NPs also inhibit hemolysis and confer a significant survival benefit. Furthermore, L&K-NPs show no obvious toxicity in mice. and the design provides a platform technology for a safe and effective anti-PLA2 approach.
Asunto(s)
Materiales Biomiméticos/farmacología , Meliteno/farmacología , Nanopartículas/química , Inhibidores de Fosfolipasa A2/farmacología , Fosfolipasas A2/metabolismo , Fosforilcolina/análogos & derivados , Animales , Materiales Biomiméticos/química , Materiales Biomiméticos/toxicidad , Membrana Eritrocítica/química , Hemólisis/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Meliteno/química , Meliteno/toxicidad , Ratones Endogámicos ICR , Nanopartículas/toxicidad , Inhibidores de Fosfolipasa A2/química , Inhibidores de Fosfolipasa A2/toxicidad , Fosforilcolina/química , Fosforilcolina/farmacología , Fosforilcolina/toxicidadRESUMEN
Human cathepsin D (CatD), a pepsin-family aspartic protease, plays an important role in tumor progression and metastasis. Here, we report the development of biomimetic inhibitors of CatD as novel tools for regulation of this therapeutic target. We designed a macrocyclic scaffold to mimic the spatial conformation of the minimal pseudo-dipeptide binding motif of pepstatin A, a microbial oligopeptide inhibitor, in the CatD active site. A library of more than 30 macrocyclic peptidomimetic inhibitors was employed for scaffold optimization, mapping of subsite interactions, and profiling of inhibitor selectivity. Furthermore, we solved high-resolution crystal structures of three macrocyclic inhibitors with low nanomolar or subnanomolar potency in complex with CatD and determined their binding mode using quantum chemical calculations. The study provides a new structural template and functional profile that can be exploited for design of potential chemotherapeutics that specifically inhibit CatD and related aspartic proteases.
Asunto(s)
Catepsina D/antagonistas & inhibidores , Catepsina D/metabolismo , Péptidos Cíclicos/química , Péptidos Cíclicos/metabolismo , Inhibidores de Proteasas/química , Inhibidores de Proteasas/metabolismo , Sitios de Unión , Materiales Biomiméticos/síntesis química , Materiales Biomiméticos/química , Materiales Biomiméticos/metabolismo , Materiales Biomiméticos/toxicidad , Células CACO-2 , Catepsina D/química , Pruebas de Enzimas , Humanos , Cinética , Estructura Molecular , Pepstatinas/química , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/toxicidad , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/toxicidad , Unión Proteica , Relación Estructura-ActividadRESUMEN
Electrospun collagen is commonly used as a scaffold in tissue engineering applications since it mimics the content and morphology of native extracellular matrix (ECM) well. This report describes "toxic solvent free" fabrication of electrospun hybrid scaffold consisting of Collagen (Col) and Poly(l-lactide-co-ε-caprolactone) (PLLCL) for three-dimensional (3D) cell culture. Biomimetic hybrid scaffold was fabricated via co-spinning approach where simultaneous electrospinning of PLLCL and Collagen was mediated by polymer sacrificing agent Polyvinylpyrrolidone (PVP). Acidified aqueous solution of PVP was used to solubilize collagen without using toxic solvents for electrospinning, and then PVP was readily removed by rinsing in water. Mechanical characterizations, protein adsorption, as well as biodegradation analysis have been conducted to investigate feasibility of biomimetic hybrid scaffold for 3D cell culture applications. Electrospun biomimetic hybrid scaffold, which has 3D-network structure with 300-450â¯nm fiber diameters, was found to be maximizing cell adhesion through assisting NIH 3T3 mouse fibroblast cells. 3D cell culture studies confirmed that presence of collagen in biomimetic hybrid scaffold have created a major impact on cell proliferation compared to conventional 2D systems on long-term, also cell viability increased with the increasing amount of collagen.
Asunto(s)
Materiales Biomiméticos/química , Colágeno/química , Electricidad , Poliésteres/química , Andamios del Tejido/química , Adsorción , Animales , Materiales Biomiméticos/metabolismo , Materiales Biomiméticos/toxicidad , Supervivencia Celular/efectos de los fármacos , Matriz Extracelular/metabolismo , Fenómenos Mecánicos , Ratones , Células 3T3 NIH , Poliésteres/metabolismo , Poliésteres/toxicidad , Albúmina Sérica Bovina/químicaRESUMEN
Heparin and heparan sulfate (HS) are attractive components for constructing biomaterials due to their ability to recruit and regulate the activity of growth factors. The structural and functional heterogeneity of naturally derived heparin and HS is, however, an impediment for the preparation of biomaterials for regenerative medicine. To address this problem, we have prepared hydrogels modified by well-defined synthetic HS-derived disaccharides. Human induced pluripotent cell-derived neural stem cells (HIP-NSCs) encapsulated in a polyethylene glycol-based hydrogel modified by a pendent HS disaccharide that is a known ligand for fibroblast growth factor-2 (FGF-2) exhibited a significant increase in proliferation and self-renewal. This observation is important because evidence is emerging that undifferentiated stems cells can yield significant therapeutic benefits via their paracrine signaling mechanisms. Our data indicate that the HS disaccharide protects FGF-2, which has a very short biological half-live, from degradation. It is anticipated that, by careful selection of a synthetic HS oligosaccharide, it will be possible to control retention and release of specific growth factor, which in turn will provide control over cell fate.
Asunto(s)
Materiales Biomiméticos/farmacología , Diferenciación Celular/efectos de los fármacos , Disacáridos/farmacología , Hidrogeles/farmacología , Células-Madre Neurales/metabolismo , Materiales Biomiméticos/síntesis química , Materiales Biomiméticos/toxicidad , Proliferación Celular/efectos de los fármacos , Disacáridos/síntesis química , Disacáridos/toxicidad , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Heparitina Sulfato/química , Humanos , Hidrogeles/síntesis química , Hidrogeles/toxicidad , Células-Madre Neurales/citología , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/metabolismo , Prueba de Estudio Conceptual , Estabilidad Proteica/efectos de los fármacosRESUMEN
Implant infections frequently occur in various kinds of surgery. Apart from antibiotics, the surface modification of implant material is a promising avenue to resolve this global problem. An ideal implant interface is expected to possess good biocompatibility, as well as broad-spectrum and long-term bacterial inhibition capabilities. Here, a delicate cicada and catkin inspired dual biomimetic structure was proposed, for the first time, to improve the antibacterial properties of implant material. By using poly(ether-ether-ketone) (PEEK) as a model implant, the relative in vitro and in vivo evaluations demonstrated that this dual biomimetic structure could simultaneously provide less bacterial adhesion, wider antimicrobial range and longer antibacterial durability. Meanwhile, the modified implant also retained ideal biocompatibility. Most importantly, the relative dual biomimetic structure engineering process could be accomplished through a simple, economic and fast hydrothermal chemical reaction, which might have an impact on the development of future biomedical materials.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Flores , Hemípteros , Células 3T3 , Animales , Antibacterianos/toxicidad , Adhesión Bacteriana/efectos de los fármacos , Benzofenonas , Materiales Biomiméticos/toxicidad , Hemólisis/efectos de los fármacos , Cetonas/química , Masculino , Ratones , Nanoestructuras/química , Polietilenglicoles/química , Polímeros , Prótesis e Implantes , Conejos , Ratas , Staphylococcus aureus/efectos de los fármacos , Propiedades de Superficie , Óxido de Zinc/químicaRESUMEN
Fluorescent nanoarchitectures, such as hydrophobic micelles and hydrophilic vesicles decorated with fluorescent carbon nanoparticles, were fabricated from one fatty acid by means of photo-triggering. The biomimetic nanostructures, like cell membrane structures, have applications in fluorescence imaging in both the cell cytoplasm and nucleus. Besides, hydrophobic micelles can be used as very stable fluorescent inks.
Asunto(s)
Materiales Biomiméticos/química , Ácidos Grasos/química , Colorantes Fluorescentes/química , Nanopartículas/química , Células A549 , Materiales Biomiméticos/síntesis química , Materiales Biomiméticos/efectos de la radiación , Materiales Biomiméticos/toxicidad , Carbono/química , Carbono/efectos de la radiación , Carbono/toxicidad , Ácidos Grasos/efectos de la radiación , Ácidos Grasos/toxicidad , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/efectos de la radiación , Colorantes Fluorescentes/toxicidad , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Tinta , Membranas Artificiales , Micelas , Microscopía Confocal , Nanopartículas/efectos de la radiación , Nanopartículas/toxicidad , Rayos Ultravioleta , Agua/químicaRESUMEN
Tumor-targeting nano-drug-delivery systems hold great potential to improve the therapeutic efficacy and alleviate the side effects of cancer treatments. Herein, folic acid (FA)-decorated amphiphilic copolymer of FA-P(MPC- co-MaPCL) (MPC: 2-methacryloxoethyl phosphorylcholine, MaPCL: poly(ε-caprolactone) macromonomer) is synthesized and its micelles are fabricated for doxorubicin (DOX) delivery. And non-FA-decorated P(MPC- co-MaPCL) micelles are used as the control. Dynamic light scattering and scanning electron microscopy measurements reveal that FA-P(MPC- co-MaPCL) and P(MPC- co-MaPCL) micelles are spherical with average diameters of 140 and 90 nm, respectively. The evaluation in vitro demonstrates that the blank micelles are nontoxic, while DOX-loaded FA-P(MPC- co-MaPCL) micelles show significant cytotoxicity to HeLa cells and slight cytotoxicity to L929 cells. Moreover, the cellular uptake of DOX-loaded FA-P(MPC- co-MaPCL) micelles in HeLa cells are 4.3-fold and 1.7-fold higher than that of DOX-loaded P(MPC- co-MaPCL) micelles and free DOX after 6 h of incubation, respectively. These results indicate the great potential of this system in anticancer target drug-delivery applications.
Asunto(s)
Antineoplásicos/farmacología , Doxorrubicina/farmacología , Portadores de Fármacos/química , Ácido Fólico/química , Micelas , Polímeros/química , Animales , Materiales Biomiméticos/síntesis química , Materiales Biomiméticos/química , Materiales Biomiméticos/toxicidad , Línea Celular Tumoral , Membrana Celular/química , Portadores de Fármacos/síntesis química , Portadores de Fármacos/toxicidad , Ácido Fólico/toxicidad , Humanos , Polímeros/síntesis química , Polímeros/toxicidadRESUMEN
Heparanase is a mammalian endoglycosidase that cleaves heparan sulfate (HS) polysaccharides and contributes to remodelling of the extracellular matrix and regulation of HS-binding protein bioavailabilities. Heparanase is upregulated in malignant cancers and inflammation, aiding cell migration and the release of signaling molecules. It is established as a highly druggable extracellular target for anticancer therapy, but current compounds have limitations, because of cost, production complexity, or off-target effects. Here, we report the synthesis of a novel, targeted library of single-entity glycomimetic clusters capped with simple sulfated saccharides. Several dendrimer HS glycomimetics display low nM IC50 potency for heparanase inhibition equivalent to comparator compounds in clinical development, and potently inhibit metastasis and growth of human myeloma tumor cells in a mouse xenograft model. Importantly, they lack anticoagulant activity and cytotoxicity, and also inhibit angiogenesis. They provide a new candidate class for anticancer and wider therapeutic applications, which could benefit from targeted heparanase inhibition.
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Antineoplásicos/uso terapéutico , Materiales Biomiméticos/uso terapéutico , Dendrímeros/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Glucuronidasa/antagonistas & inhibidores , Mieloma Múltiple/tratamiento farmacológico , Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Inhibidores de la Angiogénesis/toxicidad , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , Materiales Biomiméticos/síntesis química , Materiales Biomiméticos/farmacología , Materiales Biomiméticos/toxicidad , Línea Celular Tumoral , Dendrímeros/síntesis química , Dendrímeros/farmacología , Dendrímeros/toxicidad , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/toxicidad , Factor 2 de Crecimiento de Fibroblastos/antagonistas & inhibidores , Glicósidos/síntesis química , Glicósidos/farmacología , Glicósidos/uso terapéutico , Glicósidos/toxicidad , Heparitina Sulfato/química , Humanos , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
New biomimetic magnetite nanoparticles (hereafter BMNPs) with sizes larger than most common superparamagnetic nanoparticles were produced in the presence of the recombinant MamC protein from Magnetococcus marinus MC-1 and functionalized with doxorubicin (DOXO) intended as potential drug nanocarriers. Unlike inorganic magnetite nanoparticles, in BMNPs the MamC protein controls their size and morphology, providing them with magnetic properties consistent with a large magnetic moment per particle; moreover, it provides the nanoparticles with novel surface properties. BMNPs display the isoelectric point at pH 4.4, being strongly negatively charged at physiological pH (pH 7.4). This allows both (i) their functionalization with DOXO, which is positively charged at pH 7.4, and (ii) the stability of the DOXO-surface bond and DOXO release to be pH dependent and governed by electrostatic interactions. DOXO adsorption follows a Langmuir-Freundlich model, and the coupling of DOXO to BMNPs (binary biomimetic nanoparticles) is very stable at physiological pH (maximum release of 5% of the drug adsorbed). Conversely, when pH decreases, these electrostatic interactions weaken, and at pH 5, DOXO is released up to â¼35% of the amount initially adsorbed. The DOXO-BMNPs display cytotoxicity on the GTL-16 human gastric carcinoma cell line in a dose-dependent manner, reaching about â¼70% of mortality at the maximum amount tested, while the nonloaded BMNPs are fully cytocompatible. The present data suggest that BMNPs could be useful as potential drug nanocarriers with a drug adsorption-release governed by changes in local pH values.
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Proteínas Bacterianas/química , Materiales Biomiméticos/química , Doxorrubicina/química , Portadores de Fármacos/química , Nanopartículas de Magnetita/química , Adsorción , Alphaproteobacteria/química , Proteínas Bacterianas/toxicidad , Materiales Biomiméticos/toxicidad , Línea Celular Tumoral , Portadores de Fármacos/síntesis química , Portadores de Fármacos/toxicidad , Liberación de Fármacos , Hemólisis/efectos de los fármacos , Humanos , Concentración de Iones de Hidrógeno , Nanopartículas de Magnetita/toxicidad , Tamaño de la Partícula , Proteínas Recombinantes/química , Proteínas Recombinantes/toxicidad , Propiedades de SuperficieRESUMEN
Atomically dispersed Fe-N4 sites anchored on N-doped porous carbon materials (Fe-SAs/NC) can mimic two antioxidative enzymes of catalase (CAT) and superoxide dismutase (SOD), and therefore serves as a bifunctional single-atom-based enzyme (SAzyme) for scavenging reactive oxygen species (ROS) to remove excess ROS generated during oxidative stress in cells.
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Antioxidantes/farmacología , Materiales Biomiméticos/farmacología , Hierro/química , Nanocompuestos/química , Nitrógeno/química , Antioxidantes/síntesis química , Antioxidantes/química , Antioxidantes/toxicidad , Materiales Biomiméticos/síntesis química , Materiales Biomiméticos/química , Materiales Biomiméticos/toxicidad , Carbono/química , Catalasa/química , Células HeLa , Humanos , Peróxido de Hidrógeno/química , Peróxido de Hidrógeno/metabolismo , Nanocompuestos/toxicidad , Nanopartículas/química , Nanopartículas/toxicidad , Estrés Oxidativo/efectos de los fármacos , Porosidad , Superóxido Dismutasa/química , Superóxidos/química , Superóxidos/metabolismoRESUMEN
Angiotensin converting enzyme (ACE) is involved in proteolytic processing of the amyloid-ß(Aß) peptide implicated in the development of Alzheimer's disease (AD) and known products of ACE-based processing of Aß42 are characterized by reduced aggregability and cytotoxicity. Recently it has been demonstrated that ACE can act as an arginine specific endopeptidase cleaving the N-terminal pentapeptide (Aß1-5) from synthetic Aß peptide analogues. In the context of proteolytic processing of full length Aß42, this suggests possible formation of Aß6-42 species. The aim of this study was to test a hypothesis that some N-terminally truncated Aß peptide(s) could retain aggregability and neurotoxic properties typical for Aß42. We have investigated aggregability of two amyloid-ß peptides, Aß6-42 and isoD7-Aß6-42, mimicking potential proteolytic products of Aß42 and isoD7-Aß42, and evaluated their effects on the repertoire of brain Aß binding proteins, and cytotoxicity towards neuroblastoma SH-SY5Y cells. Aggregability of isoD7-Aß6-42 and Aß6-42 was higher than that of full-length peptides Aß42 and isoD7-Aß42, while the repertoire of mouse brain Aß binding proteins dramatically decreased. Aß6-42 and isoD7-Aß6-42 exhibited higher neurotoxicity towards SH-SY5Y cells than Aß42 and isoD7-Aß42, respectively. They effectively stimulated production of ROS and NO, and also TNFα secretion by cells. Thus, our results suggest that ACE-dependent processing of full-length Aßs could result in formation of more pathogenic peptides.
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Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/toxicidad , Materiales Biomiméticos/metabolismo , Materiales Biomiméticos/toxicidad , Peptidil-Dipeptidasa A/metabolismo , Peptidil-Dipeptidasa A/toxicidad , Secuencia de Aminoácidos , Péptidos beta-Amiloides/genética , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Línea Celular Tumoral , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Peptidil-Dipeptidasa A/genéticaRESUMEN
CD4 mimics such as YIR-821 and its derivatives are small molecules which inhibit the interaction between the Phe43 cavity of HIV-1 gp120 with host CD4, an interaction that is involved in the entry of HIV to cells. Known CD4 mimics generally possess three structural features, an aromatic ring, an oxalamide linker and a piperidine moiety. We have shown previously that introduction of a cyclohexyl group and a guanidine group into the piperidine moiety and a fluorine atom at the meta-position of the aromatic ring leads to a significant increase in the anti-HIV activity. In the current study, the effects of conformational flexibility were investigated by introduction of an indole-type group in the junction between the oxalamide linker and the aromatic moiety or by replacement of the oxalamide linker with a glycine linker. This led to the development of compounds with high anti-HIV activity, showing the importance of the junction region for the expression of high anti-HIV activity. The present data are expected to be useful in the future design of novel CD4 mimic molecules.