Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The commercially available formulations of cyclosporine (cyclosporin A, CyA) are associated with acute hemodynamic changes that result in high nephrotoxicity. Among colloidal vectors, nanoparticles (NPs) are receiving much attention as potential drug carriers that would avoid the therapeutic risks of conventional formulations. Two different mechanisms for obtaining polymeric NPs loaded with CyA were studied with regard to their preparation and physicochemical characterization. Isobutyl-2-cyanoacrylate monomer (IBCA) was polymerized, whereas poly-E-caprolactone (PCL, a preformed polymer) was precipitated; both reactions took place in an aqueous medium containing Pluronic F-68 (polyoxypropylene polyoxyethylene block copolymer) as a surface active agent. The encapsulation efficiencies were 78.49 +/- 5.87 and 84.85 +/- 5.02%, respectively, and they remained stable over a wide range of drug concentrations. The polymeric NP had average sizes of 81 +/- 25 and 95 +/- 25 nm for poly-IBCA and PCL, respectively, as confirmed by photon correlation spectroscopy. Poly-IBCA NPs were built from oligomers with molecular weights of 157 to 2644 that joined to form a polymeric nanomatrix. In vitro activity of the drug and the carrier was tested by inhibition of lymphocyte proliferation induced by Concanavalin A. Drug-loaded PCL NPs and free CyA inhibited lymphocyte proliferation by 91.40 and 86.19%, respectively. However, drug-free NPs also exhibited statistically significant (p < 0.05) immunosuppressive activity.
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PMID:Formation and characterization of cyclosporine-loaded nanoparticles. 836 Aug 26

Amphiphilic block copolymers based on PEO-PPO-PEO block copolymer (Pluronic) and poly(epsilon-caprolactone) were synthesized by bulk polymerization. The structural analysis of Pluronic/PCL block copolymer was carried out using FT-IR, 1H NMR, GPC, WAXD, DSC and TGA measurements. To prepare copolymeric nanospheres with a micellar structure, Pluronic/PCL amphiphilic block copolymers were dialyzed against water. The size and size distribution of Pluronic/PCL block copolymeric nanospheres were examined by dynamic light scattering measurement. They showed an average diameter of 116 to 196 nm depending on the type of copolymer. All the nanosphere samples exhibited a narrow size distribution. The critical micelle concentrations of Pluronic/PCL amphiphilic block copolymers determined by fluorescence spectroscopy were lower than that of common low molecular weight surfactants. We confirmed the formation of stable copolymeric nanospheres through the solution behavior of amphiphilic block copolymer in selective solvents.
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PMID:Poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (Pluronic)/poly(epsilon-caprolactone) (PCL) amphiphilic block copolymeric nanospheres. I. Preparation and characterization. 1052 75

Amphiphilic block copolymers composed of relatively hydrophilic PEO-PPO-PEO block copolymer (Pluronic) and poly (epsilon-caprolactone) with hydrophobic character were synthesized by ring-opening polymerization of epsilon-caprolactone in the presence of PEO-PPO-PEO block copolymer using stannous octoate as a catalyst. Pluronic/PCL block copolymeric nanospheres with core-shell structure were prepared by dialysis method. They showed the average diameter of 116-196 nm depending on the type of copolymer. All the nanosphere samples exhibited a narrow size distribution. The critical micelle concentrations of Pluronic/PCL amphiphilic block copolymers determined by fluorescence spectroscopy were lower than that of the common low molecular weight surfactant. Their core-shell structure was confirmed by 1H NMR spectroscopy. Pluronic/PCL block copolymeric nanospheres exhibited the reversible change of size depending on the temperature. Release behaviors of indomethacin from Pluronic/PCL block copolymeric nanospheres also showed temperature dependence and a sustained release pattern. In addition, cytotoxicity test using an MTT assay method revealed that these indomethacin-loaded Pluronic/PCL nanospheres could remarkably reduce the cell damage compared with the unloaded free indomethacin.
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PMID:Poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide)/poly(epsilon-caprolactone) (PCL) amphiphilic block copolymeric nanospheres. II. Thermo-responsive drug release behaviors. 1069 93

The phagocytosis of drug-loaded polymeric microspheres by white blood cells, such as neutrophils or mononuclear cells, represents the major clearance mechanism by which this foreign material is eliminated from the body. The process of phagocytosis requires the activation of the white blood cells by the microsphere surface, followed by binding and engulfment. Phagocytosis may result in the removal of the microspheres from the blood or the disease site and an inflammatory response. Therefore, we have studied the level of neutrophil activation by microspheres ( +/- opsonization) manufactured from various biomaterials or polymers. Polymer microspheres with equivalent size distributions were made from poly (DL-lactic acid) (PLA), poly(epsilon-caprolactone) (PCL), poly(methyl methacrylate) (PMMA) or a 50 : 50 blend of PLA: poly(ethylene-co-vinyl acetate) (PLA: EVA). Neutrophils were isolated from human blood and activation of these cells by microspheres was measured by chemiluminescence (CL). All four types of microspheres induced only low levels of CL, however these levels were enhanced significantly if the microspheres were pretreated with plasma or IgG suggesting an opsonization effect. The adsorption of IgG or proteins from plasma was confirmed by polyacrylamide gel electrophoresis (SDS-PAGE). The poloxamer Pluronic F127 inhibited the opsonization effect of IgG and plasma on all four types of microspheres and inhibited protein adsorption as measured by SDS-PAGE. Since neutrophil activation is part of the inflammation process in vivo, these in vitro data suggest that all four types of microspheres are likely to be inflammatory if injected into body compartments containing plasma-derived fluids. Pretreatment of the microspheres with Pluronic F127 may reduce the inflammatory potential of the microspheres.
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PMID:Neutrophil activation by plasma opsonized polymeric microspheres: inhibitory effect of pluronic F127. 1087 77

This study was carried out to evaluate and compare the biodistribution profile of tamoxifen when administered intravenously (i.v.) as a simple solution or when encapsulated in polymeric nanoparticulate formulations, with or without surface-stabilizing agents. Tamoxifen-loaded, poly(ethylene oxide)-modified poly(epsilon-caprolactone) (PEO-PCL) nanoparticles were prepared by solvent displacement process that allowed in situ surface modification via physical adsorption of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) triblock polymeric stabilizer (Pluronic). The nanoparticles were characterized for particle size and surface charge. Presence of PEO chains on nanoparticle surface was ascertained by electron spectroscopy for chemical analysis (ESCA). In vivo biodistribution studies were carried out in Nu/Nu athymic mice bearing a human breast carcinoma xenograft, MDA-MB-231 using tritiated [(3)H]-tamoxifen as radio-marker for quantification. PEO-PCL nanoparticles with an average diameter of 150-250 nm, having a smooth spherical shape, and a positive surface charge were obtained with the formulation procedure. About 90% drug encapsulation efficiency was achieved when tamoxifen was loaded at 10% by weight of the polymer. Aqueous wettability, suspendability, and ESCA results showed surface hydrophilization of the PCL nanoparticles by the Pluronics. The primary site of accumulation for the drug-loaded nanoparticles after i.v. administration was the liver, though up to 26% of the total activity could be recovered in tumor at 6h post-injection for PEO-modified nanoparticles. PEO-PCL nanoparticles exhibited significantly increased level of accumulation of the drug within tumor with time as well as extended their presence in the systemic circulation than the controls (unmodified nanoparticles or the solution form). Pluronic surfactants (F-68 and F-108) presented simple means for efficient surface modification and stabilization of PCL nanoparticles to achieve preferential tumor-targeting and a circulating drug reservoir for tamoxifen.
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PMID:Poly(ethylene oxide)-modified poly(epsilon-caprolactone) nanoparticles for targeted delivery of tamoxifen in breast cancer. 1577 64

A representative poly(beta-amino ester) (PbAE) with biodegradable and pH-sensitive properties was used to formulate a nanoparticle-based dosage form for tumor-targeted paclitaxel delivery. The polymer undergoes rapid dissolution when the pH of the medium is less than 6.5 and hence is expected to release its contents at once within the acidic tumor microenvironment and endo/lysosome compartments of cells. PbAE nanoparticles were prepared by solvent displacement method and characterized for particle size, charge, and surface morphology. Pluronic F-108, a triblock copolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), was blended with PbAE to induce surface modification of the nanoparticles. In vitro cellular uptake of tritiated [(3)H]-paclitaxel in solution form and as a nanoparticulate formulation was studied in MDA-MB-231 human breast adenocarcinoma cells grown in 12-well plates. We also examined the intracellular degradation pattern of the formulations within the cells by estimating the drug release profile. Cytotoxicity assay was performed on the formulations at different doses and time intervals. Nanoparticles prepared from poly(epsilon-caprolactone) (PCL) that do not display pH-sensitive release behavior were used as control. Spherical nanoparticles having positive zeta potential ( approximately 40 mV) were obtained in the size range of 150-200 nm with PbAE. The PEO chains of the Pluronic were well-anchored within the nanomatrix as determined by electron spectroscopy for chemical analysis (ESCA). The intracellular accumulation of paclitaxel within tumor cells was significantly higher when administered in the nanoparticle formulations as compared to aqueous solution. Qualitative fluorescent microscopy confirmed the rapid release of the payload into the cytosol in the case of PbAE nanoparticles, while the integrity of the PCL nanoparticles remained intact. The cytotoxicity assay results showed significantly higher tumoricidal activity of paclitaxel when administered in the nanoparticle formulations. The cell-kill effect was maximal for paclitaxel-loaded PbAE nanoparticles when normalized with respect to intracellular drug concentrations. Thus, PEO-modified PbAE nanoparticles show tremendous potential as novel carriers of cytotoxic agents for achieving improved drug disposition and enhanced efficacy.
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PMID:Poly(ethylene oxide)-modified poly(beta-amino ester) nanoparticles as a pH-sensitive system for tumor-targeted delivery of hydrophobic drugs. 1. In vitro evaluations. 1619 88

A new, facile method to prepare the heparin-functionalized PLGA nanoparticle (HEP-PLGA NP) for the controlled release of growth factors is developed. This system is composed of PLGA as a hydrophobic core, Pluronic F-127 as a hydrophilic surface layer, and heparin as the functional moiety. HEP-PLGA NPs were prepared by a solvent-diffusion method without chemical modification of the components. The entrapment of heparin molecules was confirmed by a negatively increased zeta potential value and the specific binding affinity to antithrombin III. The average diameter and the surface charge of the nanoparticles were ranged from 139+/-2 to 188+/-4 nm and from -26.0+/-1.1 to -44.1+/-1.3 mV by increasing the amount of heparin during the nanoparticle preparation. Accordingly, the amount of heparin on the nanoparticle increased from 0% to 4.7%. As a model in vitro release experiment, lysozyme was loaded into HEP-PLGA NPs, and a sustained release profile over 2 weeks was obtained with maintaining its bioactivity. The release of rhVEGF, one of the heparin-binding growth factors, showed a more sustained and prolonged profile than that of lysozyme over one month.
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PMID:A facile method to prepare heparin-functionalized nanoparticles for controlled release of growth factors. 1636 Feb 4

The effects of four sugars (glucose, saccharose, maltose, trehalose) and one surfactant (Poloxamer 188), on the freeze-drying of poly(isobutylcyanoacrylate) (PIBCA), poly(epsilon-caprolactone)-poly(ethylene glycol) (PCL-PEG), and novel core (mainly PIBCA)-shell (principally PEG) composite nanoparticles (CNP) obtained by co-precipitation were investigated. The efficiency of the additives against the adverse effect of freeze-drying on the redispersibility of the nanoparticles was evaluated, based on the visual appearance of the nanoparticle suspensions (Tyndall effect and aggregation), and on the determination of the mean diameter ratio of the nanoparticles before and after freeze-drying. The results indicated that the addition of both sugars and surfactant was essential for the good redispersion of freeze-dried nanoparticles displaying hydrophobic (PIBCA) or hydrophilic (PCL-PEG and CNP) surfaces.
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PMID:Freeze-drying of composite core-shell nanoparticles. 1690 21

An MPEG-PCL diblock copolymer was synthesized as an in situ gel carrier, and its phase transition behavior in aqueous solutions was examined. For comparison, aqueous solutions of Pluronic F-127, a widely used injectable gel-forming solution, were also studied. Both MPEG-PCL copolymer and Pluronic aqueous solutions were sols at room temperature. As the temperature was increased above room temperature, the diblock copolymer and Pluronic solutions underwent a sol-to-gel phase transition, which manifested as an increase in viscosity indicative of the formation of a gel. All of the copolymer solutions became gels at body temperature, although the gel viscosity increased with the increasing concentration of the MPEG-PCL diblock copolymer in the solution. In in vitro experiments, in which the gels were exposed to PBS, the MPEG-PCL gels maintained their structural integrity for more than 28 days, whereas the Pluronic gel disappeared within 2 days. The same results were observed when the polymer solutions were subcutaneously injected into rats. The MPEG-PCL gels maintained their structural integrity longer than 30 days, while the Pluronic gel could not be observed after 2 days. The ability of the gels as drug carriers was studied by measuring the release of fluorescein isothiocyanate-labeled bovine serum albumin (BSA-FITC) from MPEG-PCL diblock copolymer gels in vitro as well as in vivo. In vitro, BSA release was sustained above 20 days, with a greater release at lower diblock copolymer concentration; by contrast, Pluronic gels exhibited almost complete release of BSA-FITC within 1 day. When the BSA-FITC-loaded diblock copolymer and Pluronic solutions were subcutaneously injected into rats, they immediately transformed into a gel. In vivo, sustained release of BSA-FITC over 30 days was observed from the MPEG-PCL gel, whereas BSA-FITC release from the Pluronic gel ceased within 3 days. Collectively, the present findings show that MPEG-PCL diblock copolymer solutions are thermo-responsive and maintain their structural integrity under physiological conditions, indicating that they are suitable for use as injectable drug carriers.
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PMID:In vitro and in vivo release of albumin using a biodegradable MPEG-PCL diblock copolymer as an in situ gel-forming carrier. 1732 78

Nonwoven nanofiber scaffolds fabricated by electrospinning technology have been widely used for tissue engineering applications. Although electrospun nanofiber scaffolds fulfill many requirements for tissue engineering applications, they sometimes lack the necessary biomechanical properties. To attempt to improve the biomechanical properties of electrospun poly(epsilon-caprolactone) (PCL) scaffolds, fibers were bonded by thermal treatment. The thermal fiber bonding was performed in Pluronic F127 solution at a range of temperatures from 54 degrees C to 60 degrees C. Thermally bonded electrospun PCL scaffolds were characterized by analyzing the changes in morphology, fiber diameter, pore area, tensile properties, suture retention strength, burst pressure strength, and compliance. The biomechanical properties of the thermally bonded electrospun PCL scaffolds were significantly increased without any gross observable and ultrastructural changes when compared to untreated PCL scaffolds. This study suggests that the introduction of thermal fiber bonding to electrospun PCL scaffolds improved the biomechanical properties of these scaffolds, making them more suitable for tissue engineering applications.
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PMID:The use of thermal treatments to enhance the mechanical properties of electrospun poly(epsilon-caprolactone) scaffolds. 1809 19


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