Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
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The adsorption of amphiphilic poly(ethylene oxide)-b-poly(epsilon-caprolactone) and poly(ethylene oxide)-b-poly(gamma-methyl-epsilon-caprolactone) copolymers in aqueous solution on silica and glass surfaces has been investigated by flow microcalorimetry, small-angle neutron scattering (SANS), surface forces, and complementary techniques. The studied copolymers consist of a poly(ethylene oxide) (PEO) block of M(n) = 5000 and a hydrophobic polyester block of poly(epsilon-caprolactone) (PCL) or poly(gamma-methyl-epsilon-caprolactone) (PMCL) of M(n) in the 950-2200 range. Compared to homoPEO, the adsorption of the copolymers is significantly increased by the connection of PEO to an aliphatic polyester block. According to calorimetric experiments, the copolymers interact with the surface mainly through the hydrophilic block. At low surface coverage, the PEO block interacts with the surface such that both PEO and PCL chains are exposed to the aqueous solution. At high surface coverage, a dense copolymer layer is observed with the PEO blocks oriented toward the solution. The structure of the copolymer layer has been analyzed by neutron scattering using the contrast matching technique and by tapping mode atomic force microscopy. The experimental observations agree with the coadsorption of micelles and free copolymer chains at the interface.
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PMID:Adsorption of poly(ethylene oxide)-b-poly(epsilon-caprolactone) copolymers at the silica-water interface. 1577 68

The commercial formulation of Cyclosporine A (CsA) for intravenous administration contains Cremophor EL, a low molecular weight surfactant known to be toxic. In this study, micelles of methoxy poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PEO-b-PCL) were investigated as alternative vehicles for the solubilization and delivery of CsA. PEO-b-PCL block copolymers having identical PEO chain lengths and PCL molecular weights of 5000, 13,000, or 24,000 g mol(-)(1) were synthesized and assembled into polymeric micelles using a co-solvent evaporation method. PEO-b-PCL micelles were then compared to Cremophor EL micelles for their functional properties in drug delivery including micellar size, thermodynamic stability, core viscosity, CsA encapsulation, and in vitro CsA release. Among different PCL block lengths, optimum solubilization was achieved by utilizing polymeric micelles having a PCL block of 13,000 g mol(-)(1). CsA reached an aqueous solubility of 1.3 mg/mL in the presence of PEO-b-PCL micelles. This concentration is comparable to injectable CsA levels in its Cremophor EL formulation (0.5-2.5 mg/mL). In contrast to the Cremophor EL formulation, the in vitro rate of CsA release was significantly sustained by the polymeric micellar carrier. Within 12 h, only 5.8% of CsA was released from polymeric micelles while Cremophor EL micelles released 77% of their drug content. Accordingly, viscosity of the PEO-b-PCL micellar core was found to be significantly higher than Cremophor EL micelles. The results points to a potential for PEO-b-PCL micelles as nanoscopic drug carriers for efficient solubilization and controlled delivery of CsA.
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PMID:Micelles of methoxy poly(ethylene oxide)-b-poly(epsilon-caprolactone) as vehicles for the solubilization and controlled delivery of cyclosporine A. 1590 81

The biodegradable poly(epsilon-caprolactone) (PCL)/poly(ethylene oxide) (PEO) microcapsules and the analyzing of form and features for the manufacturing conditions were investigated in a prospective drug delivery systems (DDS) through drug release. The effects of emulsifier, emulsifier concentration, and stirring rate on the diameter and form of the microcapsules were examined using image analyzer (IA) and scanning electron microscope (SEM). The role of interfacial adhesion between PCL/PEO and drug was determined by contact angle measurements, and the drug release rate of the microcapsules was characterized by UV-vis spectroscopy. As a result, the microcapsules were made in spherical forms with a mean particle size of 170 nm approximately 68 microm. And the work of adhesion between water and PCL/PEO was increased with increasing the PEO content, which is due to higher hydrophilicity of PEO. The drug release rate of the microcapsules was significantly increased as the PEO content increased, which could be attributed to the increasing of the hydrophilic groups or the degree of adhesion at the interfaces.
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PMID:Effect of poly(ethylene oxide) on the release behaviors of poly(epsilon-caprolactone) microcapsules containing erythromycin. 1597 89

The aim of this study was to assess the potential of polymeric micelles to modify the pharmacokinetics and tissue distribution of cyclosporine A (CsA). Drug-loaded methoxy poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PEO-b-PCL) micellar solutions in isotonic medium were prepared and administered intravenously to healthy Sprague-Dawley rats. Blood and tissues were harvested and assayed for CsA, and resultant pharmacokinetic parameters and tissue distribution of CsA in its polymeric micellar formulation were compared to its commercially available intravenous formulation (Sandimmune). In the pharmacokinetic assessment, a 6.1 fold increase in the area under the blood concentration versus time curve (AUC) was observed for CsA when given as polymeric micellar formulation as compared to Sandimmune. The volume of distribution and clearance of CsA as PEO-b-PCL formulation were observed to be 10.0 and 7.6 fold lower, respectively, compared to the commercial formulation. No significant differences in t(1/2) or MRT could be detected. In the biodistribution study, analysis of tissue samples indicated that the mean AUC of CsA in polymeric micelles was lower in liver, spleen and kidney (1.5, 2.1 and 1.4-fold, respectively). Similar to the pharmacokinetic study in these rats, the polymeric micellar formulation gave rise to 5.7 and 4.9-fold increase in the AUC of CsA in blood and plasma, respectively. Our results show that PEO-b-PCL micelles can effectively solubilize CsA, at the same time confining CsA to the blood circulation and restricting its access to tissues such as kidney, perhaps limiting the onset of toxicity.
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PMID:Polymeric micelles for the solubilization and delivery of cyclosporine A: pharmacokinetics and biodistribution. 1600 61

Upon addition of silica to aqueous solutions of poly(ethylene oxide)-b-poly(epsilon-caprolactone) copolymers (PEO-b-PCL) and sodium dodecyl sulfate (SDS), adsorption of the solutes occurs at the silica-water interface. The amount of the adsorbed constituents has been measured by the total concentration depletion method. Small-angle neutron scattering experiments (SANS) have been carried out to investigate the structure of the adsorbed layer. Although SDS is not spontaneously adsorbed onto hydrophilic silica, adsorption is observed in the presence of PEO-b-PCL diblocks, in relation to the relative concentration of the two compounds. Conversely, SDS has a depressive effect on the adsorption of the copolymer, whose structure at the interface is modified. Copolymer desorption is however never complete at high SDS content. These observations have been rationalized by the associative behavior of PEO-b-PCL and SDS in water.
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PMID:Concomitant adsorption of poly(ethylene oxide)-b-poly(epsilon-caprolactone) copolymers and sodium dodecyl sulfate at the silica-water interface. 1608 73

Gold nanoparticles of improved stability against aggregation were prepared using poly(ethylene oxide)-block-poly(epsilon-caprolactone) (PEO-b-PCL) star-block copolymers. A five-arm star-shaped macroinitiator (PEO) was utilized for the automated parallel controlled ring-opening polymerization of epsilon-caprolactone to prepare a series of PEO-b-PCL star-block copolymers with a constant PEO core linked to PCL blocks of variable length. The PEO core was swelled with KAuCl4 in N,N-dimethylformamide (DMF), and gold nanoparticles were subsequently obtained by reduction with NaBH4. Since the process was always templated by the same PEO core for all investigated polymers, the average dimension of the formed gold nanoparticles was in the same range for all star-block copolymers. In sharp contrast, the size distribution and long-term stability against aggregation of the gold nanoparticles dispersed in DMF were strongly dependent on the PCL block length, confirming the role of PCL blocks as stabilizing blocks for these nanoparticles.
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PMID:Star-block copolymers as templates for the preparation of stable gold nanoparticles. 1608 12

The objective of this study was to assess the effect of hydrophilic/hydrophobic block chain lengths on the internalization of poly(ethylene oxide)-block-poly(epsilon-caprolactone) (PEO-b-PCL) micelles by cancer cells. PEO-b-PCL block copolymers with varied PEO and PCL chain lengths were synthesized, assembled to polymeric micelles and loaded with a hydrophobic fluorescent probe (DiI) through a co-solvent evaporation method of physical encapsulation. The slow release of the fluorescent probe from the micellar structure was evidenced following DiI transfer to lipid vesicles. The extent of micellar uptake by cancer cells was investigated through their incubation with MCF-7 cells followed by measurement of the fluorescent emission intensity of DiI (lambda=550 nm) in separated lysed cells. Cellular internalization of polymeric micelles was confirmed by laser scanning microscopy. The mechanism of micellar uptake was investigated by pretreatment of MCF-7 cells with chlorpromazine and cytochalasin B. Encapsulation of DiI in PEO-b-PCL micelles lowered the extent and rate of hydrophobic probe internalization by cancer cells. For polymeric micelles with 5000 gmol(-1) of PCL and varied PEO molecular weights of 2000, 5000 and 13,000 gmol(-1), maximum uptake was observed at a PEO molecular weight of 5000 gmol(-1). For polymeric micelles with 5000 gmol(-1) of PEO and varied PCL molecular weights of 5000, 13,000 and 24,000 gmol(-1), maximum uptake was observed at 13,000 gmol(-1) of PCL. Chlorpromazine reduced the cellular uptake of PEO-b-PCL micelles independent from the block copolymer structure, pointing to the involvement of clathrin mediated endocytosis mechanisms in the uptake of polymeric micelles by cancer cells. Inhibition of cellular uptake of PEO-b-PCL micelles by cytochalasin B, on the other hand, was found to be dependent on the chemical structure of the core/shell forming blocks.
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PMID:The effect of block copolymer structure on the internalization of polymeric micelles by human breast cancer cells. 1614 61

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

Microspheres of amphiphilic multi-block poly(ester-ether)s (PEE)s and poly(ester-ether-amide)s (PEEA)s based on poly(epsilon-caprolactone) (PCL) were investigated as delivery systems for proteins. The interest was mainly focused on the effect of their molecular structure and composition on the overall properties of the microspheres, encapsulating bovine serum albumin (BSA) as a model protein. PEEs and PEEAs were prepared using a alpha,omega-dihydroxy-terminated PCL macromer (Mn= 2.0 kDa) as a hydrophobic component. Hydrophilic oxyethylene sequences were generated using poly(ethylene oxide)s (PEO)s of different molecular mass (Mn= 300-600 Da) in the case of PEEs, or 4,7,10-trioxa-1,13-tridecanediamine (Trioxy) and PEO150 (Mn= 150 Da) in the case of PEEAs. The copolymers showed a decrease of Tm and crystallinity values as compared with PCL. Within each class of copolymers, the bulk hydrophilicity increased with increasing the number of oxyethylene groups in the chain repeat unit. PEEAs were more hydrophilic than PEEs with a similar number of oxyethylene groups. Discrete spherical particles were prepared by both PEEs and PEEAs and their BSA encapsulation efficiency related to copolymer properties. Interestingly, the insertion of short hydrophilic segments is enough to significantly affect protein distribution inside microspheres and its release profiles, as compared to PCL microspheres. Different degradation rates and mechanisms were observed for copolymer microspheres, mainly depending on the distribution of oxyethylene units along the chain. The results highlight that a fine control over the structural parameters of amphiphilic PCL-based multi-block copolymers is a key factor for their application in the field of protein delivery.
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PMID:Microspheres made of poly(epsilon-caprolactone)-based amphiphilic copolymers: potential in sustained delivery of proteins. 1620 80

Bioresorbable linear poly(ester-ether urethane)s with different hydrophilic character were synthesized from block copolymers of poly(epsilon-caprolactone)-poly(ethylene oxide)-poly(epsilon-caprolactone) (PCL-PEO-PCL) as macrodiols, and L-lysine diisocyanate (LDI). A series of PCL-PEO-PCL triblock copolymers with different PEO and PCL chain length was obtained by reacting PEO with epsilon-caprolactone. Polyurethanes were synthesized by reacting the triblock copolymers with LDI in solution using stannous 2-ethylhexanoate as catalyst. The prepared triblock copolymers and polyurethanes were fully characterized by proton nuclear magnetic resonance spectroscopy, size exclusion chromatography, differential scanning calorimetry, and wide-angle X-ray diffraction. Water uptake, hydrolytic stability, and tensile properties of polyurethanes with different composition were evaluated and discussed in terms of the chain length and molecular weight of the polymers and its block components. Water uptake seems to depend on the ethylene oxide unit content of the polyurethane regardless of the triblock structure. Mechanical properties of the synthesized polymers were strongly affected by the molecular weight achieved during polymerization. The use of triblock macrodiols with different hydrophilicity allowed the preparation of a series of polyurethanes having a broad range of properties.
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PMID:Bioresorbable poly(ester-ether urethane)s from L-lysine diisocyanate and triblock copolymers with different hydrophilic character. 1631 20


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