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)

Poly(ethylene oxide)-block-poly(epsilon-caprolactone) (PEO-b-PCL) copolymers bearing paclitaxel (PTX) side groups on PCL (PEO-b-P(CL-PTX) were synthesized and assembled to particles of 123 nm average diameter. At 20% (w/w) PTX to polymer conjugation, PEO-b-P(CL-PTX) demonstrated only 5.0 and 6.7% PTX release after 72 h incubation at pH 7.4 and 5.0, respectively, but revealed signs of chain cleavage at pH 5.0. The cytotoxicity of PEO-b-P(CL-PTX) against MDA-MB-435 cancer cells increased as incubation time was raised from 72 to 96 h (IC(50) of 680 and 475 ng/mL, respectively), but it was still significantly lower than the cytotoxicity of free PTX (IC(50) of 3.5 ng/mL at 72 h). In further studies, micelles of PEO-b-PCL and those bearing benzyl or PTX on PCL were used for physical encapsulation of PTX, where maximum level of loading was achieved by PEO-b-P(CL-PTX) (2.22%, w/w). The release of PTX from this carrier was rapid; however. The in vitro cytotoxicity of physically loaded PTX was independent of carrier and similar to that of free PTX. This was attributed to the low concentration of polymers which fell below their critical micellar concentration in the cytotoxicity study. The results point to the potential of chemically tailored PEO-b-PCL for optimum PTX solubilization and delivery.
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PMID:Novel self-associating poly(ethylene oxide)-b-poly(epsilon-caprolactone) based drug conjugates and nano-containers for paclitaxel delivery. 2008 Jan 63

Aligned nanofibrous scaffolds can recapitulate the structural hierarchy of fiber-reinforced tissues of the musculoskeletal system. While these electrospun fibrous scaffolds provide physical cues that can direct tissue formation when seeded with cells, the ability to chemically guide a population of cells, without disrupting scaffold mechanical properties, would improve the maturation of such constructs and add additional functionality to the system both in vitro and in vivo. In this study, we developed a fabrication technique to entrap drug-delivering microspheres within nanofibrous scaffolds. We hypothesized that entrapping microspheres between fibers would have a less adverse impact on mechanical properties than placing microspheres within the fibers themselves, and that the composite would exhibit sustained release of multiple model compounds. Our results show that microspheres ranging from 10 - 20 microns in diameter could be electrospun in a dose-dependent manner to form nanofibrous composites. When delivered in a sacrificial PEO fiber population, microspheres remained securely entrapped between slow-degrading PCL fibers after removal of the sacrificial delivery component. Stiffness and modulus of the composite decreased with increasing microsphere density for composites in which microspheres were entrapped within each fiber, while stiffness did not change when microspheres were entrapped between fibers. The release profiles of the composite structures were similar to free microspheres, with an initial burst release followed by a sustained release of the model molecules over 4 weeks. Further, multiple model molecules were released from a single scaffold composite, demonstrating the capacity for multi-factor controlled release ideal for complex growth factor delivery from these structures.
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PMID:An anisotropic nanofiber/microsphere composite with controlled release of biomolecules for fibrous tissue engineering. 2014 32

Thermosensitive nanoparticles with a core-shell structure were prepared by self-assembly of PCL-b-PEO-b-PNIPAAm triblock copolymers, which were synthesized by anionic ring-opening polymerization and reversible addition fragmentation chain transfer (RAFT) polymerization. At temperatures above the lower critical solution temperature (LCST), the collapse of PNIPAAm chains in the outer shell and in the core of nanoparticle caused a decrease in size, while the constantly hydrophilic PEO chains in the shell endowed nanoparticles with excellent stability in water. The release of doxorubicin from these nanoparticles showed that both the length of PNIPAAm chains and temperature have great influence on drug release, which indicates the great potential of thermosensitive nanoparticles as drug carriers.
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PMID:Thermosensitive nanoparticles self-assembled from PCL-b-PEO-b-PNIPAAm triblock copolymers and their potential for controlled drug release. 2016 33

The aim of this study was to assess the potential of polymeric micelles to solubilize valspodar and modify its pharmacokinetics following intravenous and oral administration in rat. Drug-loaded methoxy poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PEO-b-PCL) micellar solutions were prepared and administered either intravenously or orally to healthy Sprague-Dawley rats. Plasma pharmacokinetic parameters of valspodar in its polymeric micellar formulation were compared to its clinical formulation, which uses Cremophor EL and ethanol as solubilizing agents. High loading level was achieved for valspodar in PEO-b-PCL leading to an aqueous solubility of 2.8 mg/mL. Following i.v. administration (5 mg/kg), valspodar in the PEO-b-PCL micelles provided significantly higher (approximately 77%) plasma AUC compared to the Cremophor EL formulation. The PEO-b-PCL micelles also significantly decreased the volume of distribution (Vd(ss)) and clearance (CL) of valspodar by nearly 49% and 34%, respectively. After oral administration (10 mg/kg), the average C(max) were similar for both formulations and were both reached at approximately 2 h. The plasma unbound fraction of valspodar in the polymeric micellar formulation was significantly lower than control (8.27% versus 14.85%). Our results show that PEO-b-PCL micelles can efficiently solubilize valspodar and favorably modify its pharmacokinetic profile in rat after i.v. administration by decreasing the CL and Vd.
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PMID:Development of a polymeric micellar formulation for valspodar and assessment of its pharmacokinetics in rat. 2033 28

We show that vesicles made of block copolymers with aldehyde end groups can be covalently attached to aminated and non-aminated, untreated glass surfaces. The attached vesicles were sufficiently stable to allow a detailed investigation of vesicle shapes by confocal laser scanning microscopy (CLSM) and AFM in aqueous solutions allowing reconstruction of 3D images of the vesicle structure. Covalently attached PCL-PEO, PLA-PEO, and PI-PEO block copolymer vesicles have different footprint areas and different shapes due to their differences in bilayer stiffness.
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PMID:Covalent attachment of polymersomes to surfaces. 2035 8

In this study, an engineered non-viral polymer based delivery systems with structural features mimicking that of viral vectors was developed and the potential of this carrier for siRNA delivery was assessed. The developed siRNA carrier was based on poly(ethylene oxide)-block-poly(epsilon-caprolactone) (PEO-b-PCL) micelles decorated with integrin alphavbeta3 targeting peptide (RGD4C) and/or cell penetrating peptide (TAT) on the PEO shell, and modified with a polycation (spermine) in the PCL core for siRNA binding and protection. We observed increased cellular uptake and effective endosomal escape of siRNA delivered with the peptide-functionalized micelles especially those with dual functionality (RGD/TAT-micelles) compared to unmodified micelles (NON-micelles) in MDA435/LCC6 resistant cells. Transfection of mdr1 siRNA formulated in peptide-modified micelles led to P-gp down regulation both at the mRNA and protein level. Subsequent to P-gp down regulation, increased cellular accumulation of P-gp substrate, doxorubicin (DOX), in the cytoplasm and nucleus of resistant MDA435/LCC6 cells after treatment with peptide decorated polymeric micelle/mdr1 siRNA complexes was observed. As a result, resistance to DOX was successfully reversed. Interestingly, RGD/TAT-micellar siRNA complexes produced improved cellular uptake, P-gp silencing, DOX cellular accumulation, DOX nuclear localization and DOX induced cytotoxicity in MDA435/LCC6 cells when compared to micelles decorated with individual peptides. Results of this study indicated a potential for RGD/TAT-functionalized virus-like micelles as promising carriers for efficient delivery of mdr1 siRNA to MDA435/LCC6 resistant cells as means to reverse the P-gp mediated multidrug resistance to DOX.
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PMID:Virus-mimetic polymeric micelles for targeted siRNA delivery. 2042 82

The aim of the study was to develop a polymeric nano-carrier based on methoxy poly(ethylene oxide)-b-poly(epsilon-caprolactone) (MePEO-b-PCL) for the optimum solubilization and delivery of Amphotericin B (AmB). For this purpose, MePEO-b-PCL block co-polymers containing palmitoyl substituent on PCL (at a 100% substitution level) were synthesized through preparation of substituted monomer, that is, alpha-palmitoyl-epsilon-caprolactone, and further ring opening polymerization of this monomer by methoxy PEO (5000 g mol(-1)) using stannous octoate as catalyst. Prepared block co-polymers were characterized for their molecular weight by (1)H NMR and gel permeation chromatography, and assembled to polymeric nano-carriers. The self-assembly of synthesized MePEO-b-PPaCL to spherical particles of nanometer size range was shown by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The efficacy of nano-carriers formed from this structure (abbreviated as MePEO-b-PPaCL) in comparison to unmodified MePEO-b-PCL and those with benzyl and cholesteryl substituent on PCL (abbreviated as MePEO-b-PBCL and MePEO-b-PChCL, respectively) on the solubilization and hemolytic activity of AmB against rat red blood cells was assessed. Under identical conditions, the maximum solubilization of AmB was achieved by nano-carriers prepared from MePEO-b-PPaCL (436 microg/mL), followed by MePEO-b-PChCL (355 microg/mL), MePEO-b-PBCL (296 microg/mL) and MePEO-b-PCL (222 microg/mL). The hemolytic activity of AmB was reduced the most by its encapsulation in MePEO-b-PChCL nano-particles which showed only 7% hemolysis at 30 microg/mL AmB concentration. This was followed by MePEO-b-PCL nano-particles which illustrated 15% hemolysis, MePEO-b-PPaCL with 40% hemolysis and MePEO-b-PBCL with 60% hemolysis at 30 microg/mL AmB concentrations, respectively. In contrast Fungizone showed 90% hemolysis at 30 microg/mL AmB concentration. Based on the improved solubility and reduced hemolytic activity, the MePEO-b-PChCL nano-carriers are considered as optimum structures for AmB delivery.
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PMID:Optimization of the hydrophobic domain in poly(ethylene oxide)-poly(varepsilon-caprolactone) based nano-carriers for the solubilization and delivery of Amphotericin B. 2067 92

We introduce a new approach for stabilizing oil-in-water nanoemulsions using a semisolid interphase formed by the phase separation of amphiphilic block copolymers from the organic phase. This system is illustrated using an amphiphilic diblock copolymer, poly(ethylene oxide)-block-poly(epsilon-caprolactone) (PEO-b-PCL), with commonly used oils. PEO-b-PCL can be miscible with oil at elevated temperatures (70-80 degrees C); however, polymer/oil demixing occurs as the temperature drops below the melting temperature of PEO-b-PCL (approximately 55 degrees C). A homogeneous polymer/oil mixture was dispersed in water at 80 degrees C to generate embryonic emulsions, and then the emulsion size was reduced to a nanometer range through microfluidic homogenization. The structure of the generated nanoemulsions is irreversibly frozen as they are cooled down to ambient temperature. The nanoemulsions stabilized by PEO-b-PCL show the excellent colloidal stability against thermal and chemical stresses, exhibiting no significant changes in the size distribution during incubation for 4 months at ambient temperature or 10 days at 60 degrees C. This study demonstrates that PEO-b-PCL is an attractive emulsifying material for practical nanoemulsion formulations requiring structural stability under a broad range of conditions.
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PMID:Nanosized emulsions stabilized by semisolid polymer interphase. 2069 38

Oil-in-water (O/W) emulsions are typically stabilized using water-soluble surfactants, which anchor to the surface of oil droplets dispersed in an aqueous solution. The structure of the anchored surfactants is often susceptible to physical and chemical stresses because of their highly mobile properties. Here we introduce a new approach to prepare stable silicone oil emulsions under various external stresses using a water-insoluble amphiphilic block copolymer, poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PEO-b-PCL). Above the melting temperature (around 60 degrees C) of the hydrophobic segment (PCL), PEO-b-PCL can be dissolved in silicone oil. When the polymer/oil mixture is dispersed in water, PEO-b-PCL is irreversibly reorganized into solid nanostructures at the interface of the aqueous/organic phases. The resulting interfacial structures provide a robust physical barrier to the emulsion coarsening processes. Accordingly, the prepared emulsions exhibit excellent structural tolerance against external stresses, including variations in pH, ionic strength, and temperature.
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PMID:Silicone oil emulsions stabilized by semi-solid nanostructures entrapped at the interface. 2070 20

In this paper we have investigated the behavior of core-shell poly(ethylene oxide)-poly(epsilon-caprolactone) (PEO-PCL) micelles derived from copolymers with linear triblock (TR) and 4-arm star-diblock (ST) architectures for the delivery of docetaxel (DTX). DTX was loaded inside micelles (DTX-TR(m) and DTX-ST(m)) with high efficiency and released slowly for more than two weeks. DTX-loaded micelles based on both copolymers had very similar properties in terms of mean size, zeta potential, loading ability and release rate in buffered saline. However, the stability of DTX-ST(m) was very poor in aqueous media with proteins resulting in a strong and progressive aggregation. We studied the effect of increasing concentrations of free DTX or DTX-loaded micelles on growth inhibition of human breast MCF-7 and MDA-MB468 and prostate PC3 and DU145 adenocarcinoma cell lines. DTX-loaded TR micelles induced cell growth inhibition similarly to free DTX whereas DTX-ST(m) showed lower cytotoxicity. On the other hand, by normalizing IC(50) values for the actual amount of DTX released from micelles in the medium, DTX-loaded ST micelles became more active than free DTX in all cell lines tested. Both free DTX and DTX-loaded TR micelles displayed a significantly lower cytotoxic activity in G(2)/M phase synchronized cells, whereas cytotoxicity of DTX-loaded ST micelles did not change. Cytotoxicity was related to micelle stability, uptake and release rate in cell culture media. Our results suggest that for a correct interpretation of cytotoxicity of nanocarriers, the evaluation of their behavior in biologically relevant conditions is of utmost importance to select proper systems for further in vivo testing.
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PMID:In vitro anticancer activity of docetaxel-loaded micelles based on poly(ethylene oxide)-poly(epsilon-caprolactone) block copolymers: Do nanocarrier properties have a role? 2081 10


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