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)

A room-temperature, open-air method is devised to selectively intercalate relatively low-molecular-weight polymers (approximately 10-100 kDa) from dilute, volatile solutions into open-end, as-grown, wettable carbon nanotubes with 50-100 nm diameters. The method relies on a novel self-sustained diffusion mechanism driving polymers from dilute volatile solutions into carbon nanotubes and concentrating them there. Relatively low-molecular-weight polymers, such as poly(ethylene oxide) (PEO, 600 kDa) and poly(caprolactone) (PCL, 80 kDa), were encapsulated in graphitic nanotubes as confirmed by transmission electron microscopy, which revealed morphologies characteristic of mixtures in nanoconfinements affected by intermolecular forces. Whereas relatively small, flexible polymer molecules can conform to enter these nanotubes, larger macromolecules (approximately 1000 kDa) remain outside. The selective nature of this process is useful for filling nanotubes with polymers and could also be valuable in capping nanotubes.
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PMID:Selective intercalation of polymers in carbon nanotubes. 1755 34

The objective of this study was to overcome drug resistance upon systemic administration of combination paclitaxel (PTX) and the apoptotic signaling molecule C(6)-ceramide (CER) in biodegradable poly(ethylene oxide)-modified poly(epsilon-caprolactone (PEO-PCL) nanoparticles. Subcutaneous sensitive (wild-type) and multidrug resistant (MDR-1 positive) SKOV-3 human ovarian adenocarcinoma xenografts were established in female Nu/Nu mice. PTX and CER were administered intravenously either as a single agent or in combination in aqueous solution and in PEO-PCL nanoparticles to the tumor-bearing mice. There was significant (p< 0.05) tumor growth suppression in both wild-type SKOV-3 and multidrug resistant SKOV-3(TR) models upon single dose co-administration of PTX (20 mg/kg) and CER (100 mg/kg) in nanoparticle formulations as compared to the individual agents and administration in aqueous solutions. For instance, in SKOV-3 wild-type model, more than 4.3-fold increase (p < 0.05) in tumor growth delay and 3.6-fold (p < 0.05) increase in tumor volume doubling time (DT) were observed with the combination treatment in nanoparticles as compared to untreated animals. Similarly, 3-fold increase (p < 0.05) in tumor growth delay and tumor volume DT was observed in SKOV-3(TR) model. Body weight changes and blood cells counts were used as measures of safety and, except for an increase in platelet counts (p < 0.05) in PTX + CER treated animals, there was no difference between various treatment strategies. The results of this study show that combination of PTX and CER in biodegradable polymeric nanoparticles can serve as a very effective therapeutic strategy to overcome drug resistance in ovarian cancer.
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PMID:Paclitaxel and ceramide co-administration in biodegradable polymeric nanoparticulate delivery system to overcome drug resistance in ovarian cancer. 1755 85

The purpose of this study was to design an in vitro experiment that can assess the stability of polymeric micellar formulations of hydrophobic drugs such as cyclosporine A (CyA) in blood, and predict the in vivo performance of the examined delivery system. Poly(ethylene oxide)-block-poly(epsilon-caprolactone) (PEO-b-PCL) copolymers were assembled to polymeric nano-containers for the physical encapsulation of CyA by a co-solvent evaporation method using different loading conditions. CyA-loaded micelles were prepared and compared to commercially available intravenous formulation of CyA (Sandimmune) for in vitro release, protein binding, and pharmacokinetic parameters in Sprague-Dawley rats. The unbound fraction (fu) of CyA was determined using an erythrocyte vs. plasma and buffer partitioning technique. Different polymeric micellar formulations of CyA did not show any significant difference in CyA release when dialyzed against bovine serum albumin. The fu experiments, however, revealed a significant decrease in the fu of the loaded drug with an increase in the drug/polymer loading ratio, while the fu of all micellar formulations were significantly lower than Sandimmune. The pharmacokinetic study showed that fu of CyA in each formulation correlated with its in vivo performance determined by pharmacokinetic parameters: the lower fu of the formulation, translated to a higher area under the concentration versus time curve (AUC), and a lower clearance (CL) and volume of distribution (Vd). In conclusion, determination of the unbound fraction of encapsulated drug can be used to predict the in vivo stability of polymeric micellar nano-containers. PEO-b-PCL micelles containing higher CyA-loaded levels are shown to be more stable changing the pharmacokinetics of the encapsulated CyA to a higher extent.
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PMID:A novel use of an in vitro method to predict the in vivo stability of block copolymer based nano-containers. 1764 7

Microspheres fabricated by biodegradable polymers with tunable surface properties show great potentials as microcarriers in in vitro cell cultivation and tissue engineering. Herein we reported a new method to regulate the surface property and morphology of microspheres via the synthesis of biodegradable amphiphilic block copolymers with adjustable compositions. The poly(epsilon-caprolactone-b-ethylene oxide) diblock copolymers with functional amino end groups bonding to the PEO block (PCL-b-PEO-NH(2)) were synthesized by sequential ring-opening polymerization with potassium bis(trimethylsilyl) amide as initiator. The copolymers were characterized by gel permeation chromatography (GPC) and (1)H NMR, and then used to fabricate microspheres by w/o/w double emulsion solvent evaporation technique. The surface properties of microspheres were studied by means of scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). The results indicated that both the fabrication conditions and copolymer composition have great influences on the surface morphology and property of microspheres. The reactive amino functional groups are dominantly located on the surface of microspheres. The in vitro degradation of microspheres was studied by following the morphological changes of microspheres. The influences of hydrophilic PEO out-layers on the enzymatic degradation of microspheres were discussed. These microspheres with controllable surface morphology and amino functional groups are expected to be promising alternatives for the further biomimetic modification to promote cell growth on materials.
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PMID:Surface property and in vitro biodegradation of microspheres fabricated by poly(epsilon-caprolactone-b-ethylene oxide) diblock copolymers. 1764 29

Poly(ethylene oxide)-block-poly(epsilon-caprolactone) (PEO-b-PCL) and newly developed poly(ethylene oxide)-block-poly(alpha-benzyl carboxylate epsilon-caprolactone) (PEO-b-PBCL) micelles were evaluated for the solubilization and delivery of cucurbitacin I and B, poorly water soluble inhibitors of signal transducer and activator of transcription 3 (STAT3). Encapsulation of cucurbitacins in PEO-b-PCL and PEO-b-PBCL by co-solvent evaporation technique resulted in polymeric micelles <90 nm in diameter. The aqueous solubility of both derivatives increased from less than 0.05 mg/mL in the absence of the copolymer to around 0.30-0.44 and 0.65-0.68 mg/mL in the presence of 5000-5000 and 5000-24,000 PEO-b-PCL micelles, respectively. Maximum cucurbitacin solubilization was achieved with PEO-b-PBCL micelles for both derivatives. PEO-b-PCL micelles having longer PCL block were found to be more efficient in sustaining the rate of release for cucurbitacins. The anti-cancer and STAT3 inhibitory activity of polymeric micellar cucurbitacins were comparable with free drugs in B16.F10 melanoma cell line in vitro. Intratumoral injection of 1 mg/kg/day cucurbitacin I resulted in the regression of established B16.F10 mouse melanoma tumors in vivo. In comparison to free cucurbitacin I, PEO-b-PBCL micellar cucurbitacin I was found to provide comparable anti-cancer effects against B16.F10 tumors and limit drug levels in animal serum while maintaining high drug levels in tumor following intratumoral administration. The results indicate the potential of polymeric micelles as suitable vehicles for the delivery of cucurbitacin- I and B.
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PMID:Polymeric micelles for the solubilization and delivery of STAT3 inhibitor cucurbitacins in solid tumors. 1768 40

Fast dynamics within the microwave frequency range (approximately gigahertz) in polymer systems as a function of temperature (in the range from 20 to 190 degrees C) were studied using high frequency dielectric spectroscopy. The frequency of radiation was varied from 0.5 to 18 GHz. The isochronal dielectric loss data were taken to eliminate the complexity arising from the frequency-independent, temperature-dependent background loss in the condensed phase. These studies were conducted for poly(caprolactone) (PCL), poly(ethylene oxide) (PEO), poly(ethylene oxide) with methoxy end group (PEO-CH3), PLA-b-PEO-b-PLA triblock copolymers, and several polymers with high glass transition temperatures. These polymers possess glass temperatures ranging from -62 degrees C (PCL) to 110 degrees C (PMMA). One broad relaxation process was found only for polymers (PCL, PEO, and PLA-b-PEO-b-PLA) with low glass transition temperatures. The effect due to end groups was investigated by comparing the results of PEO with hydroxy versus methoxy end groups. The measured relaxation process was determined not to be associated with end groups. The results from temperature-dependent dielectric spectroscopy indicate that the relaxation process follows an Arrhenius T dependence suggesting that it is due to local motions. The activation energy of the relaxation process was measured and investigated based on the coupling model. The results suggest that the observed relaxation process behaves as a Johari-Goldstein beta relaxation.
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PMID:Analysis of rapid chain dynamics in isochronal dielectric measurements of polymers. 1768 58

A novel bioeliminable amphiphilic poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PEO-b-PCL) diblock copolymer end-capped by a mannose residue was synthesized by sequential controlled polymerization of ethylene oxide and epsilon-caprolactone, followed by the coupling of a reactive mannose derivative to the PEO chain end. The anionic polymerization of ethylene oxide was first initiated by potassium 2-dimethylaminoethanolate. The ring-opening polymerization of epsilon-caprolactone was then initiated by the omega-hydroxy end-group of PEO previously converted into an Al alkoxide. Finally, the saccharidic end-group was attached by quaternization of the tertiary amine alpha-end-group of the PEO-b-PCL with a brominated mannose derivative. The copolymer was fully characterized in terms of chemical composition and purity by high-resolution NMR spectroscopy and size exclusion chromatography. Furthermore, measurements with a pendant drop tensiometer showed that both the mannosylated copolymer and the non-mannosylated counterpart significantly decreased the dichloromethane/water interfacial tension. Moreover, these amphiphilic copolymers formed monodisperse spherical micelles in water with an average diameter of approximately 11 nm as measured by dynamic light scattering and cryo-transmission electron microscopy. The availability of mannose as a specific recognition site at the surface of the micelles was proved by isothermal titration microcalorimetry (ITC), using the BclA lectin (from Burkholderia cenocepacia), which interacts selectively with alpha-D-mannopyranoside derivatives. The thermodynamic parameters of the lectin/mannose interaction were extracted from the ITC data. These colloidal systems have great potential for drug targeting and vaccine delivery systems.
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PMID:Mannosylated poly(ethylene oxide)-b-poly(epsilon-caprolactone) diblock copolymers: synthesis, characterization, and interaction with a bacterial lectin. 1770 26

The aim of this study was to test the ability of poly(ethylene oxide)-b-poly (epsilon-caprolactone) (PEO-b-PCL) micelles to reduce the renal uptake and nephrotoxicity of Cyclosporine A (CyA) after multiple dose administration. Sprague-Dawley rats received CyA i.v. at a dose of 20 mg/kg/day delivered as the commercial formulation (Sandimmune) or polymeric micellar formulation (PM-CyA). Cremophor EL (the solubilizing agent in Sandimmune), unloaded PEO-b-PCL micelles, or normal saline were also administered i.v. to control rats. After 7 days, kidney function was assessed through measurement of creatinine (CLcr) and urea clearances, as well as electrolyte concentrations in plasma. Blood and kidney were collected and assayed for CyA. Sandimmune administration led to decreased CLcr, and increased urea and potassium levels in plasma. In contrast, functional nephrotoxicity with the PM-CyA was not apparent, as the CLcr did not change significantly. The rate of increase in body weight in control rats was 3.1-3.4% per day. Weight gains (1.8% per day) were also noted in the rats given PM-CyA, although the body weight of animals receiving Sandimmune remained constant. Compared to Sandimmune, polymeric micelles reduced kidney uptake of CyA by 2.6-fold, and increased CyA levels in blood by 2.1-fold. The results show a potential for PEO-b-PCL micelles in restricting the nephrotoxicity of CyA.
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PMID:Polymeric micellar delivery reduces kidney distribution and nephrotoxic effects of Cyclosporine A after multiple dosing. 1778 48

Spirocyclic tin dialkoxides are unique initiators for the ring-expansion polymerization of lactones leading to complex, but well-defined macromolecular architectures. In a first example, epsilon-caprolactone (epsilon CL) was polymerized, followed by the resumption of polymerization of a mixture of epsilon CL and epsilon CL alpha-substituted by a chloride (alpha Cl epsilon CL), so leading to "living" eight-shaped chains. Upon hydrolysis of the alkoxides, a four-arm star-shaped copolyester was formed, whose each arm was grafted by conversion of the chloride units into azides, followed by the Huisgen's [3+2] cycloaddition of alkyne end-capped poly(ethylene oxide) (PEO) onto the azide substituents. The complexity of this novel amphiphilic architecture was increased further by substituting the four-arm interconnecting PCL by an eight-shaped PCL. In a preliminary step, epsilon CL was polymerized followed by a few units of epsilon CL alpha-substituted by an acrylate. The intramolecular photo-crosslinking of the acrylates adjacent to the tin dialkoxides was effective in stabilizing the eight-shaped polyester while preserving the chain growth sites. This quite unusual tetrafunctional macroinitiator was used to copolymerize epsilon CL and alpha Cl epsilon CL, followed by hydrolysis of the alkoxides, conversion of the chloride units into azides and grafting of the four arms by PEO (see above). This architecture reported for the very first time is nothing but a symmetrical four-tail eight-shaped copolyester macromolecule.
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PMID:Synthesis of eight- and star-shaped poly(epsilon-caprolactone)s and their amphiphilic derivatives. 1789 59

Curcumin is recognized as a potential chemotherapeutic agent against a variety of tumors. However, the clinical application of curcumin is hindered due to its poor water solubility and fast degradation. The objective of this study was to investigate amphiphilic block copolymer micelles of poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PEO-PCL) as vehicles for the solubilization, stabilization, and controlled delivery of curcumin. Curcumin-loaded PEO-PCL micelles were prepared by a cosolvent evaporation technique. PEO-PCL micelles were able to solubilize curcumin effectively, protect the encapsulated curcumin from hydrolytical degradation in physiological matrix, and control the release of curcumin over a few days. The characteristics of resultant micelles were found to depend on the polymerization degrees of epsilon-caprolactone. Among different PEO-PCL micelles, PEO(5000)-PCL(24500) was the most efficient in solubilizing curcumin while PEO(5000)-PCL(13000) was the best carrier in reducing its release rate. PEO-PCL micelle-encapsulated curcumin retained its cytotoxicity in B16-F10, a mouse melanoma cell line, and SP-53, Mino, and JeKo-1 human mantle cell lymphoma cell lines. These results demonstrated the potential of PEO-PCL micelles as an injectable formulation for efficient solubilization, stabilization, and controlled delivery of curcumin.
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PMID:Micelles of poly(ethylene oxide)-b-poly(epsilon-caprolactone) as vehicles for the solubilization, stabilization, and controlled delivery of curcumin. 1795 21


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